Drugs for Multiple Sclerosis Activate Natural Killer Cells: Do They Protect Against COVID-19 Infection?

Abstract

COVID-19 infection caused by the newly discovered coronavirus severe acute respiratory distress syndrome virus-19 (SARS-CoV-2) has become a pandemic issue across the globe. There are currently many investigations taking place to look for specific, safe and potent anti-viral agents. Upon transmission and entry into the human body, SARS-CoV-2 triggers multiple immune players to be involved in the fight against the viral infection. Amongst these immune cells are NK cells that possess robust antiviral activity, and which do not require prior sensitization. However, NK cell count and activity were found to be impaired in COVID-19 patients and hence, could become a potential therapeutic target for COVID-19. Several drugs, including glatiramer acetate (GA), vitamin D₃, dimethyl fumarate (DMF), monomethyl fumarate (MMF), natalizumab, ocrelizumab, and IFN-β, among others have been previously described to increase the biological activities of NK cells especially their cytolytic potential as reported by upregulation of CD107a, and the release of perforin and granzymes. In this review, we propose that such drugs could potentially restore NK cell activity allowing individuals to be more protective against COVID-19 infection and its complications.

Introduction

Coronaviruses (CoVs) are large positive stranded enveloped RNA viruses that cause enteric and mild or severe respiratory diseases in animals and humans.¹ Coronaviruses are named based on their morphology as spherical virions with a core shell and surface projections, that are classified into four subfamilies, namely alpha, beta, gamma and delta. SARS-CoV-2 belongs to the beta‐coronaviruses and is closely related to the severe acute respiratory distress syndrome virus (SARS-CoV), that emerged earlier this century.^2–4 Recently, COVID-19 infection was reported to be caused by SARS-CoV-2 in Wuhan, China.⁵ Additionally, it was associated with mortality in a ratio of the patients similar to other previously reported CoVs.⁶ COVID-19 could be transmitted through huge droplets caused by coughing and/or sneezing.⁷

Similar to SARS-CoV, SARS-CoV-2 uses a unique receptor for cell entry, which is angiotensin converting enzyme 2 (ACE2).^8–11 The clinical symptoms could vary from fatigue, fever, headache, dyspnea, nasal congestion and cough, as well as gastrointestinal symptoms including nausea, vomiting, diarrhea and abdominal pain.^2,12 In severe cases, these symptoms are aggravated to shortness of breath and pneumonia that could lead to acute respiratory distress syndrome (ARDS) and other complications.^13,14 A study performed on hospitalized patients with SARS-CoV-2 associated pneumonia reported that the most common symptoms were fever (83%) and cough (82%), followed by shortness of breath (31%).¹⁵ As part of the inflammatory process, markers such as C‐reactive protein, erythrocyte sedimentation rate and proinflammatory cytokines are elevated.¹³ The extremely high concentration of cytokines “cytokine storm” was recorded in plasma of severe cases of COVID-19 patients and was associated with disease severity.¹⁶ The inflammatory cytokines include granulocyte colony stimulating factor (G-CSF), IL-2, IL-7, IL-10, TNFα and the chemokines CCL2, CCL3, and CXCL10.^16,17

Various current therapeutic agents are currently being investigated for treatment of COVID-19. Use of intravenous immunoglobulins has been described to show great efficiency especially in severe and deteriorating patients infected with SARS-CoV-2.¹⁸ Also, anti-viral agents such as remdesivir have been examined as potential candidates for COVID-19 therapy. Hydroxychloroquine and chloroquine have been suggested to inhibit viral replication and activity.¹⁹ Since antiretroviral drugs previously showed efficacy against SARS-CoV, lopinavir/ritonavir may have potential therapy in COVID-19 patients.^20,21 For instance, the JAK inhibitor baricitinib that is used for treating rheumatoid arthritis patients was suggested to control viral replication and treatment of COVID-19 infection.^22,23 Because many of the drugs used currently in COVID-19 treatment were primarily used for the treatment of autoimmune diseases, it was of interest to see if the immunomodulatory agents used in multiple sclerosis therapy could be utilized for treating of COVID-19 through activation of natural killer cells.

