Abstract
Alphaviruses, members of the enveloped, positive-sense, single-stranded RNA Togaviridae family, represent a reemerging public health threat as mosquito vectors expand into new geographic territories. The Old World alphaviruses, which include chikungunya virus, Ross River virus, and Sindbis virus, tend to cause a clinical syndrome characterized by fever, rash, and arthritis, whereas the New World alphaviruses, which consist of Venezuelan equine encephalitis virus, eastern equine encephalitis virus, and western equine encephalitis virus, induce encephalomyelitis. Following recovery from the acute phase of infection, many patients are left with debilitating persistent joint and neurological complications that can last for years. Clues from human cases and studies using animal models strongly suggest that much of the disease and pathology induced by alphavirus infection, particularly atypical and chronic manifestations, is mediated by the immune system rather than directly by the virus. This review discusses the current understanding of the immunopathogenesis of the arthritogenic and neurotropic alphaviruses accumulated through both natural infection of humans and experimental infection of animals, particularly mice. As treatment following alphavirus infection is currently limited to supportive care, understanding the contribution of the immune system to the disease process is critical to developing safe and effective therapies.
1. Introduction to alphaviruses
The Alphaviruses are a genus in the Togaviridae family, a group of enveloped, positive-sense, single-stranded RNA viruses that are found worldwide (Griffin, 2013) (Fig. 1). Alphaviruses of clinical importance in humans are transmitted by mosquitos, typically species from the Culex and Aedes genera, and represent a re-emerging public health threat as the insect vectors expand into new territories. The viruses circulate in sylvatic cycle between mosquitoes and either birds, nonhuman primates (NHP), or small mammals (Lim et al., 2018). However, promiscuous mosquitoes harboring an alphavirus sometimes feed on humans, creating an urban cycle that can result in massive widespread epidemics. Alphaviruses are divided into two major groups, Old World, and New World, which is based on their geographic distribution and typical clinical disease syndrome induced (Table 1).
Fig. 1.
Geographic range of cases of human disease induced by select Old World (CHIKV, RRV, and SINV) and New World (VEEV, EEEV, and WEEV) alphaviruses. CHIKV = chikungunya virus, RRV = Ross River virus, SINV = Sindbis virus, VEEV = Venezuelan equine encephalitis virus, EEEV = eastern equine encephalitis virus, WEEV = western equine encephalitis virus.
Table 1.
Clinical disease syndromes induced by natural alphavirus infection in humans.
| Disease syndrome | Clinical signs and symptoms | Associated alphaviruses |
|---|---|---|
| Arthritogenic disease |
|
Old World alphaviruses:
|
| Neurologic disease |
|
New world alphaviruses
|
The Old World alphaviruses, which include chikungunya virus (CHIKV), Ross River virus (RRV), o’nyong-nyong virus, (ONNV), Mayaro virus (MAYV), and Sindbis virus (SINV), are typically found in Africa, Asia, Europe, and Oceania and induce an arthritogenic disease characterized by fever, rash, and arthralgia (reviewed in Suhrbier et al., 2012). CHIKV was initially identified in 1952 in present-day Tanzania but has been responsible for sporadic epidemics of fever and arthralgia, commonly known as chikungunya fever, across Africa and Asia since the 1960s (Robinson, 1955; Ross, 1956; Zeller et al., 2016). The virus expanded throughout the Indian Ocean region in the mid-2000s, and in a separate outbreak was introduced into the Caribbean in 2013. The virus resulted in over 1 million new cases within a year of arrival in the Americas and has become endemic in Central and South America and the Caribbean (Yactayo et al., 2016; Zeller et al., 2016). Because of ease of human travel, adaptive mutations in CHIKV, and spread of Aedes spp. mosquito vectors, cases of CHIKV infection have now been reported in over 40 countries (Tsetsarkin et al., 2007; Yactayo et al., 2016; Zeller et al., 2016). Closely related to CHIKV, ONNV is responsible for periodic outbreaks of fever and arthralgia across Central and East Africa (Forrester et al., 2012; Rezza et al., 2017). First isolated from mosquitos in Queensland, Australia in 1959, RRV is now endemie in Australia and several Pacific Islands and is responsible for approximately 4000–8000 cases each year in Northern Australia (Endy, 2020; Mylonas et al., 2002). Though part of the Semliki Forest phylogenetic complex that includes RRV and therefore classified as an Old World alphavirus, MAYV is native to and responsible for increasingly frequent outbreaks of arthritogenic disease in Latin America, having first been isolated in Trinidad in 1954 (Anderson et al., 1957; Forrester et al., 2012; Ganjian and Riviere-Cinnamond, 2020). The SINV strain group is the most widely distributed alphavirus, being found across Europe, Asia, Africa and Oceania (Lundström and Pfeffer, 2010). However, most cases of arthritis and arthralgia are reported in Scandinavia, caused by the Ockelbo, Pogosta, or Karelian strains of SINV, or South Africa (Laine et al., 2004; Storm et al., 2014). While clinical disease induced by the Old World alphaviruses is typically self-limiting and rarely causes death, persistent chronic arthralgia and arthritis lasting months after recovery from acute illness is common and can be debilitating (Alla and Combe, 2011).
The New World alphaviruses, which include Venezuelan equine encephalitis virus (VEEV), Eastern equine encephalitis virus (EEEV), and Western equine encephalitis virus (WEEV), are found in North, Central, and South America and typically induce neurological disease (Hollidge et al., 2010). EEEV used to be subdivided into North American and South American variants, but recent ecologic and genetic studies have determined the variants belong to distinct separate lineages (Arrigo et al., 2010). South American EEEV, which readily infects a wide variety of mammals but has only been attributed to about a dozen human cases of encephalitis, has since been renamed Madariaga virus, while members of the North American EEEV lineage have retained the EEEV name (Carrera et al., 2013; Luciani et al., 2015). The sequences of the capsid and 3′ untranslated region of WEEV is similar to EEEV, but the El and E2 glycoprotein sequences are more closely related to the Old World alphavirus SINV, indicating that WEEV resulted from a recombination event (Hahn et al., 1988). VEEV, EEEV, and WEEV typically circulate between mosquitoes and passerine birds in the wild; however, promiscuity by permissive mosquitoes occasionally results in infection of other species, particularly humans and horses (Go et al., 2014). These large mammals are typically dead-end hosts, though VEEV is capable of replicating at high enough titers in the blood to permit continued transmission (Weaver et al., 2004).
Human cases of Venezuelan equine encephalitis (VEE), eastern equine encephalitis (EEE), and western equine encephalitis (WEE) are only sporadically reported in the United States each year, though outbreaks of EEE and VEE over the last few decades have increased and are being diagnosed in previously unreported locations. An outbreak of VEE in the mid-1990s in Venezuela and Columbia affected an estimated 75,000–100,000 people (Weaver et al., 1996), and the number of human cases of EEE in the northeastern United States has markedly increased in the last decade, with states such as Vermont and Maine reporting locally acquired human cases for the first time (Lubelczyk et al., 2013; Molaei et al., 2015). In 2019, the CDC confirmed 38 cases of EEE resulting in 15 deaths were diagnosed in 10 states, more than double the highest number of annual EEE cases in the past decade (Centers for Disease Control and Prevention et al., 2019). Unlike the Old World alphaviruses, mortality is not uncommon following infection with the New World alphaviruses. While most people infected with WEEV remain asymptomatic, EEE carries a substantial death rate, ranging from 30% to 70% of symptomatic individuals, depending on the report (Calisher, 1994; Griffin, 2013; Steele et al., 2007). People who survive the initial clinical illness, especially those infected as infants or children, tend to develop chronic persistent neurological deficits (Bruyn and Lennette, 1953; Earnest et al., 1971; León, 1975; Palmer and Finley, 1956; Villari et al., 1995).
Currently, no treatments beyond symptomatic care are available for patients infected with the alphaviruses (Go et al., 2014). Licensed combination vaccines for EEEV, WEEV, and VEEV are available for horses, but no effective vaccine is approved for non-military use in humans (Bartelloni et al., 1970; Steele et al., 2007). While the explosive increase in CHIKV outbreaks and expansion to the Americas over the past 15 years have created a renewed interest in developing effective vaccines and therapies against the arthritogenic alphaviruses, no candidates have yet been successfully developed (reviewed in Powers, 2018). The reemerging public health concern and propensity to cause chronic debilitating effects presented by the alphaviruses necessitate better understanding of the mechanisms mediating the pathogenesis of infection so that safe and effective vaccines and therapies may be developed.
2. Potential outcomes following alphavirus infection
Cellular infection by an alphavirus can ultimately result in one of three outcomes. First, the virus directly induces death of the cell, typically through a mechanism such as apoptosis. For example, infection of neonatal mouse pups with SINV results in extensive apoptosis of multiple cells in the central nervous system (CNS), including neurons (Labrada et al., 2002). Second, the virus induces death through a secondary, rather than direct, mechanism, such as through effects of the immune system or excitotoxicity. And third, which is the optimal outcome, viral infection is cleared, and the cell survives. However, viral persistence following recovery is becoming increasingly recognized with alphaviruses (Fragkoudis et al., 2018; Hoarau et al., 2010; Levine and Griffin, 1992; Morrison et al., 2011), and reactivation of viral replication and relapse of disease must be controlled by the immune system, re-opening the possibility of pathology being induced as a bystander effect. For example, Semliki Forest virus (SFV) RNA persists in the brains of immunocompetent mice following recovery from acute infection, and suppression of the antibody response several months later results in reactivation of infectious virus production (Fragkoudis et al., 2018). The outcome of infection is dependent on a myriad of factors, including viral species and strain, type of cell infected, and host age, genetics, and immune response.
3. Protective effects of the immune system during Alphavirus infection
While the focus of this review is on virus-induced immune pathology, it is also important to remember that the host immune response plays an essential role in both controlling and clearing alphaviruses, while also mediating long-term protective immunity following either primary infection or vaccination. The type I interferon (IFN) system is essential for protecting against alphavirus replication, and mice that lack a functional IFN system or even specific antiviral interferon stimulated genes exhibit enhanced susceptibility to virus replication and disease (Burdeinick-Kerr et al., 2007; Byrnes et al., 2000; Couderc et al., 2008; Gardner et al., 2012; Partidos et al., 2011; Ryman et al., 2000; Schilte et al., 2010; Wollish et al., 2013). Other components of the innate immune response, such as the complement cascade and Toll-like receptor (TLR) signaling also protect from alphaviruses such as SINV, VEEV, and CHIKV (Brooke et al., 2012; Her et al., 2015; Hirsch et al., 1980; Neighbours et al., 2012; Rudd et al., 2012; Schilte et al., 2010; Wollish et al., 2013).
