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HLA, Immune Response, and
Susceptibility to COVID-
Fataneh Tavasolian 1 , Mohsen Rashidi 2 , Gholam Reza Hatam 3 , Marjan Jeddi 4 ,
Ahmad Zavaran Hosseini 5 , Sayed Hussain Mosawi 6,7^ , Elham Abdollahi 8
and Robert D. Inman 1,9*
(^1) Spondylitis Program, Division of Rheumatology, Schroeder Arthritis Institute, University Health Network, Toronto, ON, Canada, 2 Department of Pharmacology, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran, (^3) Basic Sciences in Infectious Diseases Research Center, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran, 4 Endocrinology and Metabolism Research Center, Shiraz University of Medical Sciences, Shiraz, Iran, 5 Department of Immunology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran, 6 Medical Sciences Research Center, Ghalib University, Kabul, Afghanistan, 7 COVID-19 Directorate, Ministry of Public Health, Kabul, Afghanistan, 8 Department of Medical Immunology and Allergy, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran, 9 Department of Medicine and Immunology, University of Toronto, Toronto, ON, Canada
The severe acute respiratory syndrome caused by Coronavirus 2 (SARS-CoV-2) that appeared in December 2019 has precipitated the global pandemic Coronavirus Disease 2019 (COVID-19). However, in many parts of Africa fewer than expected cases of COVID- 19, with lower rates of mortality, have been reported. Individual human leukocyte antigen (HLA) alleles can affect both the susceptibility and the severity of viral infections. In the case of COVID-19 such an analysis may contribute to identifying individuals at higher risk of the disease and the epidemiological level to understanding the differences between countries in the epidemic patterns. It is also recognized that first antigen exposure influences the consequence of subsequent exposure. We thus propose a theory incorporating HLA antigens, the “original antigenic sin (OAS)” effect, and presentation of viral peptides which could explain with differential susceptibility or resistance to SARS-CoV-2 infections.
Keywords: Coronavirus Disease 2019, human leukocyte antigens, original antigenic sin, immune response, vaccine design
INTRODUCTION
More than 190 countries have experienced a recent COVID-19 pandemic, especially China, South Korea, Italy, Iran, Spain, France, the United Kingdom, and growing numbers from the United States. However, Africa, with a population of >1.2 billion people, has had a comparatively low percentage of COVID-19 deaths, especially in the malaria-endemic region (1–6). There have been several hypotheses about such unexpected findings, including a relative lack of testing and
Abbreviations: SARS-CoV-2, Severe Acute Respiratory Syndrome Coronavirus 2; COVID-19, Coronavirus Disease 2019; HLA, Human Leukocyte Antigen; OAS, Original Antigenic Sin; HIV, Human immunodeficiency virus; TB, Tuberculosis; MERS, Middle-East respiratory syndrome; SARS, Severe Acute Respiratory Syndrome; S, spike; E, envelope; N, nucleocapsid; M, membrane; ARDS, Acute Respiratory Distress Syndrome; WHO, World Health Organization; HCV, Hepatitis C virus; Flu, influenza A; ERAP, Endoplasmic Reticulum Aminopeptidase; NP, nucleoprotein; AS, Ankylosing Spondylitis; RBD, Receptor- Binding Domain; MHC, Major Histocompatibility Complex; CTL, cytotoxic T cells; DAMPs, Danger-Associated Molecular Patterns; TRAP, Thrombospondin-Anonymous-Related Protein; SSP-2, Sporozoite Surface Protein -2.
Edited by: Ruchi Tiwari, U.P. Pandit Deen Dayal Upadhyaya Veterinary University, India Reviewed by: Talha Bin Emran, Begum Gulchemonara Trust University, Bangladesh Senthilkumar Natesan, Indian Institute of Public Health Gandhinagar (IIPHG), India *Correspondence: Robert D. Inman [email protected]
Specialty section: This article was submitted to Viral Immunology, a section of the journal Frontiers in Immunology Received: 01 September 2020 Accepted: 07 December 2020 Published: 08 January 2021 Citation: Tavasolian F, Rashidi M, Hatam GR, Jeddi M, Hosseini AZ, Mosawi SH, Abdollahi E and Inman RD (2021) HLA, Immune Response, and Susceptibility to COVID-19. Front. Immunol. 11:601886. doi: 10.3389/fimmu.2020.