Natural Killer Cells

Natural killer (NK) cells are innate immune cells that are programmed to protect humans from viral infections and cancer.^24–26 The main cytotoxic function of NK cells is through apoptotic induction and lysis of virally infected cells via perforin and granzymes. Also, NK cells are able to secrete immunoregulatory cytokines such as IFN-γ and TNF-α, that regulate the immune responses.^27,28 IFN-γ and TNF-α are known to play a critical role in the control of viral infections, by indirect stimulation of the cytolytic function of NK cells.²⁹ Further, they were reported to act as immune-defensive mediators that activate and recruit other inflammatory immune cells.³⁰ Also, these cytokines were reported to influence the innate and adaptive immune cells.^31,32

NK cells are CD3⁻ and further divided into two main subsets based on the expression of certain markers. Accordingly, NK cells that express CD56 but not CD16, known as CD56^bright, represent about 10–20% of total NK cells in the blood, whereas those that express CD16 and low CD56, known as CD56^dim, represent about 80–90% of total circulating NK cells. CD56^dim cells have been shown to predominantly mediate cytotoxicity, whereas CD56^bright cells appear to principally secrete cytokines,³³ albeit both susbsets acquire both activities upon activation.³⁴ NK effector function is controlled by a complex network of signals, which interact with membrane-expressed inhibitory and activating receptors.³⁵

The inhibitory receptors maintain the immunological homeostasis by binding to the major histocompatibility complex (MHC) expressed on healthy cells. Downregulation of MHC class I or loss of its expression during viral infection lifts the inhibitory signal imposed on NK cells, resulting in their activation. These inhibitory receptors include C-type lectin-like receptors such as NKG2A, and the killer-cell immunoglobulin-like receptors (KIRs). Activation receptors recognize stressed ligands on virally infected and tumor cells. These receptors include NKG2D, and the natural cytotoxicity receptors (NCRs) such as NKp30, NKp44 and NKp46, among others.^36–40 NK cell activity depends on the balance between activation and inhibitory signals; when the threshold of the activation signal exceeds the inhibitory ones, then NK cells can perform their function, whether cytotoxicity or cytokine secretion, in order to eliminate virally infected cells.^33,37

It is worth mentioning that there are differences among human and murine NK cells. For instance, human NK cells express CD56 and can be classified into bright and dim subsets whereas murine NK cells do not express CD56 but instead express CD27.⁴¹ Additionally, human NK cells express KIR, but murine NK cells express Ly49 receptors which are not found in humans.⁴²

Search Strategy

Articles were searched in the literature using the keywords: multiple sclerosis, experimental autoimmune encephalomyelitis, drugs, COVID-19, and natural killer cells. These articles were checked thoroughly, and any unnecessary or irrelevant information was removed. Subsequently, included articles were used to search for a possible link between natural killer cells, COVID-19 and the action of various drugs. Research articles and reviews were included from those published in the past 15 years from papers using the keywords “COVID-19 and multiple sclerosis”, “multiple sclerosis and natural killer cells”, “drugs and multiple sclerosis and natural killer cells”, or “COVID-19 and natural killer cells”.

Role of NK Cells in Viral Infection

NK cells possess distinct ability to recognize and fight viruses by performing cytolytic activity against infected cells and by producing the antiviral cytokines.^43,44 IFN-γ affects viral replication and entry into host cells, as well as recruiting and activating other effector leukocytes, including cytotoxic T lymphocytes and CD4⁺ T helper type 1 cells.⁴⁵ NK cells are crucial in the innate immune response against various viruses including human immunodeficiency virus, herpesvirus, poxvirus, papillomavirus, hepatitis B, hepatitis C, influenza and cytomegalovirus.^{24,25,46–50} The effects of NK cells on several viral infections have been previously described and discussed in other papers.^51–55 This article will focus on the possibility that activated NK cells might protect against COVID-19 infection.