Adaptive immunity is essential for clearance of alphaviruses from infected tissues and mediating long term protective immunity. While glutamine antagonist-mediated inhibition of lymphocyte proliferation and CNS infiltration results in mitigated clinical disease and pathology in SINV infected mice, viral clearance is also delayed (Baxter et al., 2017; Potter et al., 2015). Virus-specific antibody is responsible for viral clearance from the serum and is a major mediator of protective immunity following either primary alphavirus infection or vaccination (Lum et al., 2013; Mallilankaraman et al., 2011). Virus specific antibody directed against the E2 glycoprotein also mediates non-cytolytic clearance of alphaviruses from the CNS (Levine et al., 1991). T cells also make important contributions to alphavirus protective immunity, with local IFN-γ production by CD4+ and CD8+ T cells playing a cooperative role with anti-SINV antibody in facilitating clearance of SINV from the CNS (Baxter and Griffin, 2020; Binder and Griffin, 2001; Burdeinick-Kerr et al., 2007). CD4+ T cells promote recovery from VEEV-induced CNS disease (Brooke et al., 2010), and CD8+ T cells mediate clearance of RRV from infected muscle tissues (Burrack et al., 2015). CD8+ T cell responses can also mediate vaccine-induced protection against CHIKV (Broeckel et al., 2019), and γδ T cells protect from CHIKV-induced joint disease (Long et al., 2015). Mice lacking functional adaptive immune systems are also prone to developing chronic alphavirus infection (Burrack et al., 2015; Hawman et al., 2013; Lum et al., 2013; Nilaratanakul et al., 2018; Seymour et al., 2015; Teo et al., 2013). Therefore, while understanding how alphavirus-interactions with the immune system promote virus-induced disease, it is also important to keep in mind the beneficial aspect of the immune response when considering immune suppressive strategies for treating alphavirus-induced disease. Table 2 provides a summary of the pathologic and protective effects of different components of the immune response seen during infection with different alphaviruses.
Table 2.
Pathogenic and protective roles of the immune response during alphaviral infection.
4. Natural infection with alphaviruses
4.1. Clinical disease, pathology, and immune response in human patients
4.1.1. Old World alphaviruses
Clinical disease induced by the Old World alphaviruses is variable but most commonly characterized by fever, rash, and polyarthritis (inflammation of multiple joints), and polyarthralgia (pain in multiple joints) (Table 1, reviewed in Suhrbier et al., 2012). The frequency of clinical disease development varies by virus, with most RRV and SINV infections being asymptomatic but as high as 80% of CHIKV and MAYV infections resulting in clinical symptoms (Azevedo et al., 2009; Brummer-Korvenkontio et al., 2002; Endy, 2020; Harley et al., 2001; Suhrbier et al., 2012; Vijayakumar et al., 2011). Following an incubation period ranging from 2 to 10 days, patients generally first present with a fever (Suhrbier et al., 2012). Soon after, polyarthralgia most commonly affecting small joints, such as hands/fingers, wrists, ankles, and knees, develops. Synovial fluid sampled early in the RRV disease process contains high numbers of monocytes and activated macrophages with RRV antigen variably detected by immunofluorescence (Clarris et al., 1975; Fraser et al., 1981). Other clinical symptoms commonly seen during acute infection include headache, myalgia (muscle pain), and a maculopapular rash extending over the trunk, limbs, and face (Suhrbier et al., 2012). Histologically, the CHIKV-induced rash is characterized by edema of the epidermis and dermis and perivascular inflammation consisting of lymphocytes and melanophages in the dermis (Riyaz et al., 2010).
Multiple case reports and series have examined the immune response throughout the course of Old World alphavirus infection, particularly with CHIKV. Numerous pro-inflammatory cytokines and chemokines are reported to be elevated in patients’ serum during the acute phase of infection and include tumor necrosis factor alpha (TNF-α), IFN-α, IFN-γ, interleukin (IL) 1 beta (IL-lβ), IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-12, IL-13, IL-15, IL-17, IL-18, IL-17A, IL-18, IL-27, IL-29, granulocyte-colony stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), CC chemokine ligand 2 (CCL2), CCL3, CCL4, CCL5, CXC chemokine ligand 9 (CXCL9), and CXCL10 (Chaaitanya et al., 2011; Chen et al., 2017; Chirathaworn et al., 2013; Chopra et al., 2014; Chow et al., 2011; Gualberto Cavalcanti et al., 2019; Kelvin et al., 2011; Lohachanakul et al., 2012; Ng et al., 2009; Reddy et al., 2014; Santiago et al., 2015; Tappe et al., 2016; Teng et al., 2015; Venugopalan et al., 2014; Wauquier et al., 2011). Vascular endothelial growth factor and platelet endothelial growth factor, potent angiogenic factors, have also been found elevated in serum starting early in MAYV infection (Santiago et al., 2015; Tappe et al., 2016). During the acute phase of CHIKV infection, peripheral blood mononuclear cells (pBMCs) show elevated NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) and caspase-1 mRNA expression (Chen et al., 2017), and circulating CD8+ T cells express high levels of cytotoxic markers such as granzyme B, perforin, and the degranulation marker CD107A (Dias et al., 2018). Increased levels of pro-inflammatory cytokines, lymphopenia, monocytopenia, and neutrophilia are all associated with more severe CHIKV viremia (Chow et al., 2011; Reddy et al., 2014; Teng et al., 2015). Patients with more severe RRV-induced disease have higher levels of serum mannose binding lectin (MBL), a pattern recognition receptor involved in activation of the complement system (Gunn et al., 2012). During the recovery or convalescent phase of alphavirus infection, multiple cytokines and chemokines in the serum have been reported to stay elevated or even increase further compared to the acute phase, including TNF-α, IFN-γ, IL-1β, IL, 2, IL-5 IL-6, IL-7, IL-8, IL-9, IL-12, IL-10, IL-13, IL-17A, IL-18, GM-CSF, CCL2, CCL4, and CXCL10 (Chirathaworn et al., 2010, 2013; Chopra et al., 2014; Kelvin et al., 2011; Santiago et al., 2015). This indicates that even in individuals who are considered recovered from alphavirus infection, the immune response remains activated.
Death following Old World alphavirus infection is rare but can occur, especially in neonatal or elderly patients with comorbidities (Economopoulou et al., 2009; Tandale et al., 2009). Fatal cases have been associated with respiratory, renal, hepatic and neurological disease, and hypertension and underlying respiratory and cardiovascular disease increase the risk of severe and fatal disease (Chua et al., 2010; Economopoulou et al., 2009; Hoz et al., 2015; Mercado et al., 2018). Postmortem histopathological reports are rarely published due to the low mortality rate associated with arthritogenic alphavirus infection and lack of medical infrastructure in the geographical locations where transmission and disease tend to occur. However, postmortem CHIKV-induced pathology described in case reports includes acute tubulointerstitial nephritis with lymphocytic intertubular inflammation and tubular necrosis, viral pneumonia with pulmonary edema and congestion, hepatocellular necrosis with mixed inflammation, and acute pericarditis with mild mononuclear inflammation (Mercado et al., 2018; Mercado et al., 2016; Reilly et al., 2020). Neurological disease associated with CHIKV infection has the highest mortality rate of potential atypical disease manifestations (Economopoulou et al., 2009; Tandale et al., 2009). Patients who develop neurological complications following CHIKV infection have shown elevated TNF-α, IFN- α, IL-6, IL-8, CCL2, CCL5, CCL17, and CXCL9 in cerebrospinal fluid (CSF) samples compared with patients with non-CHIKV-induced neurological disease (Kashyap et al., 2014). Autopsy of a 73-year-old man who died of CHIKV-associated encephalomyeloradiculitis (inflammation of the brain, spinal cord, and spinal nerve roots) revealed a grossly swollen brain with severe edema and multifocal ischemic changes (Ganesan et al., 2008). Microscopically, demyelination in the subcortical white matter with edema and myelin pallor was noted, and mild perivascular lymphocytic inflammation with phagocytic microglia (gitter cells) was found in the basal ganglia. Pooled risk of neonatal death following maternal-fetal transmission of CHIKV has been reported to be 2.8% (Contopoulos-Ioannidis et al., 2018). Fetal death due to CHIKV infection during early gestation results in no gross malformations, and while babies infected during late gestation are born without any clinical symptoms, within a week of birth, they develop joint edema, petechiae (small red or purple spots due to bleeding in the skin), rash, thrombocytopenia, disseminated intravascular coagulopathy (small blood clots throughout the bloodstream that deplete platelets and clotting factors and block small blood vessels), and encephalopathy with a high rate of persistent disabilities (Gérardin et al., 2008; Touret et al., 2006).