REVIEW
published: 08 January 2021 doi: 10.3389/fimmu.2020.
documentation. The confirmation studies have suggested that most of these countries have close ties with China in terms of
trade, migration, or commerce. All of these may play a role, yet it has also been proposed that several African nations more
vigorously implemented public health policies than many other countries. Another consideration is that epidemic preparedness
may be much higher, with prior experience with Ebola, human immunodeficiency virus (HIV), tuberculosis (TB), etc. The
strong burden of endemic infectious diseases in sub-Saharan Africa, and ongoing outbreaks of Lassa fever and Ebola in
Nigeria and Congo, suggest an unpredictable and unusual response to COVID-19 (5, 7). This background illustrates the
need to utilize a range of mitigation approaches even during the pandemic to establish a broad-based response. Our hypothesis
emphasizes that HLA antigens and the OAS phenomenon could be important determinants for outcomes following SARS-CoV-
infection or vaccination (8, 9). Coronaviruses are a category of respiratory viruses that can
cause infections ranging from the common cold to Middle-East respiratory syndrome (MERS) and severe acute respiratory
syndrome (SARS). An increasing body of literature reveals that these coronaviruses are originally zoonotic, targeting the lower
respiratory tract, and causing potentially lethal inflammation in extra-pulmonary organs (10). Within two decades, there have
emerged three highly pathogenic and deadly human coronaviruses: SARS-CoV, MERS-CoV, and SARS-CoV-2 (11).
What started as a novel outbreak of atypical viral pneumonia in December 2019 in Wuhan, China is now officially recognized as
COVID-19, with the causative virus classified as SARS-CoV-2, which expresses a genomic homology of about 80% to SARS-
CoV, and lesser homology (50%) with MERS-CoV. Researchers have discovered that cross-reactive antibodies react with, but do
not confer cross-protection against, the SARS-CoV-2 receptor- binding domain (RBD) and non-RBD domains, nor is there
cross-neutralization between SARS-CoV and SARS-CoV-2 are uncommon (12–15).
SARS-CoV-2 is a single-strand RNA coronavirus composed of four main structural proteins: spike (S), envelope (E), nucleocapsid
(N), and membrane (M) proteins that induce extreme respiratory disease and an aggressive pneumonia-like infection (16). Clinical
studies have demonstrated that fever, exhaustion, dry cough, shortness of breath, and acute respiratory distress syndrome
(ARDS) are predominant clinical manifestations. Several research studies have confirmed that the severity of the infection has been correlated with lymphopenia and the development of a cytokine
storm (17).
ASSOCIATION BETWEEN HLA
AND COVID-
In humans, the HLA system orchestrates immune regulation. The
research effort, therefore, aims to identify the mechanisms that are potentially responsible for activating an immune response to
SARS‐CoV‐2, including the role of HLA alleles in affected individuals (18). It is recognized that T-cell receptors recognize
the conformational structure of the antigen binding-grove in the HLA molecule along with the accompanying antigen peptides. Thus, particular HLA haplotypes are associated with distinct genetic predispositions to disease (9, 19, 20). The repertoire of the HLA molecules composing a haplotype is thought to contribute to survival during evolution. As a result, it is advantageous to have enhanced binding capabilities of HLA molecules for viral peptides on the surface from novel viral infections, such as SARS-CoV-2, on the cell surface of antigen-presenting cells (9, 20–22). We speculate that population HLA variability in a population could be correlated with COVID-19 incidence since HLA plays such a crucial role in the immune response to pathogens and the development of infectious diseases. The HLA system affects clinical outcomes in multiple infectious diseases, including HIV and SARS (23, 24). For the latter, population studies observed correlations between certain HLA alleles and the incidence and severity of SARS (24–26). HLA-B07:03, B46:01, DRB103:01, DRB1 12:02 alleles were correlated with SARS susceptibility (27, 28). The SARS-CoV-2 sequence displays considerable homology with SARS, but the two viruses do have distinct variations (29). Therefore, it will