Status of NK Cells During COVID-19 Infection

Upon entry of microbial particles into the respiratory mucosa and infection of lung resident cells, a series of immune reactions take place corroborated with a cytokine storm within the body, resulting in the impairment of the coagulation system, and the generation of disseminated intravascular coagulation leading to septic shock and multi-organ disorder.⁵⁶ Lymphopenia has been reported to be associated with COVID-19 infection, indicating that SARS-CoV-2 destroys numerous immune cells and hinders the cellular immune responses. This suggests that SARS-CoV-2 might primarily act on monocytes and T cells, similar to the previously reported SARS-CoV.⁵⁷

The most crucial antiviral players are the adaptive immune system members cytotoxic CD8⁺ T lymphocytes and innate immune NK cells. In persistent/chronic viral infections, the functional activity of NK cells is impaired and worn out.⁵⁸ However, the status of NK cells in patients infected with SARS-CoV-2 is still under investigation. A recent study reported that there is a marked decrease in the total number of NK and CD8⁺ T lymphocytes in patients with COVID-19 infection.⁵⁹ Furthermore, this decrease in NK cell count was only observed in the severe COVID-19 patients in comparison to the mild cases or the healthy controls.⁵⁹ Additionally, there was an increase in the expression of the inhibitory receptor NKG2A on NK cells of COVID-19 patients, that was decreased after therapy with lopinavir/ritonavir, chloroquine phosphate, interferon, or antibiotic.⁵⁹ Hence, downregulation of NKG2A expression may be correlated with disease amelioration and therapy in COVID-19 patients. Furthermore, NK cells of COVID-19 patients displayed impaired functional activity as observed by low expression of CD107a and granzyme B, the effector molecules of cytotoxicity.⁵⁹ For cytokine secretion, IFN-γ was lower in COVID-19 patients. This was further supported by other studies where interferon responses are highly impaired in patients with severe COVID-19 infection, as indicated by low levels of interferon and interferon stimulating genes, despite the elevation in the inflammatory responses and cytokines such as TNF and IL-6.⁶⁰ IFN-γ is known to have antiviral effects, and is efficient against coronaviruses, as well as inhibiting SARS-CoV replication in vitro.⁶¹ In support of this, IFN-γ is among the highly released cytokines during COVID-19 infection.⁶²

The impairment of immune system in COVID-19 was further supported by another study where a significant decrease in the total number of lymphocytes in COVID-19 pneumonia patients was observed.⁶³ Furthermore, NK cells were found to be significantly lower in COVID-19 pneumonia patients. This alteration in the immune population and specifically of NK cells was previously reported in other pneumonia studies of the same virus family, ie, MERS-CoV and SARS-CoV.^64,65 Upon classification of cases into mild and severe ones, NK cells were found to be slightly lower in the severe cases, but this change was not statistically significant. Additionally, the percentage of NK cells was not restored after 1 week of treating pneumonia. These observations provide an insight into NK cell exhaustion during COVID-19 infection, and highlighting their vital roles in fighting against coronaviruses such as SARS-CoV-2.⁵⁹

As indicated, several reports showed that NK cells are impaired in coronavirus infections. For instance, a study by the National Research Project for SARS described a decrease in the total number of NK cells as well as in NK cells and other cells expressing KIR2DL2/L2 (CD158b) in SARS-CoV patients when compared to healthy controls and individuals infected with the bacteria Mycoplasma pneumoniae.⁶⁶ This decline in NK cell numbers was positively correlated with disease severity, as severe cases showed a larger decline in the total NK and CD158b⁺ NK cells compared to mild cases. A possible explanation for the decline in NK cells could be that these cells migrate from the circulation into the sites of infection such as the lungs. Alternatively, NK cell death could occur directly by SARS-CoV and SARS-CoV-2 as an immune evasion strategy. Hence, higher viral load might cause more NK cells to be destroyed resulting in more severe clinical symptoms.⁶⁶

NK Cells: Potential Therapeutic Target in COVID-19

Since NK cells are key anti-viral players, they could be utilized as a therapeutic tool in fighting COVID-19. A study by Osman et al reported that NK cells are not only important for the viral clearance of SARS-CoV-2 but they also limit the severe cytokine storm associated with COVID-19.⁶⁷