Acute symptoms usually resolve within a week or two, but the accompanying arthralgia and arthritis can last months to years following initial infection, creating significant physical, emotional, mental, and financial disability in affected patients. Multiple reports have described the incidence of persistent arthralgia and arthritis following alphavirus infection, especially with CHIKV, but also RRV, MAYV, and ONNV. Up to 81% of patients develop persistent symptoms, including joint tenderness, swelling, and pain, musculoskeletal stiffness and pain, and fatigue (Bonifay et al., 2018; Borgherini et al., 2008; Chang et al., 2017; Couzigou et al., 2018; Duvignaud et al., 2018; Forechi et al., 2018; Gauri et al., 2016; Gérardin et al., 2011; Huits et al., 2018; Lima et al., 2019; Llagonne-Barets et al., 2016; Murillo-Zamora et al., 2018; Ninla-aesong et al., 2020; Panato et al., 2019; Sánchez et al., 2019; Sissoko et al., 2009; Sosa-Martínez et al., 2018; Theilacker et al., 2013; Tritsch et al., 2019; Watson et al., 2020). Similar to acute clinical disease, small joints such as fingers, hands, wrists, ankles, and knees are more likely to be chronically affected (de Souza et al., 2019; Ninla-aesong et al., 2020; Sánchez et al., 2019). Radiographic and ultrasonographic findings include joint effusions, bone erosions, bone marrow edema, and inflammation of the subcutaneous connective tissues (cellulitis), synovial membranes of a joint (synovitis), and tendons (tendonitis) (Amaral et al., 2020a; Mogami et al., 2017). On synovial biopsy of patients with chronic polyarthritis from CHIKV infection, synovitis with inflammation consisting of macrophages, natural killer (NK) cells, CD4+ T cells, and plasma cells, synovial lining hyperplasia, and vascular proliferation is found (Ganu and Ganu, 2011; Hoarau et al., 2010). Synovial cytology in chronic CHIKV-induced arthritis consists mostly of CD14+ monocytes/macrophages, less than 5% of which stain positive for CHIKV, with smaller numbers of activated NK cells and CD4+ T cells (Hoarau et al., 2010). Mononuclear cells, mostly consisting of CD4+ T cells, have also been detected in synovial effusions from chronic RRV disease cases (Fraser and Becker, 1984). Risk factors that are associated with development of chronic arthralgia or arthritis include being female, older age, smoking, more severe acute disease with involvement of multiple joints, persistent viremia, preexisting co-morbidities such as diabetes mellitus, cardiovascular disease, or joint disease, and dengue virus (DENV) co-infection (Amaral et al., 2020a,b; Badawi et al., 2018; Delgado Enciso et al., 2018; Elsinga et al., 2017, 2018; Heath et al., 2018; Huits et al., 2018; Murillo-Zamora et al., 2018; Ninla-aesong et al., 2020; Patel et al., 2019; Sosa-Martínez et al., 2018; Tritsch et al., 2019). Chronic CHIKV arthritis has also been determined to be a risk factor for acute coronary syndrome (OR = 3.0), possibly because the chronic arthritis may trigger plaque destabilization in patients with concomitant cardiovascular disease (Patel et al., 2019).
Overall, persistent arthralgia and arthritis following alphavirus infection is associated with a pro-inflammatory state. Patients who develop chronic arthralgia or arthritis following alphavirus infection tend to have elevated serum levels of pro-inflammatory cytokines and chemokines, including IFN-α, IFN-γ, TNF-α, IL-1β, IL-6, IL-7, IL-8, IL-10, IL-12, IL-15, IL-17, IL-27, GM-CSF, CCL2, CCL3, CCL4, CXCL9, and CXCL10 (Amaral et al., 2020a; Chaaitanya et al., 2011; Chow et al., 2011; Gualberto Cavalcanti et al., 2019; Hoarau et al., 2010; Kelvin et al., 2011; Ninla-aesong et al., 2019; Reddy et al., 2014; Santiago et al., 2015; Sepúlveda-Delgado et al., 2017). Chronic chikungunya patients with tender joints and arthritis show significantly elevated IL-27 and IL-17A serum levels, respectively (Gualberto Cavalcanti et al., 2019). Compared to patients who recover from CHIKV infection, individuals with persistent arthralgia and arthritis tend to show anemia, elevated platelets (thrombocytosis), and elevated C-reactive protein (Amaral et al., 2020a). pBMCs from chikungunya patients with chronic arthralgia possess more IFN-α mRNA and more TNF-α- and IFN-γ-secreting NKT cells with lower cytotoxic activity compared to recovered patients (Hoarau et al., 2010; Thanapati et al., 2017). Chronic CHIKV patients have a delayed IgG3 response and lower antibody avidity index despite mounting an adequate neutralizing antibody response (Anfasa et al., 2019; Kam et al., 2012). Intensity of T cells responses in chronic chikungunya patients versus recovered chikungunya patients has not been found to differ (Hoarau et al., 2013). Osteoblasts from RRV patients with osteoarthritis show enhanced RRV infectivity and replication associated with increased expression of cytokines that favor bone resorption, including TNF-α, IL-1β, IL-6, and CCL2, and delayed type I IFN signaling (Chen et al., 2014).
4.1.2. New World alphaviruses
Neurological manifestations following VEEV, EEEV, or WEEV infection mainly consist of encephalitis or encephalomyelitis (Table 1). The likelihood of encephalitis development following infection with the New World alphaviruses depends on the viral species but is overall the minority of infections, especially with VEEV and WEEV (Greenlee, 2014). Neurological disease, when present, is similar for VEE, EEE, and WEE, though EEEV infections tend to be more severe. Following a prodromal phase lasting approximately 2–7 days consisting of fever and headache sometimes accompanied by myalgia, signs of irritability, and abdominal pain, onset of encephalitis is typically abrupt and progression rapid (Deresiewicz et al., 1997; Greenlee, 2014; Steele et al., 2007). Neurological manifestations include headache, stupor or coma, seizures, focal weakness, and cranial-nerve palsies. Blood chemistries reveal leukocytosis with a left shift (increased immature cells) and low blood sodium (hyponatremia), and CSF analysis shows elevated protein and increased cells (pleocytosis) initially consisting primarily of neutrophils but evolving primarily to lymphocytes (Deresiewicz et al., 1997; Przelomski et al., 1988; Rozdilsky et al., 1968; Silverman et al., 2013). Changes on brain MRI include symmetric or asymmetric lesions in multiple brain regions, including the basal ganglia, hippocampi, thalami, insular cortex, midbrain, and brainstem (Deresiewicz et al., 1997; Nickerson et al., 2016). Edema and periventricular white matter changes similar to those seen in multiple sclerosis patients have also been seen (Deresiewicz et al., 1997). Prognostic indicators for a poorer outcome include young age, particularly infants and children, shorter prodromal phase (<5 days), severe CSF pleocytosis, and coma (Deresiewicz et al., 1997; Finley et al., 1955; Przelomski et al., 1988; Rozdilsky et al., 1968).
Death, mostly associated with EEE, has mainly been reported to occur during second to third week of hospitalization (Deresiewicz et al., 1997). On postmortem examination, brains tend to be grossly congested and edematous, with diffuse meningoencephalitis found microscopically (Greenlee, 2014). Histopathological changes in the central nervous system (CNS) include perivascular and parenchymal inflammation consisting of mononuclear cells and neutrophils accompanying neuronal loss, especially in the basal ganglia and thalamus (Booss and Esiri, 2003; Lindenberg and Haymaker, 1982; Przelomski et al., 1988; Rozdilsky et al., 1968). Demyelinating lesions and oligodendrocyte death have also been reported, and inflammation of the spinal cord (myelitis) and blood vessels (vasculitis) are frequently present with EEE. Intranuclear or intracytoplasmic viral inclusion bodies are conspicuous by their absence (Rozdilsky et al., 1968; Steele et al., 2007).
Patients who survive the initial course of infection with VEEV, EEEV, and WEEV, especially those infected as infants or children, are often left with persistent neurological sequalae (Silverman et al., 2013). Reports of neurological sequelae are best described in patients who have recovered from WEE and include decreased motor skills and altered gait, intellectual and/or learning disability, facial paralysis, impaired speech, and Parkinson-like symptoms (Bruyn and Lennette, 1953; Earnest et al., 1971; Herzon et al., 1957; Mulder et al., 1951; Palmer and Finley, 1956). Neuropsychological symptoms, including anxiety, depression, paranoia, attention deficit disorder, and schizophrenia-like personality changes have also been associated with WEE (Deaton et al., 1986; Fulton and Burton, 1953; Herzon et al., 1957; Palmer and Finley, 1956). VEE has been associated with recurrent headaches, fatigue, depression, seizures, paralysis, and intellectual disability (Bowen et al., 1976; León, 1975; Rivas et al., 1997). The course of neurological sequelae has been reported to range from a static nonprogressive condition to relapsing-remitting disease to complete recovery and reversion to normal function (Bowen et al., 1976; Palmer and Finley, 1956; Silverman et al., 2013). Regardless, neurological sequalae induced by New World alphavirus infection represent a significant source of physical, emotional, mental, and financial disability for affected patients and their caretakers (Villari et al., 1995).
4.2. Immune-mediated disease induced by alphaviruses
As discussed above, alphaviruses can be directly cytolytic, and direct virus-induced cell killing is likely to contribute to alphavirus-induced disease processes. However, there is also abundant evidence that alphaviruses can interact with the host immune system to cause virus-induced disease. These interactions include evidence that alphavirus-induced inflammation contributes to the pathogenesis of arthralgia and/or myalgia that are characteristic of Old World alphaviruses such as CHIKV and RRV, as well as the role of immune cells in driving pathologic aspects of alphavirus-induced CNS disease. However, alphavirus infections are also associated with autoimmune or inflammatory syndromes, and we will discuss each of these alphavirus-induced disease outcomes in the following section (Table 3).
Table 3.
Immune-mediated conditions induced by alphavirus infection.
| Organ system | Condition | Description | alphaviruses |
|---|---|---|---|
| Musculoskeletal | Chronic polyarthritis | Persistent pain, stiffness, and swelling in and around multiple joints | CHIKV, RRV, MAYV, SINV |
| Integumentary | Psoriasis | Chronic disease characterized by raised, red, scaly patches on the skin | CHIKV |
| Lichen planus | Inflammatory skin condition characterized by bumps, sores, and rough scaly patches on the skin and mouth that often itch | ||
| Type I leprosy reaction | Delayed hypersensitivity to Mycobacterium leprae antigens characterized by increased redness and hardness of existing lesions | ||
| Nervous | Guillain Barre Syndrome | Autoimmune disorder where the immune system attacks the myelin sheaths or axons of peripheral nerves | CHIKV |
| Acute disseminated encephalomyelitis | Autoimmune disorder characterized by sudden widespread inflammation that damages brain and spinal cord white matter | ||
| Transverse myelitis | Autoimmune disorder characterized by sudden transient inflammation of the spinal cord | ||
| Ocular | Anterior uveitis | Inflammation of the middle layer of the eye, which includes the iris and ciliary body | CHIKV |
| Choroiditis | Inflammation of the choroid, the pigmented vascular layer between the retina and sclera | ||
| Panuveitis | Inflammation of all layers of the uvea, which includes the iris, ciliary body, and choroid | ||
| Retinitis | Inflammation of the retina, the thin layer of tissue at the back of the eye that converts light to neural signal | ||
| Neuroretinitis | Inflammation of the retina defined by optic disc edema and stellate macular exudates | ||
| Optic neuritis | Inflammation of the optic nerve |
Persistent arthralgia and arthritis have been reported with high incidence following infection with many of the Old World alphaviruses. Multiple characteristics and findings of alphavirus-induced chronic arthralgia and arthritis suggest the pathogenesis is mediated by the immune system rather than directly by the virus. While some studies have found evidence of CHIKV persistence during chronic infection (Hoarau et al., 2010; Ozden et al., 2007), several other studies evaluating synovial fluid in patients with chronic CHIKV- or RRV-induced arthritis found no evidence of CHIKV RNA via PCR, viral proteins via immunohistochemistry or mass spectrometry, or infectious virus via culture (Chang et al., 2018; Fraser and Becker, 1984; Ganu and Ganu, 2011). Regardless of whether chronic viral replication is driving disease pathogenesis, these results suggest that chronic alphavirus-induced arthralgia may be driven by indirect mechanisms. Patients infected with CHIKV have shown flare-ups of preexisting immune-mediated dermatoses, such as psoriasis, lichen planus, and type I leprosy reactions, indicating viral infection induces strong activation of the immune system (Riyaz et al., 2010). Most patients who develop persistent arthralgia following alphavirus infection are females, who are also far more prone to developing autoimmunities than males (Amaral et al., 2020a,b; de Souza et al., 2019; Heath et al., 2018; Huits et al., 2018; Sosa-Martínez et al., 2018; Tritsch et al., 2019). While treatment of chronic alphavirus-induced arthralgia and arthritis is primarily limited to supportive care anchored by nonsteroidal anti-inflammatory drugs, positive outcomes have been reported following treatment with disease modifying anti-rheumatic drugs. Both sulfasalazine and methotrexate, immunosuppressive drugs used to treat autoimmune conditions such as psoriasis, Crohn’s disease, and rheumatoid arthritis, have been used to inhibit proinflammatory cytokine production and reduce joint swelling, tenderness, and pain in patients with CHIKV- or MAYV-induced persistent arthralgia and arthritis with some success (Amaral et al., 2020a,b; Ganu and Ganu, 2011; Malvy et al., 2009; Poon et al., 2019; Theilacker et al., 2013; Zaid et al., 2018). Together, these findings strongly suggest that persistent arthralgia and arthritis induced by alphaviruses are immune-mediated.
