key: cord-0860197-01q4pu9k authors: Yaqinuddin, Ahmed title: Cross-immunity between respiratory coronaviruses may limit COVID-19 fatalities date: 2020-06-30 journal: Med Hypotheses DOI: 10.1016/j.mehy.2020.110049 sha: 851d49424efd3853b10f802490707651bdfbefa4 doc_id: 860197 cord_uid: 01q4pu9k Of the seven coronaviruses associated with disease in humans, SARS-CoV, MERS-CoV and SARS-CoV-2 cause considerable mortality but also share significant sequence homology, and potentially antigenic epitopes capable of inducing an immune response. The degree of similarity is such that perhaps prior exposure to one virus could confer partial immunity to another. Indeed, data suggests a considerable amount of cross-reactivity and recognition by the hosts immune response between different coronavirus infections. While the ongoing COVID-19 outbreak rapidly overwhelmed medical facilities of particularly Europe and North America, accounting for 78% of global deaths, only 8% of deaths have occurred in Asia where the outbreak originated. Interestingly, Asia and the Middle East have previously experienced multiple rounds of coronavirus infections, perhaps suggesting buildup of acquired immunity to the causative SARS-CoV-2 that underlies COVID-19. This article hypothesizes that a causative factor underlying such low morbidity in these regions is perhaps (at least in part) due to acquired immunity from multiple rounds of coronavirus infections and discusses the mechanisms and recent evidence to support such assertions. Further investigations of such phenomenon would allow us to examine strategies to confer protective immunity, perhaps aiding vaccine development. Of the seven coronaviruses associated with disease in humans, SARS-CoV, MERS-CoV and SARS-CoV-2 cause considerable mortality but also share significant sequence homology, and potentially antigenic epitopes capable of inducing an immune response. The degree of similarity is such that perhaps prior exposure to one virus could confer partial immunity to another. Indeed, data suggests a considerable amount of cross-reactivity and recognition by the hosts immune response between different coronavirus infections. While the ongoing COVID-19 outbreak rapidly overwhelmed medical facilities of particularly Europe and North America, accounting for 78% of global deaths, only 8% of deaths have occurred in Asia where the outbreak originated. Interestingly, Asia and the Middle East have previously experienced multiple rounds of coronavirus infections, perhaps suggesting buildup of acquired immunity to the causative SARS-CoV-2 that underlies COVID-19. This article hypothesizes that a causative factor underlying such low morbidity in these regions is perhaps (at least in part) due to acquired immunity from multiple rounds of coronavirus infections and discusses the mechanisms and recent evidence to support such assertions. Further investigations of such phenomenon would allow us to examine strategies to confer protective immunity, perhaps aiding vaccine development. The ongoing global COVID-19 pandemic caused by the novel respiratory coronavirus SARS-CoV-2, first reported in Wuhan province in China (1), quickly spread around the world. On 11 th March 2020, the World Health Organization (WHO) officially confirmed its status as a global pandemic (2), following which COVID-19 has gone on to underlie widespread global morbidity, with >7.9 million confirmed infected cases, and >400,000 directly linked fatalities as of 14 th of June 2020 (3), with perhaps even more as an indirect consequence of this disease. (9) , and also reported that only 3000 of the 4 million pilgrims who performed Hajj in 2013 were screened for MERS-CoV with no cases reported during the pilgrimage (10, 11) . Anecdotal data from Saudi Arabia suggests that the majority of those performing both the Hajj and Umrah pilgrimages since 2012 return with 4 mild to moderate respiratory illness, which usually takes longer than two weeks to resolve, suggesting perhaps exposure to circulating bouts of viral infections. There are seven coronaviruses associated with disease in humans, which mostly amounts to mild respiratory illness. However, SARS-CoV, MERS-CoV and SARS-CoV-2 cause considerable mortality (12) . The acute lung injury seen in COVID-19 patients is perhaps due to a dysregulated innate immune response however, difference in case fatalities between different regions around the world could be due to difference in adaptive immune response due to prior exposure to coronaviruses (13, 14) . Significantly, these three viruses (SARS-CoV, MERS-CoV and SARS-CoV-2) also share significant sequence homology, potentially sharing antigenic epitopes capable of inducing an adaptive immune response. To this degree, perhaps prior exposure to one virus could confer partial immunity to another. Thus, as the majority of