Viral diseases and the brain

Abstract

Various viruses can affect the brain directly or indirectly. The specter of Long COVID has focused research on how respiratory viruses can cause infection and inflammation of brain cells.

The impact of viral infections on the brain has been long studied in the context of rabies, herpes simplex, HIV, measles, and a few other viruses that target the organ directly, but little has been known about indirect effects of viral infections. This specific research has been boosted though in light of the long‐term neurological effects of SARS‐CoV‐2 under the banner of Long COVID. Indeed, the pandemic is providing generally fresh insights into the link between viral infections, inflammation, and neurogenerative diseases like Alzheimer’s Disease (AD) and the underlying mechanisms and causes of symptoms such as fatigue or cognitive impairment.

Direct infections

Viruses can broadly affect the central nervous system (CNS) in three ways. First, they may invade the CNS directly to cause encephalitis, inflammation, or necrosis that can lead to permanent disability or death. Second, as a result of a viral infection elsewhere, inflammatory molecules such as cytokines may cross the blood/brain barrier—the semipermeable border of endothelial cells that normally prevents solutes in the circulating blood from crossing into the extracellular fluid of the CNS. Third, inflammatory changes elsewhere in the body may affect the brain through long‐range action via other mechanisms.

Rabies is an extreme example of the first category: the virus travels along the axons of the spinal cord toward the brain, where it causes acute inflammation followed by psychosis and violent aggression. As the virus radiates back out along axons into peripheral organs, it causes paralysis and inevitable death, often through respiratory or cardiovascular failure. However, the long incubation period during which the virus travels from the site of the animal bite to the brain means that vaccines or rabies‐specific antibodies can often be administered therapeutically. Still, although therapeutic rabies vaccines have been used with success for more than 30 years, the disease exacts a toll of 50,000 or more a year, mostly in developing countries where treatment is not started in time or where it is not available.

… [rabies] travels along the axons of the spinal cord towards the brain, where it causes acute inflammation followed by psychosis and violent aggression.

It was then in 2014 that an Israeli team elucidated the method of how the virus travels to the brain. They found that rabies hijacks and manipulates the mechanism used by the p75 Nerve Growth Factor (NGF) for moving along axons and between neurons: the virus piggybacks in the same acidic compartment as the p75 NGF receptor upon ligand binding and internalization to be transported along the axons (Gluska et al, ²⁰¹⁴). They also found that the rabies virus actually moves faster than p75 itself, suggesting that it had evolved an additional mechanism for manipulating and speeding up the transport machinery. The results suggest a link with neurodegenerative diseases since these too are associated with disruptions of the neuron/axon trafficking system.

Indirect effects on the brain

In contrast, most respiratory viruses do not usually access such pathways and their action on the CNS is mild compared to rabies. A notable exception is the measles virus that can infect the brain to cause encephalitis or the even more terrible subacute sclerosing panencephalitis (SSPE) that slowly leads to mental retardation and death. But since respiratory viruses infect far more people, their neurological impact has been subject to increasing research even before the COVID‐19 pandemic. Unlike rabies, many viruses occasionally enter the brain via the blood stream, either by infecting the peripheral blood vessels leading into the brain or hitchhiking inside blood cells such as monocytes or macrophages. This so‐called Trojan horse route enables viruses to slip through the blood/brain barrier inside components identified as legitimate.

… since respiratory viruses infect far more people, their neurological impact has been subject to increasing research even before the COVID‐19 pandemic.

The COVID‐19 pandemic has presented unexpected opportunities to study some of these mechanisms and the effects of viral infections on the brain. One of the most comprehensive studies took place in Germany where researchers analyzed the neuropathological features of 43 people who died from COVID‐19 in the city of Hamburg between March 13 and April 24, 2020 (Matschke et al, ²⁰²⁰). They observed neuropathological changes in most of the patients, commonly in the brainstem, but these were minor with no evidence of CNS damage caused directly by SARS‐CoV‐2. Since, the team has looked at more than 100 brains, according to Markus Glatzel from the University Medical Center Hamburg‐Eppendorf and lead author on the paper. The main findings are still that impacts on the brain are mostly the result of immune activity rather than direct entry of the virus, but more sophisticated analytical techniques have allowed the team to identify a specific immune phenotype, or activation pattern, involving the microglia, macrophage cells resident in the brain where they provide the first and primary line of immune defense. “We see that microglia are upregulated around the vessels, but also in the microglia nodules,” Glatzel explained. “The main action is around the vessels, the neurovascular niche, but then also we have the formation of microglia nodules, which we have also seen in other viral diseases, such as HIV, before treatments became better.”

The COVID‐19 pandemic has presented unexpected opportunities to study some of these mechanisms and the effects of viral infections on the brain.