Parallels have been drawn between chronic chikungunya arthritis and rheumatoid arthritis. The two conditions share numerous similarities: (1) both conditions are characterized by symmetrical polyarthritis of the small joints, (2) both conditions are most commonly diagnosed in middle-aged females, (3) symptoms for both conditions include arthralgia, arthritis, myalgia, stiffness, and fatigue, (4) both conditions have similar bloodwork and radiographic findings, and (5) many of the same pro-inflammatory cytokines are elevated in the serum and synovial fluid (Amaral et al., 2020a). Multiple case studies have found some chronic chikungunya arthritis patients meet the diagnostic criteria for rheumatoid arthritis according to the American College of Rheumatology/European League Against Rheumatism 2010 Rheumatoid Arthritis Classification Criteria; this classification system evaluates the joints involved, serologic test results for rheumatoid factor and/or anti-cycle citrullinated peptide antibody, elevated acute phase response as evidenced by abnormal C-reactive protein or erythrocyte sedimentation rate, and symptom duration (Aletaha et al., 2010; Amaral et al., 2020b; Amaral and Schoen, 2018; Bouquillard and Combe, 2009; Huits et al., 2018; Miner et al., 2015; Sepúlveda-Delgado et al., 2017). Using the American College of Rheumatology/European League Against Rheumatism 2010 Rheumatoid Arthritis Classification Criteria, a study found that in North Kerala, India, where chikungunya epidemics are frequent, CHIKV infection is significantly related to rheumatoid arthritis development (OR = 8.73) (Paul and Pariyapurath, 2018). Matrix metalloproteinases 1 and 3, which have been shown to correlate with rheumatoid arthritis disease activity and progression, are elevated in chronic chikungunya arthritis patients compared to healthy controls (Green, 2003; Ninla-aesong et al., 2019). NK cell and T cell phenotypes are similar between rheumatoid arthritis and chronic chikungunya arthritis, with pBMCs from both rheumatoid arthritis and chronic chikungunya arthritis patients having higher percentages of activated and effector CD4+ and CD8+ T cells than control patients (Miner et al., 2015). The frequency of human leukocyte antigen (HLA) alleles HLA-DRB1*01 and HLA-DRB1*04, which are associated with increased risk for developing rheumatoid arthritis (MacGregor et al., 1995; Weyand et al., 1992), is significantly higher in patients with chronic joint manifestations following CHIKV and SINV infection than the general population (Bouquillard and Combe, 2009; Sane et al., 2012). The structural polyproteins of multiple Old World alphaviruses share homology with numerous putative human proteins involved in rheumatoid arthritis and demonstrate similar binding patterns to HLA-DRB1 (Venigalla et al., 2020). These potential mimics are predicted to elicit an efficient B cell response, providing a possible autoimmune mechanism by which alphavirus infections are inducing chronic arthralgia and arthritis.
Instances of the immune response inducing pathology following alphavirus infection in human patients has been demonstrated with atypical neurological manifestations associated with the arthritogenic alphaviruses. In particular, multiple case reports of Guillain-Barre syndrome (GBS) have been reported in the literature. GBS is an autoimmune demyclinating polyneuropathy or axonal neuropathy characterized by acute onset of limb or muscle weakness usually progressing to flaccid paralysis (reviewed in Hughes and Cornblath, 2005). The general pathophysiology of GBS consists of an antibody-mediated attack of the myelin surrounding peripheral nerve axons (acute inflammatory demyelinating polyneuropathy subtype) or the axon itself (acute motor axonal neuropathy and acute motor and sensory axonal neuropathy subtypes) due to molecular mimicry between microbial antigens and axolemmal surface molecules (Bourque et al., 2015; Willison et al., 2016). Most cases are preceded by an infection less than 1 month prior, and the type of infection influences the clinical phenotype and prognosis. While GBS is most commonly associated with Campylobacter jejuni infection (Jacobs et al., 1998), infection with arboviruses, including alphaviruses, are becoming increasingly recognized as contributors to GBS development (Davis et al., 2006; Lebrun et al., 2009; Oehler et al., 2015; Sahu et al., 2014).
The first published association was a 1998 report out of Australia suggesting a connection between Barmah Forest virus infection and GBS (Phan et al., 1998). Since that report though, almost all of the associations between GBS and alphavirus infection have involved the naturally arthritogenic alphavirus CHIKV. The association between GBS and CHIKV was first proposed following an outbreak on Reunion Island in the Indian Ocean in 2006. Four reports collectively described eight patients admitted to hospitals with GBS during the 2006 CHIKV outbreak who tested negative for the typical infectious agents associated with GBS (C. jejuni, cytomegalovirus, Mycoplasma pneumoniae, Epstein-Barr virus, dengue virus) and had serum IgM against CHIKV (Lebrun et al., 2009; Lémant et al., 2008; Tourncbize et al., 2009; Wielanek et al., 2007). More cases of GBS were reported concurrent with a CHIKV outbreak in French Polynesia from October 2014 to March 2015, where an estimated 25% of the population became infected (Aubry and Cao-Lormeau, 2019; Koeltz et al., 2018; Oehler et al., 2015). Antibodies against GM2 and GDI a, gangliosides present in nodes of Ranvier along nerve axons, were each found in two patients from the outbreak, further supporting the hypothesis that CHIKV infection can trigger GBS (Oehler et al., 2015). The French Polynesia outbreak was determined to have originated from an infected individual traveling from the Caribbean (Nhan et al., 2014), where CHIKV had recently spread from Southeast Asia in 2013. Retrospective analysis of severe disease manifestations of CHIKV infections during the initial outbreak in Martinique and Guadeloupe in the French West Indies revealed six patients with GBS (Crosby et al., 2016). A case series evaluation of CHIKV-related GBS in 13 patients in the Caribbean found that 54% of cases were classified as the acute inflammatory demyelinating polyneuropathy subtype and 15% of cases were classified as the acute motor and sensory axonal neuropathy subtype, with the remaining cases classified as more uncommon variants (Balavoine et al., 2017). A case-controlled study evaluating the association between CHIKV infection and GBS in the French West Indies found an odds ratio of 8.3, indicating CHIKV infection was a risk factor for GBS (Stegmann-Planchard et al., 2019).
The association of GBS with arboviral infection became especially apparent during the Zika virus (ZIKV) outbreak in Central and South America from 2015 to 2016. Though humans cases were sporadically described in Africa, Asia, and the Pacific Islands starting in the 1950’s, ZIKV, a flavivirus, was first detected in Brazil in early 2015; by March 2016, over 50,000 suspected cases had been reported, and the approximately 5000 cases of ZIKV-associated congenital microcephaly incited public outcry (Kindhauser et al., 2016; Pinheiro et al., 2016). ZIKV, the closely related flavivirus DENV, and CHIKV, for which local infections have been reported since 2014 (Azevedo et al., 2015), are all transmitted by the same endemic Aedes spp. mosquito vectors (Weaver and Lecuit, 2015). Infection with all three viruses induces fever and rash, making it very difficult to provide an accurate diagnosis via clinical symptoms alone, and many laboratory tests are cross-reactive among the viruses, particularly the flaviviruses ZIKV and DENV (Braga et al., 2017). Reports of GBS in the Americas during the 2015–2016 Zika virus outbreak increased markedly (Capasso et al., 2019), with the inciting agent mosdy thought to be ZIKV, though many patients showed evidence of recent CHIKV or DENV infection as well (Acevedo et al., 2017; Anaya et al., 2017; de Azevedo et al., 2018; Dirlikov et al., 2016; Lima et al., 2019; Malta et al., 2017; Mancera-Páez et al., 2018; Mehta et al., 2018; Styczynski et al., 2017; Vieira et al., 2018; Zambrano et al., 2016). During the ZIKV outbreak, other cases of GBS were reported following CHIKV infection, with no evidence of prior ZIKV infection (Del Carpio-Orantes et al., 2018; Villamil-Gómez et al., 2016). Wachira et al. performed a systematic review evaluating factors reported to trigger GBS prior to and after 2007 and found that both CHIKV and ZIKV were identified in the literature as new etiological agents associated with the autoimmune condition (Wachira et al., 2019). Circulation of multiple arboviruses, particularly CHIKV, ZIKV, and DENV, in affected areas and high frequency of co-infections among patients complicate doctors’ and scientists’ ability to determine which pathogen(s) is responsible for triggering GBS. Further studies evaluating the exact mechanism by which arboviruses trigger GBS and how co-infections contribute to development of the condition are warranted.