CYNK-001 cells are allogeneic, off-the-shelf, cryopreserved natural killer cell therapy, that are derived from placental hematopoietic stem cells. These cells are currently in clinical trials for treatment of several types of cancer including leukemia and multiple myeloma. CYNK-001 cells possess NK cell activities as demonstrated by the expression of activating receptors NKG2D, DNAM-1 and the NCRs which bind stress ligands and viral antigens on infected cells. The company “Celularity” has initiated a clinical trial to use CYNK-001 cells in a Phase 1/2 clinical trials done on 86 patients with COVID-19.^68,69 The study aimed at administering NK cells to patients with moderate-severe COVID-19 symptoms, thus allowing these killer cells to migrate towards active viral infection sites in order to aid and stimulate other immune cells. Therefore, CYNK-001 could halt the replication and eliminate SARS-CoV-2 which could be of benefit to COVID-19 patients.

NK cells have been previously modified genetically to express specific receptors to target cancer cells known as chimeric antigen receptor “CAR” NK cells.^70,71 CAR-NK cells do not cause cytokine storm unlike CAR-T cells, and are relatively safer.⁷² CAR-NK cells have been suggested to be utilized to fight viral infections such as COVID-19. These CAR-NK cells were derived from human umbilical cord blood expressing the activating receptor NKG2D and the entry receptor ACE2 (NCT04324996).⁷³ Consequently, a clinical trial using CAR-NK cells was initiated in early-stage COVID-19 patients. In addition, there is currently an ongoing clinical trial (NCT04280224) by the National Institutes of Health (NIH), with the purpose of evaluating the safety and efficiency of NK Cells in combination with standard therapy for COVID-19 pneumonia patients.

Multiple Sclerosis

Multiple sclerosis (MS) is an autoimmune-mediated disorder that is likely to affect the central nervous system (CNS) including the brain and spinal cord.⁷⁴ The pathogenesis of this disease is related to the attacks of the myelin sheath that covers the nerve fibers by the immune system, leading to nerve demyelination.^75,76 These immune cells are activated in the periphery by myelin antigens followed by the extravasation of CD4⁺, CD8⁺, B, macrophages and NK cells into the CNS.^77,78 Upon destruction, the nerve transmission could be impaired partially or completely damaged, affecting the nerval communications across the human body and causing permanent irreversible damage. A hallmark of the immune response in MS is the formation of isolated areas of inflammation called MS lesions, that may appear both in the white matter and in the grey matter of the brain.⁷⁹ The clinical signs and symptoms of MS were previously discussed and reviewed in detail.⁸⁰

There are several forms and types of MS, the most common form is the relapsing-remitting MS (RRMS), where relapses of disease are separated by remission periods without any clinical progression. When the symptoms deteriorate, ie, during relapse phase, there is an active inflammation within the CNS. As the relapse period ends, the severity of symptoms is reduced and a clinical improvement is presented, referred to as remission phase.^80,81 Other less common subtypes of MS include primary progressive MS (PPMS), affecting 15% of MS patients, where neurological deterioration is present from the onset of the disease.^80,81 On the other hand, secondary progressive MS (SPMS) occurs when patients experience episodes of relapse and remission, followed by a steady progression of the disease. Lastly, progressive relapsing MS (PRMS) is a rare type of MS that is diagnosed when the disease progresses gradually with intermittent flare-ups of worsening symptoms without periods of remission.^82,83 Although there is no cure for multiple sclerosis, the available disease-modifying agents are used in treating MS patients with the aim of shortening acute exacerbations and diminishing recurrence.^84,85