The neurovascular niche is a specialized microenvironment of the CNS formed by interactions between neural progenitor cells (NPCs) and the vasculature. It is known to play an intimate role in innate immunity and is implicated in the blood–brain barrier. It is, therefore, not so surprising that it should also be involved in interactions between immunity and infectious diseases in the CNS. Yet, Glatzel argues that the question whether a virus such as SARS‐CoV‐2 actually gains access to the brain directly or not is now rather academic. “The stuff we see in the brain is caused by the virus one way or the other,” he said. “We are now looking into the mechanism of damage, how does the damage to the neurovascular niche occur, and how does entry occur.”

SARS‐CoV‐2 can infect brain cells

A US team presented evidence in a preprint that SARS‐CoV‐2 can invade astrocytes, star‐shaped glial cells, that perform various functions in the CNS including biochemical support of the endothelial cells that form the blood–brain barrier (preprint: Andrews et al, ²⁰²¹). “Brain cells can have selective vulnerabilities to viral infection usually determined by entry receptors,” commented Arnold Kriegstein from the UCSF School of Medicine in San Francisco and lead author of that paper. “For example, the Zika virus has marked tropism for radial glia cells (neural stem cells) in the developing brain. In the case of SARS‐CoV‐2, we found that the virus has tropism for human brain astrocytes.”

Unlike the German work, this was done on human brain samples resected during neurosurgical procedures and demonstrated that SARS‐CoV‐2 virus can infect brain astrocytes and replicate. “It will be important to validate whether this occurs in patients with severe SARS‐CoV‐2 infections who suffer CNS involvement,” Kriegstein commented. “Examination of postmortem brain samples could address this possibility.” Such work also opens therapeutic possibilities to block specific receptors involved. “Our study showed that SARS‐CoV‐2 tropism for astrocytes is not dependent on the ACE2 receptor but does involve the alternative DPP4 receptor,” Kriegstein added. “We also found that infection can be attenuated by blocking the DPP4 receptor, raising the possibility of using pharmacological inhibition of the DPP4 receptor as a means of protecting astrocytes from infection.” Angiotensin‐converting enzyme 2 (ACE2) is well known as the primary entry point for a number of coronaviruses; Dipeptidyl peptidase‐4 (DPP4) is an enzyme associated with immune regulation on the surface of most cell types and is therefore also an entry target for some viruses.

We postulate that once in the brain, the virus and its proteins promote inflammation and that it is likely this neuroinflammation that is the basis of Long COVID…

Another US study presenting evidence that viruses do more frequently cross the blood–brain barrier than previously assumed also suggests this as a cause of more severe cases of Long COVID, although this was done on mice rather than humans (Rhea et al, ²⁰²¹). “We postulate that once in the brain, the virus and its proteins promote inflammation and that it is likely this neuroinflammation that is the basis of Long COVID, especially the cognitive and behavioral changes,” said William Banks from the University of Washington and corresponding author on the paper. “This is not unusual. HIV‐1 started off as an immune suppressing virus but has significant long‐term effects on the CNS. SARS‐CoV‐1 also crosses the [blood‐brain barrier] and has some CNS‐like effects.” He argued that Long COVID symptoms were primarily mediated by the CNS. “Our unpublished work shows that S1 and models of SARS‐CoV‐2 induce neuroinflammation and behavioral changes,” Banks added. S1 is the SARS‐CoV‐2 protein that binds to ACE2 and is probably capable of attaching to other proteins as well. Bank also contended that Long COVID can have significant neurological implications even when the initial infection was relatively mild, and that these were more widespread than those associated with other respiratory viruses of comparable severity.

… there are some who urge caution in interpreting studies of Long COVID, […] because it often does not take into account the psychological impact of fear and anxiety…

However, there are some who urge caution in interpreting studies of Long COVID, especially in comparison to other viruses, because it often does not take into account the psychological impact of fear and anxiety engendered by governments and the media. “It’s a big problem, because for one year the only topic was COVID‐19, which leads to all sorts of issues,” Glatzel commented. Fear, anxiety, and even unfulfilled expectation have no doubt played a role in Long COVID, amid anecdotal reports that some people presenting with symptoms had never been infected by the virus in the first place. But this is not to deny that there are many serious cases, even if in the majority symptoms do alleviate after 6 months. A positive corollary of this anxiety is that psychological techniques, including cognitive behavioral therapy, could be used to treat Long COVID, and indeed post‐viral syndrome generally, alongside pharmacological interventions (https://www.apa.org/monitor/2021/07/treating‐long‐covid).