Other immune-mediated neurological conditions have been reported as atypical manifestations of CHIKV infection in human patients. Acute disseminated encephalomyelitis (ADEM) is multifocal neurologic and demyclinating syndrome usually triggered by a prior infection whose pathophysiology is thought to be due to T cell activation following formation of antibodies against myelin and other self-antigens in the CNS (reviewed in Gray and Gorelick, 2016). Several cases of ADEM have been reported following CHIKV infection (Anand et al., 2019; Carvalho et al., 2020; Maity et al., 2014; Musthafa et al., 2008; Taraphdar et al., 2015; Teixeira et al., 2019), with a cross-sectional study of CHIKV cases during an outbreak in Pakistan showing an ADEM incidence rate of 5% (Barr et al., 2018). Transverse myelitis, another immune-mediated neurologic condition with variable pathological lesions involving the spinal cord, including demyelination, axonal degeneration, and perivascular infiltration of monocytes and lymphocytes (reviewed in Krishnan et al., 2006), has also been recently documented following CHIKV infection (Choudhary et al., 2016; Farias et al., 2018; González-Galván et al., 2017; Hameed et al., 2019; Kumar et al., 2019; Neri et al., 2018). Multiple case reports and series have described atypical ocular manifestations following CHIKV infection, including anterior uveitis, choroiditis, panuveitis, retinitis, neuroretinitis, and optic neuritis (Chanana et al., 2007; Deeba et al., 2019; Lalitha et al., 2007; Lin et al., 2018; Mahendradas et al., 2008, 2010; Mahesh et al., 2009; Mittal et al., 2007; Murthy et al., 2008; Nair et al., 2012; Neri et al., 2018; Rocha et al., 2018; Rose et al., 2011; Salceanu and Raman, 2018; Scripsema et al., 2015; Ulloa-Padilla et al., 2018). Whether the pathological changes for these ocular conditions are due to a direct viral mechanism or an immune-mediated mechanism are not currently known. However, in most of the reported cases, ocular disease was bilateral, developed after a period of latency following initiation of classical CHIKV symptoms (fever, arthralgia, etc.), and responded to immunosuppressive therapy such as corticosteroids, all suggesting an immune-mediated, rather than direct viral, mechanism (Merle et al., 2018; Rose et al., 2011).
An in-depth systematic review that effectively describes the range of neurological disease induced by CHIKV infection in human patients from CHIKV outbreaks in Reunion Island, Italy, Thailand, the Caribbean, and Pacific Islands was recently published by Cerny et al. (2017). Of 64 neurological cases described, encephalitis was the most common neurological complication diagnosed (27 cases), followed by optic neuropathy (18 cases), neuroretinitis (5 cases), GBS (5 cases), and ADEM (3 cases). Encephalitis cases were more commonly diagnosed in infants and children or elderly patients with co-morbidities, but in contrast, most of the cases involving the peripheral nervous system (PNS) (optic neuropathy, neuroretinitis, GBS) were diagnosed in previously healthy young to middle-aged adults. While encephalitis cases were mainly treated with supportive care and had a high rate of moderate to severe complications (100%) and severe outcomes (47%), cases involving the brainstem, spinal cord, or PNS were treated with immunosuppressive therapy (e.g., steroids, intravenous immunoglobulin), resulting in a good (66%) or partial (33%) response to therapy, and much lower complication (29%) and severe outcome (18%) rates. These findings caused the authors to suggest that based on the treating physicians’ assumptions, CHIKV-induced encephalitis has a direct viral pathomechanism, while neurological conditions involving the brainstem, spinal cord, or PNS has an underlying autoimmune or immunopathogenic mechanism. This hypothesis is further supported by the finding that the mean latency from development of classical CHIKV infection systems (fever, arthralgia, rash, etc.) to development of neurological complications was 3.3 days for encephalitis cases but 16.2 days for brainstem, spinal cord, or PNS cases; furthermore, for several patients who developed PNS disease, the latency period was marked by a complete lack of symptoms. Evaluation of the location of different diagnoses showed that while most cases from the Reunion Island outbreak were thought to have a direct viral pathomechanism (88%), most cases from outbreaks in India were autoimmune conditions involving the PNS (82%). This suggests that genetic factors, whether viral or host, are likely contributing to the development and pathogenesis of immune-mediated neurological disease during CHIKV infection.
5. Alphavirus-induced arthralgia and myalgia
As noted above, arthritogenic alphaviruses, and especially CHIKV, have been associated with several autoimmune neurologic disease states in humans, including GBS. However, the major disease signs associated with arthralgia-associated alphaviruses, which include CHIKV, RRV, and MAYV, are severe acute arthralgia and myalgia, that can progress to chronic disease in a subset of patients (reviewed in Burt et al., 2017). As discussed above, there is evidence for the host inflammatory response contributing to alphavirus-induced arthralgia and myalgia in humans. However, much of the evidence for immune pathology in driving these disease states comes from animal models. CHIKV causes inflammatory arthritis and myositis both in mice and in non-human primates, and these models have been useful systems both for studying the pathogenesis of CHIKV-induced disease and platforms for evaluating CHIKV therapeutics and vaccines (reviewed in Haese et al., 2016). Although most analysis has focuses on CHIKV, mouse models of RRV and MAYV also indicate that host inflammatory responses play a pathologic role in virus-induced myositis and arthritis (de Castro-Jorge et al., 2019; Lidbury et al., 2000).
Components of both the innate and adaptive immune system contribute to alphavirus-induced arthritis and myositis. Monocytes and/or macrophages are a prominent feature of both CHIKV and RRV-induced arthritis or myositis in mouse models, and depletion of these cells results in decreased disease signs (Gardner et al., 2010; Lidbury et al., 2000). Given the importance of monocyte and macrophages in the pathogenesis of CHIKV and RRV, additional studies have evaluated the potential for inhibitors of monocyte recruitment as therapies for alphavirus-induced arthritis. Bindarit, an inhibitor of monocyte chemo tactic proteins (CCL2, CCL8), protects against both CHIKV and RRV-induced disease (Chen et al., 2015; Rulli et al., 2009), which suggest that targeting monocyte chemotactic proteins may be of therapeutic benefit. However, mice that are genetically deficient for CCR2, which acts as a receptor for several chemokines, including CCL2 led to enhanced CHIKV-induced arthritis characterized by neutrophil infiltration into joint tissues (Poo et al., 2014). This suggests that the inflammatory pathways that regulate monocyte recruitment into CHIKV infected tissues is complex and requires further study.
The complement cascade, which plays a protective role in the context of alphavirus-induced CNS disease (Brooke et al., 2012; Hirsch et al., 1980), has also been shown to play a role in alphavirus-induced arthritis and/or myositis. RRV infected mice show high levels of complement deposition in infected skeletal muscle (Morrison et al., 2007). Mice lacking the C3 component of complement, which is essential for activation and amplification of the pathways, show significantly reduced disease signs and muscle damage, yet viral loads and inflammatory cell recruitment into the infected muscle are unchanged. Further analysis found that complement receptor 3 deficiency led to a similar decrease in virus-induced disease and tissue damage, which suggests that complement receptor 3 expression on macrophages or other inflammatory cells may be contributing to inflammatory cell-mediated tissue damage in RRV-infected tissues (Morrison et al., 2008). Studies by Gunn, et al. went on to show that RRV-induced complement activation occurred via the MBL dependent pathway of complement activation and provided evidence that differences in MBL levels may affect RRV-induced disease severity in humans (Gunn et al., 2012). In a follow-up study, Gunn, et al., demonstrated that N-linked glycans on the RRV E2 protein were required for MBL binding, complement activation, and RRV-induced muscle damage (Gunn et al., 2018). It remains to be determined whether the complement cascade’s role in driving virus-induced tissue damage is specific to RRV or if complement plays a larger role in the pathogenesis of other arthralgia associated alphaviruses.
As noted above, adaptive immunity plays an important role in protecting from arthralgia associated alphaviruses, with both antiviral antibody and CD8+ T cells contributing to protection from virus-induced disease. However, there is also evidence that CD4+ T cells contribute to CHIKV-induced disease, since mice lacking CD4+ T cells show a reduction in CHIKV-induced footpad swelling and joint pathology (Teo et al., 2013). Follow up studies by this group showed that expansion of regulatory T cells (Tregs) ameliorates CHIKV-induced disease in the mouse by inhibiting recruitment of pathologic CD4+ T cells into sites of CHIKV infection (Lee et al., 2015). These findings not only provide important insights into the pathogenesis of CHIKV-induced disease, but also have important implications for both the development of CHIKV vaccines and for potential therapeutic approaches for treating CHIKV-induced arthritis. This latter point is illustrated by the findings of Miner et al., where the disease-modifying anti-rheumatic drug cytotoxic T-lymphocyte-associated protein 4 (CTLA4) immunoglobulin, which blocks T cell co-stimulation, had benefit in treating CHIKV-induced arthritis and joint swelling in a mouse model, and this activity was enhanced when CTLA4 immunoglobulin was combined with a potent CHIKV specific monoclonal antibody (Miner et al., 2017).
6. Alphavirus-induced encephalomyelitis
6.1. Venezuelan equine encephalitis virus (VEEV), eastern equine encephalitis virus (EEEV), and western equine encephalitis virus (WEEV)
The neurotropic alphaviruses primarily consist of VEEV, EEEV, and WEEV, and animal models have helped shed light on the pathogenesis and immune response to infection with these viruses. Horses represent a highly permissive aberrant host for natural infection with the equine encephalitides but have also been used to study experimental infection. During infection with VEEV, severity of disease ranges from asymptomatic to rapid death, with clinically affected equids demonstrating fever, lethargy, weakness, and convulsions (Dietz et al., 1978; Gleiser et al., 1962; Monlux and Luedke, 1973; Roberts et al., 1970; Sahu et al., 2003; Walton et al., 1973). Pathological changes are consistent with meningoencephalitis and include perivascular and parenchymal infiltration of lymphocytes, mononuclear cells, and neutrophils with variable presence of glial cell proliferation and/or hypertrophy (gliosis) and clustering around neurons (satellitosis), neuronal damage, and vasculitis in the CNS. EEEV infection has a much higher mortality rate in horses than VEEV, with pathological lesions in the CNS characterized by perivascular cuffing with mononuclear cells, neutrophilic infiltration in the parenchyma, gliosis, neuronophagia, and vascular damage, consistent with diffuse polioencephalomyelitis (inflammation of the gray matter of the brain and spinal cord) (Del Piero et al., 2001; Franklin et al., 2002). WEEV appears to be the least virulent of the equine encephalitides, with most horses developing non-clinical infections (Potter et al., 1977). However, the large size and expense of housing horses precludes most in depth experimental studies evaluating the pathogenesis of VEEV, EEEV, and WEEV infection, necessitating the use of smaller animal models.