Role of NK Cells in Multiple Sclerosis

The function of NK cells in MS has is controversial, with protective and pathogenic roles in MS patients and in animal model, the experimental autoimmune encephalomyelitis (EAE).^{77,78,86–89} For instance, blocking the inhibitory receptor NKG2A on NK cells inhibited CNS inflammation and caused remission by NK cell lysis of autoreactive T cells and microglial cells.⁹⁰ Additionally, NK cells have shown a regulatory role in EAE where they can improve disease status.^91–93 NK cells possess a key regulatory function by suppression of pathogenic autoreactive T-cells that cause inflammation, hence possibly leading to restoration of the demyelination.^77,78,94 On the other hand, it was shown that NK cells in MS may contribute to CNS damage.⁹⁵ NK cells in the cerebrospinal fluid (CSF) release significant amounts of cytokine and chemokines, potentially contributing to the inflammatory process in MS.⁹⁶ It was shown that the NK cell population in the CNS consists mainly of CD56^bright NK cells, which exhibit a higher migratory potential.^97,98 Further, NK17/NK1 cells, a rare subset of NK cells, are abundant in the CSF of MS patients.^99,100 These cells secrete IL-17 and IFN-γ, two highly inflammatory cytokines, which may contribute to exaggerating the inflammatory response in the brain of MS patients.^99,100 In contrast, NK cells express the inhibitory NKG2A receptor which binds MHC class molecule HLA-E, and that NKG2A⁺ NK cells reduce CNS inflammation by lysing T cells and microglial cells, thus improving the EAE disease state.¹⁰¹ Previous data showed that active MS lesions and white matter lesions of MS patients have higher expression of HLA-E.¹⁰²

Interestingly, a recent review suggested that NK cells and specifically the CD56^bright cells are increased upon treatment with various MS therapies such as interferon-beta, dimethyl fumarate, and fingolimod.¹⁰³ Such increase in CD56^bright NK cells is associated with immunoregulatory function and could be used as a potential biomarker for treatment response in MS.¹⁰³

Effects of MS Therapy on NK Cell Activity

Glatiramer acetate (GA, Copaxone) is an approved drug for the treatment of MS, especially the RRMS.^104,105 It is made up of four amino acids, namely Glutamic acid, Alanine, Lysine and Tyrosine, that are found in myelin. It improves MS symptoms by acting as a copolymer that binds to MHC molecules and competes with myelin antigens for presentation to T cells.^104,106 Additionally, GA has been reported to activate in vitro NK cell lysis of autologous and allogeneic human immature and mature monocyte-derived dendritic cells (DCs),¹⁰⁷ and in MS patients receiving this drug.¹⁰⁸ This activity of NK cells may result in impeding auto antigen presentation to autoreactive T cells and consequently, halts inflammation. Another mechanism of the ameliorating effect of GA is the initiation of the anti-inflammatory Th2 immune activity as shown by the release of IL-5 and IL-13 cytokines,¹⁰⁹ and activation of type 2 monocytes.¹¹⁰ We previously reported that the activating NK cell receptors NKp30, NKp44, NKp46 and NKG2D were elevated, whereas the expression of CD158 receptor was reduced during a one-year follow-up of RRMS patients receiving GA therapy.¹⁰⁸ Based on GA robust activity enhancing NK cell activity in vitro, in EAE mice and in MS patients receiving this drug, we would like to advocate its use in treating COVID-19 patients.

Fumaric acid esters are a group of simple structured compounds that have been used in the treatment of inflammatory disorders including psoriasis and multiple sclerosis.¹¹¹ Dimethyl fumarate (DMF), known as Tecfidera, was approved for the treatment of RRMS.^85,112 However, the exact mechanism of action remains unknown. DMF and its metabolite monomethyl fumarate (MMF) enhance the expression of Nuclear-factor (erythroid-derived 2)-related factor-2 (Nrf2), thus showing protection of potential oligodendrocytes, glial cells, and neurons.^112,113 Recent data reported a significant increase in NK cell count during two years of DMF treatment, highlighting a crucial regulatory effect of NK cells on immune system modulation in MS.¹¹⁴

Similar to GA and DMF, monomethyl fumarate (MMF) has anti-inflammatory properties due to its ability to promote a Th2 immune response as shown by an enhanced secretion of IL-4 and IL-5.¹¹⁵ Another common feature with GA, MMF decreased the EAE clinical score along with an enhanced NK cell lysis of dendritic cells.¹¹⁶ Additionally, MMF potentiates the killing activity of NK cells of several cancer cell lines including K562, RAJI and HCT-116.^117,118 This occurs with a concomitant increase in the expression of the activating receptor NKp46, the degranulation marker CD107a and the cytolytic granzyme B.¹¹⁸ In addition, CCR10 chemokine receptor was upregulated on NK cells using GA, DMF or MMF,¹¹⁹ leading to a higher migration of NK cells towards the chemokine ligands for CCR10, which include CCl27 and CCL28.¹¹⁷ The latter chemokine is important for protection against HIV-1 infection,¹²⁰ which could plausibly be similar during COVID-19 infection. Intriguingly, both DMF and MMF exert anti-inflammatory activities, hypermethylating gasdermin D and consequently, inhibiting pyroptosis and IL-1β secretion from NK cells.¹²¹