Asian/Middle Eastern populations have experiences repeated exposure to multiple rounds of coronavirus infections, this has perhaps facilitated the buildup of an adaptive immune response to SAR-CoV-2 exposure. This adaptive immune response could be one of the reasons for low death rates seen in this region. Before SARS-CoV, only two human coronaviruses (HCoV-229E and HCoVOC43) were known to cause mild respiratory infections and associated mortality (12, 15) . In 2004/2005, two additional CoVs were identified including HCoV-NL63 and HCoV-HKU1, respectively (16, 17) . Collectively these four CoVs are thought to underlie 15-30% of the common colds seen globally; possibly also causing severe lower respiratory tract infections in elderly and immunocompromised patients (18) (19) (20) . Typically, all coronaviruses are spherical in structure, 5 consisting of transmembrane trimeric spike (S) glycoproteins, (21) , an abundant membrane (M) glycoprotein, and transmembrane envelope (E) protein (21) . Finally, the RNA of the CoVs is bound to the nucleocapsid (N) protein in a manner resembling string-on-beads (21) . (25) . Indeed, cross reactivity is common among peptides with have sequence homology; but also between peptides with non-homologous sequences (26) (27) (28) . In the case of MHC I, TCR cross-reactivity is demonstrated between peptides of the same length, while non-homologous peptide sequences can be recognized by TCRs via hotspot recognition (29) . Plasma and B cells also produce antibodies that bind to toxins and antigens to neutralize them. Such antigen binding occurs at the fragment antigen binding (Fab) site. All antibodies are polyspecific, as their binding sites consist of several paratopes corresponding to several Bcell epitopes on antigens (30) . On average, 15 amino acids form B-cell epitopes that are mainly conformational or discontinuous and their recognition is hotspot based (31) . CD8 + T cells are 6 cytotoxic, capable of attacking and killing viruses, while CD4 + T cells activate B-cells and plasma cells to produce antibodies against infecting agents (32) . Indeed, 80% of infiltrative cells following CoV infection in the lung interstitium following CoV infection are CD8 + T cells, that are thought to be responsible for inflammatory damage to the lung (33) . In MERS-CoV infection, the T-cell response is considered more important in controlling the infection as compared to the B-cell response (34) . Indeed, in T-cell deficient mouse models, T-cells can survive and kill virus infected cells (34) , while a decrease in MERS-CoV infection corresponded to cross-reactivity of T-cell response (35) . immune mediated interstitial pneumonitis and acute lung injury. However, this depletion is not associated with viral replication at the time of SAR-CoV infection (36, 37) . In fact, reduced Tcell recruitment and decreased antibody and cytokine production during SARS-CoV infection is attributed to depletion of CD4 + T cells. MERS-CoV and SARS-CoV infection activates apoptotic pathways within T-cells, culminating in prolonged infection and increased viral survival (38, 39) . Interestingly, patients recovering from SARS-CoV seemed to exhibit a 'memory' of T-cell responses against viral structural proteins (S, M and N), that can last as long as 11 years (32) . This suggests a persistent long-term immune response against viral structural proteins which share sequence homology between SARS-CoV and SARS-CoV-2, opening doors for a common vaccine development for SARS-like viruses. Comparative analysis of B-cell and T-cell epitopes between SARS-CoV and SAR-CoV-2 using the Immune Epitope Database and Analysis Resource (IEDB) showed a high degree of 7 homology between the two viruses (40) . Grifoni CoV to SARS-CoV-2 that out of 6/10 regions exhibited more than 90% homology, while 2/10 have 80-89% identical sequences (40) . Additionally, T cell epitopes for N and M proteins are most conserved between SARS-CoV and SARS-CoV-2 (40) . In a recent study, investigators used HLA predicted peptide pools to identify circulating SARS-CoV-2 specific CD4 + and CD8 + T cells in convalescent COVID-19 patients (41), finding reactive CD4+ T cells in 40-60% of healthy controls, demonstrating cross-reactive T cell recognition in individuals previously exposed to coronaviruses like SARS-CoV-2 (41). Anderson et al used convalescent SARS sera to neutralize SARS-CoV-2 (42), demonstrating cross-neutralization of SARS-CoV-2 by neutralizing antibodies produced against SARS-CoV. Importantly, these neutralizing antibodies persisted for 9-17 years (42), further demonstrating long term immunity against SARS-CoV. Intriguingly, the neutralizing antibodies against the N protein of the two viruses was indistinguishable, suggesting of cross reactivity of antibodies against viral antigens (42). It thus seems obvious that there is a high