While experimental infections have been performed in other animals such as hamsters, rabbits, and guinea pigs, mice and nonhuman primates are considered to be the most relevant animal models for evaluating the pathology and immune response induced by VEEV, EEEV, and WEEV. Experimental infection of mice with virulent strains of VEEV by subcutaneous or footpad inoculation (considered to mimic natural infection by mosquito bite) results in CNS invasion via axonal transport up olfactory neurons following initial infection of dermal dendritic cells, replication in the draining lymph nodes, and viremic dissemination throughout the body (Charles et al., 1995; Davis et al., 1994; MacDonald and Johnston, 2000; Ryzhikov et al., 1991; Steele et al., 1998, 2006; Vogel et al., 1996). Aerosol or intranasal infection leads to a direct infection of olfactory neuroepithelium, resulting in infection of the brain as early as 16 h post infection (HPI) (Bocan et al., 2019; Cain et al., 2017; Ryzhikov et al., 1991; Steele et al., 1998; Vogel et al., 1996). Once in the CNS, VEEV rapidly disseminates, primarily targeting neurons in both the brain and spinal cord, though macrophages may also be infected (Jackson et al., 1991; Steele et al., 1998; Vogel et al., 1996). Histopathological changes are consistent with encephalomyelitis and characterized by thick perivascular cuffs and parenchymal infiltration, initially of neutrophils but then evolving to mostly mononuclear cells, as well as an increase in astrocytes (astrocytosis) (Ryzhikov et al., 1991; Schoneboom et al., 2000a; Sharma et al., 2008; Sharma and Maheshwari, 2009; Steele et al., 1998, 2007). Neuronal damage has been reported to occur through both apoptosis and necrosis (Bocan et al., 2019; Jackson and Rossiter, 1997; Schoncboom et al., 2000a; Steele et al., 1998; Steele and Twenhafel, 2010).
Infection of NHPs with VEEV via the intraperitoneal route results in transient fever and viremia within the first 3 days post infection (DPI) and infection of the brain by 6 DPI (Gleiser et al., 1962). Histopathological changes are similar but generally less severe than those seen in mouse models and include multifocal perivascular cuffs composed mostly of lymphocytes, gliosis, and rare evidence of neuronal damage associated with microglial clusters (glial nodules). Experimental intranasal infection with VEEV results in lesions in the olfactory bulbs by 48 HPI but is otherwise results in similar, though slightly more severe, pathological lesions in the CNS (Danes et al., 1973). Most experimental VEEV infection studies in NHP’s are conducted in the context of vaccine research using aerosol exposure. Infection of the CNS following challenge by this route is variable but induces lesions similar to those seen in humans when present, such as perivascular cuffing and gliosis (Fine et al., 2008; Steele and Twenhafel, 2010).
Unlike VEEV, EEEV does not initially replicate in dendritic cells or macrophages (Gardner et al., 2008; Levitt et al., 1979) but instead in fibroblasts, skeletal muscle, and osteoblasts (Vogel et al., 2005). Also unlike with the mouse model of VEEV infection, neuroinvasion by EEEV occurs via the hematogenous route rather than via axonal transport into the olfactory bulb (Vogel et al., 2005). EEEV can be detected in the brains of mice infected subcutaneously as early as 24 HPI, and multifocal positive EEEV antigen staining seen in multiple regions of the brain supports hematogenous spread. Similar to VEEV, neurons represent the main infected cell, though glial cells may also be infected (Roy et al., 2009; Vogel et al., 2005). Pathological changes in the brain include diffuse neuronal necrosis but fairly mild infiltration of neutrophils and eosinophils. Though not a known natural route of infection, aerosol challenge with EEEV has been studied mainly in the context of biodefense, as many strains of EEEV are classified as Select Agents. In this challenge model, infection has been demonstrated to first occur in the olfactory bulb and then disperse throughout the brain via transneuronal spread, similar to aerosol models of VEEV infection (Honnold et al., 2015a; Roy et al., 2009; Steele and Twenhafel, 2010). Histopathological findings include fulminant meningoencephalitis with abundant neuronal vacuolation, degeneration, and necrosis but few inflammatory infiltrates (Honnold et al., 2015b; Phelps et al., 2019). An aerosol challenge guinea pig model of EEE has shown a similar route of viral entry into the CNS, and pathological changes in the brain consist of marked neuronal necrosis and both perivascular and parenchymal inflammation (Roy et al., 2009). When inoculated with EEEV subcutaneously, hamsters have been shown to be exquisitely sensitive to infection, with virus detected in lung, liver, muscle, heart, kidney, spleen early in infection and titers increasing in the brain from 3 DPI to death at 5 or 6 DPI (Paessler et al., 2004). Similar to humans infected with EEEV, hamsters demonstrate fulminant vasculitis and subependymal hemorrhages with mixed inflammation in the brain. Neuronal death is mainly attributed to virus-mediated apoptosis (Honnold et al., 2015b; Vogel et al., 2005).
NHPs have also been used to evaluate the pathology induced by EEEV infection. Direct inoculation of virus into the brains of juvenile rhesus macaques results in severe encephalitis characterized by neuronal necrosis and loss with relatively mild inflammation (Nathanson et al., 1969). Aerosol challenge of cynomolgus macaques with virulent EEEV results in severe meningoencephalomyelitis, characterized by diffuse neuronal necrosis, perivascular cuffing with mononuclear cells and neutrophils, gliosis, satellitosis, and vasculitis (Reed et al., 2007; Roy et al., 2013; Steele and Twenhafel, 2010). Perivascular spaces are often expanded by edema or hemorrhage, and viral antigen is detected in multiple brain regions, primarily targeting neurons. Marmosets, small callitrichid monkeys native to Central and South America, have also been evaluated as potential models for EEE, and infection with EEEV induces meningoencephalitis with perivascular hemorrhages, similar to what is seen in human patients (Adams et al., 2008; Porter et al., 2017). When comparing the pathology induced by VEEV versus EEEV in different animal models, despite both viruses primarily targeting neurons, EEEV infection induces markedly more severe neuronal damage and death. However, these pathological changes are associated with relatively little inflammation, whereas VEEV infection of the brain results in massive immune cell infiltration, but only minimal damage to neurons.
Generally considered the least neurovirulent of the New World alphaviruses, animal studies of WEEV infection have shown variable pathology. Mice infected with more virulent WEEV strains demonstrate high mortality via multiple inoculation routes and develop severe meningoencephalitis characterized by neuronal degeneration and necrosis, edema, and mild infiltration of mononuclear cells (Aguilar, 1970; Logue et al., 2009; Phelps et al., 2017). Infection with the less virulent strains demonstrate more perivascular inflammation but minimal neuronal damage (Logue et al., 2009). Following recovery from WEEV, CD-1 mice demonstrate persistent gliosis (Bande et al., 2019). High mortality in WEEV-infected neonatal mice due to severe inflammation and/or necrosis in peripheral tissues such as bone marrow, skeletal muscle, and peripheral nerves without any CNS involvement (Aguilar, 1970) is similar to disease seen in some reports of hamsters infected with VEEV (Gorelkin and Jahrling, 1975; Jackson et al., 1991; Jahrling and Scherer, 1973; Walker et al., 1976). Challenge experiments via subcutaneous, intranasal, and aerosol routes in mice indicate WEEV invades the brain via axonal transport up the olfactory tract similar to VEEV (Bantle et al., 2019; Phelps et al., 2017; Phillips et al., 2013, 2016). Experimental infection of hamsters with WEEV demonstrates that, similar to the other equine encephalitides, neurons are the preferred cell for infection in the CNS (Julander et al., 2007), though infection of microglia has also been demonstrated in an aerosol challenge model of WEEV in cynomolgus macaques (Reed et al., 2005).
The immune response has been shown to play a major role in the pathogenesis of VEEV infection. Following subcutaneous inoculation with VEEV, mice show upregulation of proinflammatory genes Ifng, Il6, Il12, Il17, and Tnf, chemokine genes Cxcl9, Cxcl10, Cxcl11, Cxcl13, Ccl2, Ccl3, Ccl5,and Ccl12, and genes associated with TLR signaling, including Tlr1, Tlr2, Tlr3, Tlr7, and Tlr9, correlating with blood brain barrier compromise and infiltration of neutrophils and mononuclear cells into the brain (Grieder et al., 1997; Gupta et al., 2017; Sharma et al., 2008; Sharma and Maheshwari, 2009). Infection of multiple strains of mice with the V3000 strain of VEEV results in induction of proinflammatory cytokines, including inducible nitric oxide synthase, IL-1β, IL-6, IL-12, and TNF-α (Schoneboom et al., 1999, 2000a, 2000b). Mice administered magnesium or cadmium demonstrate more rapid development and severe histopathological CNS lesions concurrent with upregulation of proinflammatory cytokines following infection with both VEEV and SFV (Seth et al., 2003). Treatment of BALB/c mice with IFN-α prior to VEEV challenge results in improved survival, reduced TNF-α production by macrophages, and delayed activation of the adaptive immune response (Lukaszewski and Brooks, 2000). Inhibition of GSK-3β, a serine/threonine protein kinase with immunomodulatory capabilities, protects C3H mice from VEEV TC83-induced encephalitis (Kehn-Hall et al., 2012).
The adaptive immune response also contributes to pathological changes in the CNS during VEEV infection. Severe combined immunodeficiency (SCID) mice, which lack both T cells and B cells, show improved survival times compared to wild-type mice despite demonstrating higher viral titers (Charles et al., 2001). Nude mice, which lack T cells, infected with VEEV do not develop the inflammatory demyelinating spinal cord lesions seen in wild-type (WT) counterparts, and mice administered anti-thymocyte serum, which depletes T cells, have delayed mortality, indicating T cells play a role in inducing VEEV pathology (Dal Canto and Rabinowitz, 1981; Woodman et al., 1975). However, the role and contributions of CD4+ versus CD8+ T cells or other immune cells, such as macrophages, to immune-mediated damage during VEEV infection has not yet been elucidated.
