An immunogenetic view of COVID-19

Abstract

Meeting the challenges brought by the COVID-19 pandemic requires an interdisciplinary approach. In this context, integrating knowledge of immune function with an understanding of how genetic variation influences the nature of immunity is a key challenge. Immunogenetics can help explain the heterogeneity of susceptibility and protection to the viral infection and disease progression. Here, we review the knowledge developed so far, discussing fundamental genes for triggering the innate and adaptive immune responses associated with a viral infection, especially with the SARS-CoV-2 mechanisms. We emphasize the role of the HLA and KIR genes, discussing what has been uncovered about their role in COVID-19 and addressing methodological challenges of studying these genes. Finally, we comment on questions that arise when studying admixed populations, highlighting the case of Brazil. We argue that the interplay between immunology and an understanding of genetic associations can provide an important contribution to our knowledge of COVID-19.

Figure 1 -. Features of severe COVID-19 and acute respiratory distress syndrome (ARDS) in the lung. SARS-CoV-2 enters the body by the airways and infects lung cells (1). Immune cells, including macrophages (2), and the infected cells (3) react to the virus and produce cytokines, interferons, and additional inflammatory signals (4), which attract other leukocytes. These also produce cytokines (5) that may lead to hyper inflammation and the “cytokine storm” (6). The inflamed capillaries allow fluid to sweep into the alveoli and fill the lung cavities (7). Damage to the lung occurs through several processes, including the consequences of surfactant loss (8), the accumulated liquid, and the formation of fibrin and scar tissue (9). With the participation of complement components, coagulation factors, neutrophils, and platelets, blood clots are formed in the inflamed blood vessel (10). The association between thromboembolic events and higher levels of von Willebrand’s factor (vWF) and factor VIII with non-group O (see main text) may underlie the association of blood group A with increased susceptibility to severe COVID-19. The deregulated immune response and disturbed coagulation spark inflammation throughout the body damaging other organs and fuels the respiratory failure responsible for most deaths caused by COVID-19. Moreover, the virus may evade the immune response by blocking the effect of immune cells and soluble as well as membrane-bound mediators of immunity and complete its cycle in infected cells, spreading throughout the body. Figure created with Biorender.

Figure 2 -. Global distribution of HLA alleles that are either strong or weak binders of SARS-CoV-2 epitopes. Upper left panel: The frequency of the predicted SARS-CoV-2 strong binder HLA-B*15:03 is high in African populations (usually > 8%) and rare among Europeans, Asians, and Americans. Lower left panel: The frequency of the predicted SARS-CoV-2 weak binder HLA-B*14:02 is high in American populations, particularly Brazil, and also among European and Africans. Upper right panel: The frequency of the cosmopolitan allele A*24:02. Lower right panel: The frequency of the Asian-restricted B*46:01 allele. Frequency data were obtained from the Brazilian and 1000 Genomes high-coverage sequencing data processed with specific HLA bioinformatics workflow (Naslavsky et al., 2020), and from the allelefrequencies.net website (Gonzalez-Galarza et al., 2020).

Figure 3 -. Predicted HLA involvement in T cell, B cell, and NK cell responses to SARS-CoV-2 infection. Left: T and B cells are central to adaptive immunity, whose effectivity is influenced by the individual’s HLA genotype. (1a) Dendritic cells (DC) present viral peptides bound to HLA Ia and HLA II to, respectively, CD8+ and CD4+ T cell clones displaying specific TCR. (1b) The effector cytotoxic CD8+ T cell recognizes the infected target cell by interaction of its specific receptor (TCR) with HLA Ia/peptide on the target and lyses the infected cell. (2a) B cells bind viral antigens through specific membrane immunoglobulin receptors (BCR). The internalized antigens go through the class II pathway and HLA II plus viral peptide displayed at the B cell membrane are recognized by the previously primed helper CD4+ T cell to activate the B cells. (2b) The activated B cells differentiate in antibody-secreting plasma cells. The neutralizing specific antibodies bind to the virus’s antigen, blocking the viral entry into the cell. Other types of antibodies (not shown) may bind to viral antigens at the surface of infected cells to recruit NK cells or trigger the complement cascade. Besides, all the cell-cell interactions indicated in this schematic view depend on signals by accessory membrane molecules (not shown) and soluble factors such as interferons and specific sets of cytokines. Right: The natural killer cells (NKc) are important players in innate immunity. NKc repertoires differ among individuals due to the high polymorphism ofKIRandHLAclass I, resulting in differential susceptibility to infection and disease. (3a) Each individual has numerous NK cell clones that differ for the number and types of inhibitory and activating KIR receptors. (3b) During NKc development, the high-affinity binding of inhibitory KIRs (iKIR) with HLA class I (HLA I) enhances the functions of NKc through a process known as licensing. The strength of the interactions depends on the individual’s HLA and KIR genotype and dictates the efficiency of mature NK effector function. (4a) The KIR/HLA I interaction inhibits apoptosis of the infected cells even in the presence of activating interactions, especially of NKc licensed by strong interactions; (4b) signaling by the activating receptor/ligand leads to apoptosis of the infected target cell when HLA I is absent; (4c) strong activating signals may overcome the iKIR/HLA I interaction especially if this interaction is weak, resulting in apoptosis of the target. Moreover, in severe COVID-19, NKc often are reduced in number and dysregulated. Figure created with Biorender.

Figure 4 -. Some critical molecules involved in antiviral innate immune response, whose loss-of-function mutations and polymorphisms may result in severe COVID-19. SARS-CoV-2 entry into the cell is mediated by TMPRSS2 (transmembrane protease, serine 2) and the receptor ACE2 (angiotensin-converting enzyme 2). (1) The interferon-induced transmembrane proteins (IFITM) may inhibit the entry of viruses to the host cell cytoplasm. (2) The interferon-induced GTP-binding protein MXA may block endocytic traffic of incoming virus particles. (3) The 2’-5’-oligoadenylate synthase 1 (OAS1) binds ribonuclease L (RNase L) leading to its activation with subsequent degradation of the viral and cellular RNA, thus terminating viral replication. (4) Toll-like receptors 3 and 7 (TLR3, TLR7) recognize viral RNA leading to activation and (5) nuclear translocation of transcription factors NF-kappa-B (NF-kB) and IFN regulatory factors 3 and 7 (IFR3, IRF7). (6) IFR3 and IRF7 regulate the transcription of type I IFN genes (IFN-alpha and IFN-beta) and IFN-stimulated genes (ISG); NF-kB is a pleiotropic transcription factor crucial for regulation of numerous genes involved in immunity and other biological processes, such as apoptosis. (7) The lysosomal enzymes digest viral components in the phagolysosome. (8) Type I and III (IFN-lambda) interferons, NF-kB, and cytokines promote expression of numerous genes involved in innate and adaptive immune responses in different cells, including (9) up-regulation of HLA gene expression in antigen-presenting cells. Figure created with Biorender.