It has been reported that there is an increase of CD56^bright NK cells in MS patients treated with DMF, which is correlated with a decrease in the number of cytotoxic T cells “CTLs”.¹²² In fact, CD56^bright NK cell enrichment takes place after six months of DMF treatment.¹²³ The relationship between increased NK cell number and activity and reduced CTLs is not clear. However, it might be plausible that such a process might give the opportunity for NK cells to perform a more robust function against virally infected cells in the absence of other cell types that could impede NK cell activity, although such hypothesis has not been examined yet.

The anti-tumor effects exerted by NK cells after pretreatment with DMF or MMF, along with the ability of these drugs to recruit NK cells towards the sites of inflammation, strongly suggest that they can be used to potentiate NK cells against COVID-19-infected cells. The fact that DMF or MMF reduced or completely inhibited inflammation also supports using these molecules in such therapy. It is plausible that DMF and MMF not only activate NK cells to fight COVID-19 infected cells, but they may also help in reducing the cytokine burst, which is the major cause of death in COVID-19 patients.

Another risk factor of MS is vitamin D₃ deficiency,¹²⁴ where it was observed that its administration prevented EAE development,^125,126 and caused less relapses in MS patients.¹²⁷ On the other hand, another study by Hupperts et al indicated that vitamin D₃ could lead to a reduction in the development of new MS lesions.¹²⁸ It was also reported that MS patients may have increased vitamin D₃ binding proteins, suggesting that such a binding protein may halt the activity of vitamin D₃ in MS patients.¹²⁹ Similar to other drugs used to treat MS patients, it was reported that vitamin D₃ and its derivative calcipotriol enhance NK cell activation and in vitro cytolysis of DCs, thus reducing antigen presentation to CD4⁺ T cells.¹³⁰ Vitamin D₃ also shifts the immune system towards Th2 immune response,¹³¹ along with an improvement in the function of Treg cells in relapsing remitting MS patients.¹³²

The drug FTY720 “fingolimod; 2-amino-2-(2-[4-octylphenyl]ethyl)-1,3-propanediol)” is an immunosuppressive drug derived from myriocin, a fungal metabolite that is similar to sphingosine. This drug has been tried on RRMS patients where it showed a reduction in MS lesions and relapse rates.^133,134 Regarding its activity on NK cells, FTY720 upregulated the expression of the activating receptors NKp30, NKp44 and NKG2D on NK cells. Moreover, FTY720 enhanced IL-2-activated NK cell lysis of immature and mature DCs, impeding autoreactive T cell activation,¹³⁰ in addition to activating NK cell lysis of tumor target cells.¹³⁵ It is worth mentioning that FTY720 is currently under clinical trial to assess the efficacy of fingolimod for treatment of COVID-19 (NCT04280588). Although not yet examined, however, it is highly plausible that FTY720 might induce robust NK cell activity in COVID-19 patients. This is based on FTY720 effects on NK cells described in vitro.¹³⁰

One of the known and established therapeutic agents for MS is interferon-β (IFN- β). IFN-β was found to alter the phenotype and activation of NK cells. For instance, IFN-β upregulated MHC class I expression, thus increasing the inhibitory signals and reducing NK cell cytotoxicity. Additionally, IFN-β expands the CD56^bright NK cells in the peripheral blood of MS treated patients.¹³⁶ This was accompanied by an alteration in their phenotype as reported by a decrease in the expression of the inhibitory LILRB1 receptor and an increase of NKG2A receptor.¹³⁷

Natalizumab (Tysabri), a drug for MS patients, is an adhesion molecule inhibitor, that blocks α4β1-integrin, a receptor which is crucial in the migration and recruitment of inflammatory activated immune cells into the CNS.⁸⁸ Upon natalizumab treatment, there was a reported increase in circulating NK cells,¹³⁸ as possible reduction in their migration capacity into the CNS.