As inflammation in the brain is not a key aspect of brain pathology during EEEV infection, less is understood about the role the immune system plays in the pathogenesis of EEE. However, mice infected via the intranasal or aerosol route with EEEV do demonstrate upregulation of proinflammatory cytokines IFN-γ, CCL4, CCL5, CXCL9, and G-CSF (Honnold et al., 2015a). While few articles describing the local immune response to WEEV have been published, increases in pro-inflammatory cytokines such as IFN-γ, TNF-α, IL-12, CCL2, and CXCL10 have also been demonstrated at 3 DPI in the brains of WEEV MCM strain-infected CD-1 mice before death at 4–5 DPI (Logue et al., 2010; Phillips et al., 2013). Significant differences in clinical outcomes among various inbred mouse strains following WEEV infection, with C57BL/6 and BALB/c mouse strains showing high susceptibility and BALB/cBy and DBA/2 mouse strains being more resistant to severe disease, suggest that some of these disparities in neurovirulence due to host genetics are likely due to differences in the immune response (Blakely et al., 2015).
6.2. Sindbis virus (SINV)
Numerous extensive studies have been conducted using the naturally arthritogenic alphavirus SINV to study the neuropathogenesis of alphavirus infection. SINV is neurotropic in mice but, unlike most strains of the equine encephalitides, can be handled under biosafety level 2 conditions and therefore represents a more accessible model of alphavirus encephalomyelitis. Disease severity is dependent on the strain of SINV used; for example, while both viruses effectively disseminate throughout the CNS, AR339, the pro-totypic strain of SINV, is fatal in neonatal mice but nonvirulent in weanling mice, while neuroadapted SINV (NSV) induces ascending paralysis and 100% mortality in susceptible mice of all ages (Griffin, 1976; Griffin and Johnson, 1977; Jackson et al., 1987; Taylor et al., 1955). Similar to VEEV and WEEV, neuroinvasion occurs via transaxonal transport from the neuro-epithelium to the olfactory bulb, after which SINV disseminates caudally throughout the brain and to the brainstem and spinal cord (Lee et al., 2013; Passoni et al., 2017; Thach et al., 2000). Ascending paralysis seen with SINV NSV infection is due to infection and degeneration of motor neurons in the lumbar spinal cord (Havert et al., 2000; Jackson et al., 1988). In brains of C57BL/6 mice infected with SINV, marked loss of neurons, particularly in the CA regions of hippocampus, is a key feature (Baxter et al., 2018; Kimura and Griffin, 2003). Perivascular cuffing and parenchymal infiltration of mononuclear cells is also considerable (Baxter et al., 2018; Irani and Griffin, 1991; Kimura and Griffin, 2003; Moench and Griffin, 1984; Stohlman et al., 1998). Hydrocephalus and dilation of the lateral ventricles may also be seen (Baxter and Griffin, 2020; Kimura and Griffin, 2003). Mice infected with the nonfatal TE strain of SINV demonstrate clinical disease characterized by gait deficits and exhibit behavioral changes concurrent to the development of these pathological changes in the brain (Baxter and Griffin, 2016; Baxter et al., 2018; Potter et al., 2015). In particular, hippocampal-dependent memory changes persist beyond the period of recovery from clinical disease and virus clearance (Potter et al., 2015). The mechanism of neuronal damage is dependent on the type of neuron, with evidence of both apoptosis and necrosis demonstrated (Havert et al., 2000; Kerr et al., 2002; Lewis et al., 1996; Nargi-Aizenman and Griffin, 2001).
Studies have shown that the immune system, particularly T cells, play the predominant role in inducing CNS pathology during SINV infection. During nonfatal SINV infection, inflammatory cells begin to infiltrate the CNS around 3 DPI, peaking at 7–10 DPI (Moench and Griffin, 1984). While NK cells peak early in infection, at 7 DPI, CD8+ T cells and macrophages predominate, though numbers of CD4+ T cells rapidly increase, becoming the main immune cell type by 10 DPI (Baxter and Griffin, 2020; Irani and Griffin, 1991, 1996; Metcalf and Griffin, 2011; Moench and Griffin, 1984). Onset of neurological disease and mortality in mice infected with SINV coincides with clearance of infectious virus and infiltration of immune cells into the brain (Griffin and Hardwick, 1997; Jackson et al., 1987; Kulcsar et al., 2014). SCID mice, which are deficient in both mature T and B cells, show 100% survival and minimal neuropathology following SINV NSV infection and do not develop neurological disease following SINV AR339 infection despite supporting high levels of virus replication (Levine et al., 1991; Wesselingh et al., 1994). Impaired proliferation and infiltration of lymphocytes into the brain of SINV-infected mice treated with 6-diazo-5-oxo-1-norleucine, a glutamine antagonist that arrests lymphocytes in the G1 phase of the cell cycle (Wang et al., 2011), leads to reduced mortality, weight loss, and development of neurological disease and cognitive deficits (Baxter et al., 2017; Manivannan et al., 2016; Potter et al., 2015). Mice deficient in multiple components of the cellular adaptive immune response, including TCRα, TCRβδ, β2m, TAPI, and CD4, but not CD8, show reduced mortality following SINV NSV infection, indicating T cells, especially CD4+ T cells, play a major role in inducing CNS pathology (Kimura and Griffin, 2000; Rowell and Griffin, 2002). In particular, Th17 cells expressing granzyme B, IL-22, and GM-CSF infiltrate the CNS during the development of SINV NSV-induced paralysis and fatal neurological disease (Kulcsar et al., 2014). These pathogenic Th17 cells are regulated by IL-10, with Il10−/− mice developing more severe weight loss and neurological disease and increased mortality concurrent with more CD4+ T cells skewed towards a Th1 and Th17 response but away from a Th2 and Treg response in the brain (Kulcsar et al., 2014; Kulcsar and Griffin, 2016; Martin and Griffin, 2018). BALB/c mice, which are more resistant to fatal encephalomyelitis than C57BL/6 mice, demonstrate fewer Th17 cells and more IL-10-dependcnt Tregs in the brain following SINV NSV infection (Kulcsar et al., 2015). These studies together demonstrate the importance of the T cell response in inducing neuropathology in the mouse model of alphavirus encephalomyelitis.
Proinflammatory cytokines have been shown to play a role in the immunopathogenesis in the SINV mouse model of alphavirus encephalomyelitis. Following infection with multiple strains of SINV, mouse brains show uprcgulation of proinflammatory cytokine gene expression, including Tnf, Csf2, Il1b, Il4, Il6, Il12b, Il17a, Il23, Lif, and Ifng (Baxter et al., 2018; Baxter and Griffin, 2016; Kulcsar et al., 2015; Lee et al., 2013; Martin and Griffin, 2018; Rowell and Griffin, 1999; Wesselingh et al., 1994). Mice deficient in interferon regulatory factors 3 and 7, who show increased disease severity and mortality respectively, have upregulated brain expression of multiple proinflammatory cytokines that correlate with increased severity of inflammation (Irf3−/− mice), numbers of CD4+ (Irf3−/− mice) and CD8+ (Irf7−/− mice) T cells, and TUNEL-positive cells mice) in the brain and spinal cord compared to WT mice following infection with the generally nonfatal TE strain of SINV (Schultz et al., 2019). IL-1β deficient mice are less susceptible to fatal encephalitis induced by SINV NSV, despite showing comparable histopathology and levels of apoptosis as WT mice (Liang et al., 1999). TNF-α deficient mice infected with SINV NSV show improved survival and reduced neuronal death compared to WT mice (Carmen et al., 2009), and TNF-receptor-1-deficient mice show reduced mortality and delayed development of paralysis compared to WT mice infected with the neurovirulent SVNI strain of SINV (Sarid et al., 2001). IFN-γ, the sole type II IFN, is known to contribute to the clearance of SINV in cooperation with anti-SINV antibody (Baxter and Griffin, 2016; Binder and Griffin, 2001; Burdeinick-Kerr et al., 2007; Lee et al., 2013) but is also involved in inducing pathology. WT mice lose more weight following SINV TE infection compared to Ifng−/− and Ifngr1−/− mice due to changes in feed intake indirectly related to levels of TNF-α in the brain (Baxter and Griffin, 2016). During the height of clinical disease at 7 DPI, Ifng−/− and Ifngr1−/ mice show reduced inflammation in the brain and spinal cord and are less likely to demonstrate dilatation of the lateral ventricles compared to WT mice (Baxter and Griffin, 2020). Mice with intact IFN-γ signaling have more macrophages and degranulating NK cells in the brain but fewer CD8+ T cells producing granzyme B and perforin and show delayed initiation of viral RNA clearance compared to Ifng−/− and Ifngr1−/− mice (Baxter and Griffin, 2020; Lee et al., 2013). Upregulation of proinflammatory cytokines induced during alphavirus encephalomyelitis likely promotes the infiltration of inflammatory cells that then induce pathological changes and neuronal damage in the CNS.
Another indirect mechanism by which neurons may die during alphavirus infection of the CNS is excitotoxicity. In neuronal excitotoxicity, excess amounts of the neurotransmitter glutamate accumulate in the synaptic cleft, leading to overstimulating of a-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA), N-methyl-d-aspartate, and kainate-type receptors (reviewed in Sattler and Tymianski, 2001). Influx of metal ions, particularly Ca2+, into the neuron through channels gated by these receptors leads to metabolic destruction of the cell (Lee et al., 1999; Nicotera and Orrenius, 1998). Glutamate excitotoxicity has been shown to play a role in the pathogenesis of SINV infection, with neuronal infection by multiple strains of SINV resulting in downregulation of glutamate transporter 1, a receptor primarily expressed on astrocytes responsible for preventing glutamate excitotoxicity by taking up the majority of glutamate from the synaptic cleft (Baxter et al., 2017; Carmen et al., 2009; Darman et al., 2004; Nargi-Aizenman and Griffin, 2001; Prow and Irani, 2007). Treatment of mice with either an N-methyl-d-aspartate receptor antagonist or AMPA receptor antagonist results in fewer necrotic and apoptotic neurons in the hippocampus following infection with SINV NSV (Nargi-Aizenman et al., 2004). Furthermore, spinal cord neuronal damage and paralysis is prevented, and mortality is reduced in mice treated with the AMPA receptor antagonist in a viral replication-independent manner (Greene et al., 2008; Nargi-Aizenman et al., 2004). However, inhibition of glutamate excitotoxicity either by AMPA receptor or glutamine antagonist treatment also results in reduced proliferation and impaired infiltration of immune cells in the draining lymph nodes and brain, respectively, during SINV infection (Baxter et al., 2017; Greene et al., 2008; Manivannan et al., 2016; Potter et al., 2015). Furthermore, mice deficient in TNF-α or IL-1β do not demonstrate glutamate transporter 1 downregulation in the brain following SINV NSV infection like WT mice do (Carmen et al., 2009; Prow and Irani, 2007). These findings indicate that multiple pathways involved in excitotoxicity also affect the immune response and emphasize the interconnectedness of different mechanisms known to induce neuronal damage during alphavirus encephalomyelitis.