require further investigation to incorporate HLA alleles when analyzing COVID-19 outcomes (27, 30, 31). The SARS- related susceptibility alleles were not shown to occur in COVID- patients at a significantly different level after p-value correction in the analysis performed by Wei Wang et al. in May 2020 (32). Host genetic variability may help explain the multiplicity of immune responses to a virus within a community. Knowing how variability in HLA can impact the progression of COVID-19, in particular, may help distinguish individuals at higher risk for the disease. In a study conducted by Benlyamani et al. in critically ill patients, results indicate downregulation of HLA-DR molecules in circulating monocytes, which, based on profound lymphopenia and other functional differences, create immunosuppressed conditions for host response (33). An in silico analysis of viral peptide-major histocompatibility complex (MHC) class I binding affinity was conducted by Nguyen et al, which revealed that HLA-A02:02, HLA-B15:03, and HLA- C12:03 effectively presented a larger amount of peptides whereas A25:01, B46:01, C01:02 were the least efficient for of SARS- CoV-2 peptide presentation (30). Iturrieta-Zuazo et al. indicate that Class I HLA molecules with a better theoretical capacity to bind SARS-CoV-2 peptides were found in patients with mild disease and showed higher heterozygosity as compared with moderate and severe disease (34). Thus the genetic variability of the MHC molecules can affect the susceptibility and severity of SARS-CoV-2 (35). One potential genetic contributor to the lower incidence of SARS-CoV-2 in Africa may be the occurrence of different HLA alleles in Africa compared to other regions. HLA alleles, particularly MHCI, are major elements of the presentation system for viral antigens and have been shown to impart differential viral resistance and disease intensity. Specific HLA genotypes can stimulate the T cell- mediated anti-viral response differently and could possibly alter the symptoms and transmission of the disease (36). HLA-B*46: is expected to have the fewest possible binding peptides for
new category of highly effective neutralizing antibodies was isolated, which were efficient against those four virus serotypes,
boosting hope for the development of a universal dengue vaccine. In people that are regularly immunized, either by vaccinations or
chronic infections, the specificity and efficiency of the immune response to new influenza strains are sometimes reduced (54).
The effect of antigenic sin on protection, however, has not been well characterized and seems to vary for each vaccine with the
particular pathogen, geographical region, and age.
OAS AND CYTOTOXIC T CELLS
A similar pattern in CTLs is implicated in host immunity. With a
second infection by another type of dengue virus, it has been seen that the CTLs tend to produce cytokines rather than inducing
target cell lysis. As a consequence, the production of these cytokines is suggested to enhance vascular permeability and
the destruction of endothelial cells is intensified (55). Many researchers have attempted to formulate HIV and HCV
vaccines based on the induction of host CTL response. The observation that original antigenic sin can distort the CTL response
can shed light on understanding the restricted efficacy of such vaccinations. Viruses such as HIV are extremely variable and
regularly undergo mutation. In such circumstances, a vaccine may fail to control HIV infection if the virus expresses slightly different
epitopes compared to those in the viral vaccine due to original antigenic sin. In theory, the vaccine could exacerbate the infection
by “trapping” the immune response into the initial, inefficient response to the virus (56).
Thus, an inadequate immune response to the mutated virus due to the OAS may generate a significant number of sub-neutralizing
cross-reactive antibodies that enhance inflammation and may paradoxically promote virus entry into host cells (8). The intracellular presence of the pathogen activates a pyroptosis mechanism with the subsequent release of danger-associated molecular patterns (DAMPs) to trigger additional inflammatory cells, which in response release a great number of cytokines; which may be the basis of the “cytokine storm” identified in severe cases of COVID-19 (17, 57).
IS OAS HARMFUL?