A current drug for MS patients is ocrelizumab, an anti-CD20 monoclonal antibody that causes B cell depletion similar to rituximab. A possible mechanism of action could be upon binding to CD20, ocrelizumab triggers antibody-dependent cell-mediated cytotoxicity (ADCC) and apoptosis through NK cells.¹³⁹ Therefore, it is of interest to use natalizumab or ocrelizumab for treating COVID-19 patients where the mechanism of ocrelizumab in COVID-19 patients could be similar to its effect in lymphoma patients, ie, stimulates NK cell ADCC activity.

Concluding Remarks

In the previous sections, we highlighted the important role of NK cells in fighting viral infections especially the coronavirus family. Recent studies have shown that NK cells are impaired in number and activity during COVID-19 infection. Being important anti-viral effectors, NK cells could be vital tools for therapy of COVID-19 patients. Hence, robust activation of NK cells may be an important factor for subsiding the severity of the disease. We hypothesize that drugs used to treat MS patients such as GA, vitamin D₃, DMF, MMF, natalizumab or ocrelizumab, among others could be utilized as tools for boosting NK cell activation (Figure 1). Furthermore, studies investigating whether MS patients undertaking the above medications are less susceptible and more protected from severe complications of COVID-19 infection should be conducted. This strategy should form the basis for new therapeutic approach as the current working medications for treatment of COVID-19 include drugs that have been used for treatment of other autoimmune diseases such as rheumatoid arthritis and systemic lupus erythematosus.

Figure 1.

Multiple sclerosis drugs as potential therapeutic agents for COVID-19. Drugs such as glatiramer acetate, vitamin D₃, dimethyl fumarate, monomethyl fumarate, interferon-β, natalizumab or ocrelizumab, boost NK cell activity that could potentially eradicate SARS-CoV-2 virally infected cells.

Funding Statement

The work in the authors’ laboratory is supported by grants from Terry Fox Foundation grant number MISC051.

Abbreviations

ACE2, angiotensin converting enzyme 2; CCL, CC chemokine ligand; CNS, central nervous system; CoVs, coronaviruses; CSF, cerebrospinal fluid; CXCL, CXC chemokine ligand; DCs, dendritic cells; DMF, dimethyl fumarate; EAE, experiment autoimmune encephalitis; FTY720, fingolimod; 2-amino-2-(2-[4-octylphenyl]ethyl)-1,3-propanediol); G-CSF, granulocyte-colony stimulating factor; GA, glatiramer acetate; IFN-γ, interferon gamma; KIRs, killer immunoglobulin-like receptors; MERS-Cov, Middle East respiratory syndrome-related coronavirus; MHC, major histocompatibility complex; MMF, monomethyl fumarate; MS, multiple sclerosis; NCR, natural cytotoxicity receptors; NK cells, natural killer cells; Nrf2, nuclear-factor (erythroid-derived 2)-related factor-2; PPMS, primary progressive multiple sclerosis; PRMS, progressive relapsing multiple sclerosis; RRMS, relapsing-remitting multiple sclerosis; SARS-CoV-2/COVID-19, severe acute respiratory distress syndrome virus-19; SPMS, secondary progressive multiple sclerosis; T regs, regulatory T cells; TNF, tumor necrosis factor.

Author Contributions

Al-Ani M., Elemam N.M, Hundt J.E and Maghazachi A.A. contributed significantly to the conception, study design, execution, acquisition of data, analysis and interpretation. Al-Ani M., Elemam N.M, Hundt J.E and Maghazachi A.A. wrote and/or revised the article. All authors agreed on the journal to which the article will be submitted, and reviewed all versions of the article before submission, during revision, and the final version. All authors agree to take responsibility and be accountable for the contents of the article.

Disclosure

The authors declare that the work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The authors report no conflicts of interest for this work.