Vaccine developments

Notwithstanding the focus on Long COVID, research has continued into the neurological impacts of neurotropic viruses that target the CNS more directly and cause conditions that often require specialist neurointensive care. Such viruses include chikungunya, dengue, Japanese encephalitis B virus, and West Nile virus, all transmitted by mosquitoes, which cause meningitis, encephalitis and Guillian–Barré‐like syndromes characterized by numbness and pain in limbs, hands, and feet, as well as strokes. Vaccines are available to prevent some of these diseases including dengue. But there are still many people with severe impairments among those who survived the initial infection. The exact toll of such diseases has not been well researched, but one study in Sri Lanka found that patients who had otherwise recovered from dengue had significantly higher depressive, anxiety, and stress symptoms than controls (Gunathilaka et al, ²⁰¹⁸).

There is at least now the prospect of vaccines for prophylactically treating arboviral infections for which there is no current pharmacological therapy. This follows a recent discovery of a common epitope that is conserved among alphaviruses, an RNA virus genus, and a subset of the arboviruses (Kim et al, ²⁰²¹). “Neurotrophic alphaviruses, such as Eastern and Venezuelan equine encephalitic viruses, cross the blood‐brain barrier and cause encephalitis in humans which often results in neurological sequelae,” explained Michael Diamond, Head of Laboratory at the Washington University School of Medicine in the US and corresponding author on that paper. “We demonstrate that our antibodies protect against encephalitic alphaviruses in mice even when administered in either a prophylactic or therapeutic setting, suggesting that a universal vaccine which elicits these antibodies may hold promise as a countermeasure against encephalitic alphaviruses.”

Diamond added that while circulating antibodies are normally prevented from accessing immune‐privileged sites such as the CNS, this protection may be weakened in the event of viral infection. “Given that our antibodies confer protection against encephalitic alphaviruses in mice, this suggests an antibody‐based strategy may be effective against this family of viruses,” he said. “However, the mechanisms of antibody‐based protection in preventing neurotrophic alphavirus infections, and whether this strategy can be extended to other neurotrophic viruses, have yet to be explored.”

Links to neurodegenerative diseases

The other big neurological dimension to viral infections is their impact on neurodegenerative diseases, such as AD, and autoimmune diseases, such as MS, where the CNS is involved. One recent review concluded that, given the overwhelming evidence that viral infections can contribute to pathologies of NDs, it is time to routinely consider viral factors in the etiology and diagnosis of such conditions (Wouk et al, ²⁰²¹). The authors listed various recent studies relating the onset of neurological disorders to viral infections and called for further research to investigate the action of viruses in these pathologies to inform the development of novel control and intervention therapies.

One of those studies found growing evidence of links between infection by herpes simplex‐1 (HSV‐1) and AD pathogenesis, although it is not clear whether the virus has a causative role, has a subsequent impact on development, or is just a bystander possibly encouraged by the condition (Sait et al, ²⁰²¹). The paper noted substantial evidence indicating that HSV‐1 contributes to the pathogenesis of AD rather than just being correlated with it. This is significant because HSV‐1 is a very common contagious virus present in about two thirds of people under the age of 50, according to WHO. It has long been known that HSV‐1 can infect the brain and, in very rare cases, trigger an acute and inflammatory response that leads to herpes simplex encephalitis (HSE). This latest study details findings of HSV‐1 DNA in AD patients, localized within amyloid plaques in temporal and frontal cortices. There is still controversy, however, over whether the association is causative or reactive, but the authors noted a recent cohort study reporting that antivirals did reduce dementia.

Coronaviruses have also been linked to neurodegenerative diseases, particularly HCoV‐229E and HCoV‐OC43, which both cause common cold and which have been detected in the brains of patients with Parkinson’s disease, acute disseminated encephalomyelitis (ADEM) and MS. This has naturally prompted interest in a possible link between Sars‐CoV‐2 and such conditions. Glatzel and his team are currently seeking funding for a follow‐up project to look at patients who were diagnosed with Long COVID and then died of other causes, including dementia. “We are asking whether there is some residual state that gives a hint of how COVID‐19 infection effects development of dementia,” Glatzel explained. “One question is what happens to people with existing dementia who had COVID and have now recovered. Has that led to another phenotype of dementia?”

The paper noted substantial evidence indicating that HSV‐1 contributes to the pathogenesis of AD rather than just being correlated with it.

Glatzel noted that the Spanish flu a century ago had been associated with European sleeping sickness, which broke out around the same time, causing 500,000 deaths, before it subsided (Ravenholt & Foege, 1982). “It’s a Parkinsonian disease, and the question is whether COVID‐19 could cause something similar,” he said. In that regard, the COVID‐19 pandemic has been highly beneficial to neuroscience as it has reopened such questions and stimulated research into the link between viruses and neurological conditions generally.

EMBO reports (2022) 23: e54342.