Consequentially, the OAS phenomenon can be both advantageous and detrimental to host defense. Perhaps the biggest influence of both the risks and benefits of OAS is an ever-present threat from strongly pathogenic strains of zoonotic viruses with pandemic potential. These are new pathogens for humans and it can be dangerous for any individual who does not have an element of pre-existing cross-protective immunity once a strain of this type appears. However, imprinting with a strain from the same group of phylogenies may protect against serious infection. Both the H1N pandemics of 1918 and 2009 have been accelerated by the reduced vulnerability of aging populations to cross-protection from antibodies generated to strains throughout childhood (58, 59). Also, heterosubtypic defense against highly pathogenic avian strains may rely on the year of birth, and hence the dominant strain during early life (60). This raises the possibility of a degree of protective immunity conferred by SARS-CoV and MERS-CoV- specific antibodies to decrease the susceptibility to SARS-CoV-2 in Africa by the higher prevalence of HLA-B*15:03, which has the highest strength to present strongly conserved SARS-CoV- peptides shared by common human coronaviruses. Resolving this
FIGURE 1 | In the optimal immune response (on the left) against SARS-CoV-2 and its antigenic variants, the particular adaptive immunity is often associated with (color matching) the symbolic antibody and the spike proteins that cover the outer surface of the virion; Original antigenic sin explains the propensity of the immune response to use immunological memory that relies on the previous infection when a new slightly altered strain of the foreign pathogen is identified. As we see in the OAS model (right), the particular adaptive immune response is only installed against the original virus and is not used to combat the mutated forms of the virus, leading to a less specific and less efficient maladaptive response (Created in BioRender.com) (8).
interaction may allow cross-protective T cell immunity to be derived (8, 61).
These correlations were also found between immunodominant sequences [N protein from SARS-CoV-2/SARS-CoV and
thrombospondin-anonymous-related protein (TRAP) from P. falciparum] and [S protein-SARS-CoV-2/SARS-CoV and
predicted epitope in sporozoite surface protein -2 (SSP-2) from P. falciparum]. Individually, both epitopes could induce the response
of CD8+ CTL by HLA-A*02:01 presentation (1, 2). Lesa et al. presumed that the memory of adaptive immunity elevated against
the described TRAP immunodominant epitope could recognize peptide-HLA-A*02:01 complexes originating from SARS-CoV-
infection in malaria-endemic regions, particularly in Africa, and modify the host immune system response. Of course, such an
assumption needs further empirical testing to prove its validity and ascertain the strength of the primed response (1).
VACCINE DESIGN
The creation of an efficient subunit vaccine seems to be rather
challenging in the presence of OAS and the potential adaptive mutation of SARS-CoV-2. Thus, an attractive option is to
concentrate on an alternative method of vaccination that is capable of stimulating innate immunity instead of adaptive
immunity. In children, where the immune system is immature and susceptible to challenge with new antigenic stimuli, innate
immunity may be more effective, while adaptive immunity may play are larger role in the mature immune response in adults.
This may relate to the observation that children rarely suffer fatal complications during the current COVID-19 pandemic (8, 62).
One of the representative processes of immune evasion of pathogens is to mask or alter pathogen molecules which are
usually recognized by innate pattern recognition receptors. When developing vaccines against infectious agents, there is also a need to
focus an immune response towards a particular conformational epitope (63). The approach is to develop vaccines that can provide
epitope-specific immunofocusing and induce antibodies specifically targeting epitope (64). A specific monoclonal antibody
could be used to shield the target epitope on the protein. The remaining uncovered surface proteins would then be altered to make them non-immunogenic. The epitope is eventually unprotected by eliminating the monoclonal antibody (64). The conserved immunodominant regions from Coronaviruses have implications for vaccine design against SARS-CoV-2 because of the OAS phenomenon. Research strategies must seek to maximize antibodies to conserved epitopes and induce broadly protective immunity against multiple strains. By utilizing an adjuvant vaccine, an increased cellular reaction will yield enhanced host protection benefits (65).
CONCLUSION
The clinical course of infection with SARS-CoV-2 is strongly dependent on the relationship between the virus and the host immune system, in which the host HLA plays a central role in the activation and regulation of the immune response. There is scope for further study into the role of HLA in COVID-19, and epidemiological studies need to focus on HLA profiles as host immune determinants. Such studies should include HLA typing of COVID-19 patients, both to unravel the complexity of the disease response and also to inform customized therapies. In addition, a prior history of coronavirus infection in the patient can be relevant to the magnitude of the immune response to the current SARS-CoV-2 infection, a phenomenon referred to as “original antigenic sin”. This concept refers to cross-reacting immunity due to past infections of similar coronavirus strains, which must be considered in interpreting immune responses to infections and vaccinations.
AUTHOR CONTRIBUTIONS
All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.
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Conflict of Interest: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Copyright © 2021 Tavasolian, Rashidi, Hatam, Jeddi, Hosseini, Mosawi, Abdollahi and Inman. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