degree of cross-reactivity between T and B cell epitopes of SARS-CoV-2 and other SARS-like viruses (41) , which is also observed between antibodies produced against the relevant viral structural proteins (43) . Perhaps the comparative lack of serious cases of COVID-19 in locations where SARS-like infections have been prevalent is due to partial immunity conferred from cross reactivity of B and T cell epitopes and antibodies. To assess this hypothesis B and T cells epitopes and antibodies against SARS like viruses need to be assessed in convalescent COVID-19 patients with mild, moderate, and 8 severe disease. Finally, longevity of SARS-CoV-2 antibodies need to be assessed to attain a better understanding of protective immunity and vaccine development. No conflict of interest is declared by authors The reproductive number of COVID-19 is higher compared to SARS coronavirus WHO Declares COVID-19 a Pandemic A major outbreak of severe acute respiratory syndrome in Hong Kong Isolation of a novel coronavirus from a man with pneumonia in Saudi Arabia Identification of a novel coronavirus in patients with severe acute respiratory syndrome Characterization of a novel coronavirus associated with severe acute respiratory syndrome Coronaviruses: severe acute respiratory syndrome coronavirus and Middle East respiratory syndrome coronavirus in travelers Case characteristics among Middle East respiratory syndrome coronavirus outbreak and non-outbreak cases in Saudi Arabia from 2012 to 2015 Prevalence of MERS-CoV nasal carriage and compliance with the Saudi health recommendations among pilgrims attending the 2013 Hajj How great is the risk of Middle East respiratory syndrome coronavirus to the global population? Human Coronavirus: Host-Pathogen Interaction Novel therapeutic targets for SARS-CoV-2-induced acute lung injury: Targeting a potential IL-1beta/neutrophil extracellular traps feedback loop Innate immunity in COVID-19 patients mediated by NKG2A receptors, and potential treatment using Monalizumab, Cholroquine, and antiviral agents Epub 2020/04/29 Genomic characterization of the 2019 novel human-pathogenic coronavirus isolated from a patient with atypical pneumonia after visiting Wuhan A previously undescribed coronavirus associated with respiratory disease in humans Characterization and complete genome sequence of a novel coronavirus, coronavirus HKU1 Human coronavirus and acute respiratory illness in older adults with chronic obstructive pulmonary disease Human Coronaviruses: A Review of Virus-Host Interactions Coronavirus 229E-related pneumonia in immunocompromised patients The molecular biology of coronaviruses PubMed Central Genome Composition and Divergence of the Novel Coronavirus (2019-nCoV) Originating in China Why must T cells be cross-reactive? A direct estimate of the human alphabeta T cell receptor diversity A single autoimmune T cell receptor recognizes more than a million different peptides Cross-reactive influenza virus-specific CD8+ T cells contribute to lymphoproliferation in virus-associated infectious mononucleosis Epub 2005/11/26 Human papillomavirus type 16 E7 peptide-directed CD8+ T cells from patients with cervical cancer are cross-reactive with the coronavirus NS2 protein Molecular basis for universal HLA-A*0201-restricted CD8+ T-cell immunity against influenza viruses Respiratory virus-induced heterologous immunity: Part of the problem or part of the solution? Specificity, polyspecificity, and heterospecificity of antibodyantigen recognition Structural analysis of B-cell epitopes in antibody:protein complexes Coronavirus infections and immune responses Rapid generation of a mouse model for Middle East respiratory syndrome Pre-and postexposure efficacy of fully human antibodies against Spike protein in a novel humanized mouse model of MERS-CoV infection Virus-specific memory CD8 T cells provide substantial protection from lethal severe acute respiratory syndrome coronavirus infection Memory T cell responses targeting the SARS coronavirus persist up to 11 years post-infection Cellular immune responses to severe acute respiratory syndrome coronavirus (SARS-CoV) infection in senescent BALB/c mice: CD4+ T cells are important in control of SARS-CoV infection Epub 2009/11/13 Bcl-xL inhibits T-cell apoptosis induced by expression of SARS coronavirus E protein in the absence of growth factors A Sequence Homology and Bioinformatic Approach Can Predict Candidate Targets for Immune Responses to SARS-CoV-2 Targets of T Cell Responses to SARS-CoV-2 Coronavirus in Humans with Disease and Unexposed Individuals. Cell. 2020. Epub 2020/05/31 Lack of cross-neutralization by SARS patient sera towards SARS-CoV-2 Epub 2020/05/10 Human neutralizing antibodies elicited by SARS-CoV-2 infection The authors acknowledge the support of Ministry of Health, Kingdom of Saudi Arabia by grant number 951