6.3. Semliki forest virus (SFV)
SFV, an Old World alphavirus antigcnically related to RRV and MAYV, is generally considered to be non-pathogenic in humans, only occasionally causing fever, myalgia, and arthralgia (Mathiot et al., 1990). However, a case of fatal encephalitis due to laboratory acquired SFV infection has been reported (Willems et al., 1979), and infection of mice with multiple strains of SFV by both direct and indirect routes consistently results in demyelinating meningoencephalomyelitis (Gates et al., 1984; Kelly et al., 1982). While some SFV strains produce acute fatal encephalitis, the well-studied avirulent A7(74) strain of SFV induces a transient viral infection that is cleared by 8 DPI in susceptible immunocompetent strains, such as BALB/c mice (Amor et al., 1996; Berger, 1980; Kelly et al., 1982; Morris et al., 1997). Perivascular cuffs composed of CD8+ T cells, B cells, and macrophages are found throughout the brain starting during the first week of infection, but beginning around 10–15 DPI, mice develop demyelinating lesions in the white matter of the cerebellum, corpus callosum, and brainstem (Amor et al., 1996; Berger, 1980; Kelly et al., 1982; Morris et al., 1997; Subak-Sharpe et al., 1993). Following infection and subsequent SFV clearance, focal areas of vacuolation in the myelin are filled with necrotic cells and surrounded by mononuclear cells, particularly lymphocytes extending cytoplasmic projections to astrocytes and macrophages (Kelly et al., 1982; Sheahan et al., 1983).
Similar to EEEV, following peripheral inoculation, SFV primarily enters the CNS via hematogenous spread by infecting vascular endothelial cells (Erälinna et al., 1996; Pathak and Webb, 1974; Soilu-Hänninen et al., 1994), though intranasal infection has shown that neuroinvasion via the olfactory bulb is also possible (Keogh et al., 2003; Oliver and Fazakerley, 1998). Upregulation of intercellular adhesion molecule 1 and fibrinogen in the CNS during SFV infection indicates that blood brain barrier integrity is also compromised (Erälinna et al., 1996; Soilu-Hänninen et al., 1994). While neurons are susceptible to SFV infection in an host age-dependent manner similar to SINV (Fazakerley et al., 1993; Fragkoudis et al., 2009; Oliver et al., 1997), unlike SINV and the other New World alphaviruses, oligodendrocytes represent the primary targeted cell in the CNS (Fazakerley et al., 2006; Fragkoudis et al., 2009; Sheahan et al., 1983). In optic nerves of SFV-infected BALB/c mice, oligodendrocytes develop swellings and vacuolations along internodal myelin sheaths, appearing more like immature cells (Butt et al., 1996); this suggests SFV infection induces the oligodendrocytes to dedifferentiate rather than die, and therefore the cells are capable of remyelination.
Numerous studies have shown that demyelination following SFV infection is primarily immune mediated. Mice lacking both T and B cells through genetics (SCID mice), irradiation, or cyclophosphamide administration show reduced and/or delayed pathology despite robust viral replication (Amor et al., 1996; Berger, 1980; Fazakerley and Webb, 1987a). Nude mice do not develop the perivascular inflammation or demyelinating lesions of immunocompetent mice (Amor et al., 1996; Fazakerley et al., 1988, 2006; Gates et al., 1984), and transfer of T cells, but not hyperimmune serum, back into nude or SCID mice results in demyelination (Amor et al., 1996; Fazakerley et al., 1983; Fazakerley and Webb, 1987a, 1987b). Depletion of CD8+ T cells, but not CD4+ T cells, reduces inflammation and eliminates demyelinating lesions, suggesting that CD8+ T cells are primarily responsible for the CNS damage (Subak-Sharpe et al., 1993). Production of MHC class I, which is expressed on oligodendrocytes and makes them a target for cytotoxic T cells (Fazakerley et al., 1993), is upregulated early in SFV infection (M. M. Morris et al., 1997), and interactions between lymphocytes and oligodendrocytes have been observed by electron microscopy at 7 DPI before demyelinating lesions are seen starting at 10 DPI (Pathak et al., 1983). While CNS expression of cytokines IL-1α, IL-1β, IL-10, and TGFβ increases early in infection, TNF-α, IL-2, and GM-CSF expression increases when cellular infiltrates are at their peak; IFN-γ and IL-6 first become apparent at 10 DPI immediately prior to the demyelination phase of disease, suggesting these cytokines may play a role in induction of CNS pathology (Blackman and Morris, 1984; McKimmic et al., 2005; Morris et al., 1997). Mice that lack the IFN-γ receptor, and therefore have deficient type II IFN signaling, demonstrate higher levels of neuronal necrosis associated with increased viral antigen and more macrophages and B cells in the brain, but comparable amounts of demyelination, following SFV infection (Keogh et al., 2003). Nude mice, which have impaired antibody class switching and therefore produce only antiviral IgM, μMT mice, which lack the ability to produce antibody, and SCID mice all demonstrate delayed viral clearance and/or viral persistence (Amor et al., 1996; Fazakerley et al., 2006; Fazakerley and Webb, 1987b; Fragkoudis et al., 2008). However, administration of polyclonal or monoclonal SFV antibody quickly reduces infectious virus to undetectable levels in SCID mice, indicating that, similar to SINV, anti-SFV antibody plays a major role in SFV clearance in the CNS (Amor et al., 1996; Fragkoudis et al., 2018).
SFV A7(74) has been shown to react immunologically with immune sera against several antigens in the CNS, including galactocerebroside (found on oligodendrocytes), glucocerebroside, total ganglioside, and GT1b ganglio-side (found on neurons), indicating the possibility of SFV infection creating an autoimmune state against cells present in the CNS (Webb et al., 1984). Administering anti-SFV hyperimmune serum, but not normal mouse serum, results in CNS tissue degeneration, but no demyelination or inflammatory response, in both SFV-infected and mock-infected control mice, suggesting autoantibodies play a role in pathology (Fazakerley and Webb, 1987b). C57BL/6 mice immunized with SFV proteins show lymphocyte proliferation against peptides on the SFV E2 glycoprotein and myelin oligodendrocyte glycoprotein, inducing SFV-likc demyelination; this suggests that SFV infection creates a molecular mimicry response against myelin oligodendrocyte glycoprotein, leading to autoimmune demyelination (Mokhtarian et al., 1999). Because of this, SFV has been used in mouse models of experimental autoimmune encephalomyelitis to evaluate the pathogenesis of autoimmune conditions such as multiple sclerosis (Wu et al., 1988). In C57BL/6 mice infected with SFV A7(74), CNS inflammation and virus clearance occur from 6 to 10 DPI, demyelination occurs from 15 to 21 DPI, and remyelination follows, with brains showing almost no lesions by 35 DPI (Mokhtarian et al., 2003). In this model, CD8+ T cell numbers peak between 8 and 15 DPI, concurrent with initial myelin injury, but B cells and microglia represent the predominant inflammatory cells present during the late period of demyelination at 21–28 DPI. γδ T cells and antibody against the SFV epitope, E2 Th peptidc2, have been shown to contribute to the remyelination process (Mokhtarian et al., 2012; Safavi et al., 2011) via an unknown mechanism. The C57BL/6 experimental autoimmune encephalomyelitis model using SFV highlights the multifaceted role the immune response plays in inducing pathology and the challenges that must be overcome in understanding and addressing immunc-mcdiatcd damage following alphavirus infection.
7. Conclusion and future directions
The increase in geographic expansion and frequency of outbreaks of disease induced by alphaviruses necessitates the development of effective therapies that not only curb the initial course of infection but address and/or prevent the development of chronic disease. Thanks to information assembled from reports of human cases and experimental infection of animals, we now know the immune system is responsible for a significant amount of clinical disease following alphavirus infection. Infection by alphaviruses promotes a proinflammatory state both systemically and in the tissues targeted by the viruses, and development of clinical disease coincides with the infiltration of immune cells, particularly T cells. Furthermore, blockage or inhibition of the inflammatory response helps mitigate the development and severity of clinical disease following alphavirus infection. However, the immune response is also responsible for restriction of viral replication, clearance of infectious virus and viral RNA, and prevention of persistent viral RNA reactivation and relapse of clinical disease. Some components of the immune response, such as TNF-α, IFN-γ, and CCL2, have been reported to be both pathogenic and protective during alphavirus infection. This double-edged sword highlights the complicated balance the immune response must navigate when responding to infection by an alphavirus, and understanding this interplay between pathology and protection is critical when considering potential treatments that modulate the immune response.
Many aspects of the role the immune response plays in development of clinical disease remain to be understood. For example, the pathomechanism of chronic disease following alphavirus infection, particularly with CHIKV, is currently unknown. Despite reports of debilitating pain, swelling, and stiffness in patients suffering from chronic chikungunya arthritis, damage to affected joints is not usually severe, raising the question of what unseen factors are mediating clinical symptoms. The recent increase in detection of CHIKV-associated GBS cases, especially in light of similar co-circulating arboviruses in affected regions, warrants further evaluation of the role of molecular mimicry in development of autoimmune disease following alphavirus infection. Understanding the effect of host genetics on the immune response and the role played in the range of disease severity and development of atypical manifestations is also in its infancy. Disparate manifestations of CHIKV-induced neurological disease in various geographical regions suggest that the diverse immune systems of the human populations among affected areas are likely responding to infection and mediating the course of disease in different manners. Robust animal models that effectively replicate the course of infection and development of disease and pathology, particularly chronic or atypical disease manifestations, will greatly assist in answering these questions, and critical evaluation, characterization, and modification of these models should be ongoing. Further illumination of the immunopathogenesis of alphavirus infection will help lead to therapies that effectively target the specific components of the immune response liable for tissue damage and pathology, leading to better disease outcomes and improved quality of life in affected individuals.
Acknowledgments
V.K.B. is supported by the National Institutes of Health (NIH) grants K01 OD026529 and U19 AI100625. M.T.H. is supported by NIH grants U19 AI100625 and U19 AI142759.
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