key: cord-0788005-1smwu5lj authors: Saulle, Irma; Vicentini, Chiara; Clerici, Mario; Biasin, Mara title: Antigen presentation in sars-cov-2 infection: the role of class i hla and erap polymorphisms date: 2021-05-10 journal: Hum Immunol DOI: 10.1016/j.humimm.2021.05.003 sha: 3d1a88fc47c20ca313d9746a69fd96295b6a313c doc_id: 788005 cord_uid: 1smwu5lj Given the highly polymorphic nature of Human Leukocyte Antigen (HLA) molecules, it is not surprising that they function as key regulators of the host immune response to almost all invading pathogens, including SARS-CoV-2, the etiological agent responsible for the recent COVID-19 pandemic. Several correlations have already been established between the expression of a specific HLA allele/haplotype and susceptibility/progression of SARS-CoV-2 infection and new ones are continuously emerging. Protective and harmful HLA variants have been described in both mild and severe forms of the disease, but considering the huge amount of existing variants, the data gathered in such a brief span of time are to some extent confusing and contradictory. The aim of this mini-review is to provide a snap-shot of the main findings so far collected on the HLA-SARS-CoV-2 interaction, so as to partially untangle this intricate yarn. As key factors in the generation of antigenic peptides to be presented by HLA molecules, ERAP1 and ERAP2 role in SARS-CoV-2 infection will be revised as well. Infectious diseases are still a significant challenge for public health worldwide, as they are responsible for millions 3 of deaths, mainly, but not only, among older adults and immunosuppressed or chronically ill people. The 4 virulence of the pathogen and the efficacy of the host immune response are the key factors conditioning the 5 onset and progression of infectious diseases. In the context of adaptive immunity, a pivotal role in protection 6 and recovery from infections is played by CD8+ T lymphocytes (Woon and Purcell, 2018) . These cells detect 7 antigenic peptides bound by major histocompatibility complex (MHC) class I molecules, known as the human 8 leukocyte antigen (HLA) class I in humans, and work through different pathways in order to eradicate the 9 pathogen and the infected cells. 10 Given the major role played by CD8+ T cells in host immunity, it is conceivable that plenty of studies have tried 11 to decipher the consequences of a jam in CD8+ T cell activation in their response to pathogens. In this setting, 12 since the very first report establishing a correlation between HLA-B27 and Ankylosing Spondylitis (Brewerton et 13 al., 1973; Schlosstein et al., 1973) , the MHC has been recognized as the region of the genome that is associated 14 with the highest number of human diseases (Trowsdale and Knight, 2013) . For this same reason, allelic variants 15 and altered MHC expression have been associated with disease severity following infection with several 16 microbes. In parallel, aminopeptidases -in particular endoplasmic reticulum aminopeptidase 1 (ERAP1), ERAP2 17 and partly insulin-regulated aminopeptidase (IRAP) -have drawn the scientific attention as well. Indeed, they 18 are responsible for antigenic peptide trimming within the ER, thus conditioning the antigen processing pathway 19 (Saveanu et al., 2005a) in both physiological and pathological contexts including those mediated by infectious 20 agents, among which severe acute respiratory disease coronavirus 2 (SARS-CoV-2) (Saulle et al., 2020b). Since SARS-CoV-2 outbreak, the pathogen responsible for COronaVIrus Disease 19 , the scientific 22 community has tried to identify those factors controlling the susceptibility/outcome of the disease and playing parasite, SARS-CoV-2 replicates inside the host cells exploiting nucleic acid and protein synthesis mechanisms to 28 facilitate its spreading from one individual to another. The biology of the virus, its infectious and replicative cycle, 29 as well as the human host factors directly or indirectly contributing to its maintenance/annihilation within cells 30 have been exhaustively described elsewhere (Schurr, 2020; V'kovski et al., 2021) . Throughout these phases, viral 31 proteins can be unfolded, degraded and further processed by cytosolic and nuclear proteasomes inside host 32 cells; the resulting peptides, 8-16 amino acid long, are then transported into the endoplasmic reticulum (ER) by 1 transporter associated with antigen processing (TAP). Herein, they are further trimmed by ERAP1 and ERAP2 2 proteins in order to achieve the optimal length to be loaded onto the clefts of MHC class I molecules. In turn, 3 MHC class I molecules, by loading intracellular compartment-derived antigens, provide a recapitulation of the 4 events occurring inside the cell, thus allowing CD8+ T cells to monitor possible ongoing infections ( Figure 1 ). The results obtained suggest that patients exhibiting a mild form of the disease presented HLA class I molecules Since the very first identification of allele specific motifs for T-cell antigens by HLA class I molecules, in 1991, 25 epitope identification and characterization has been significantly simplified by in silico prediction strategies (Falk 26 et al., 1991) . Indeed, many ongoing vaccines designs, targeting infectious pathogens, have been exploiting 27 prediction algorithms, whose accuracy is progressively improving. Nevertheless, these tools present some Within the Endoplasmic Reticulum (ER), ERAP1 and ERAP2 cleave the N-terminus of precursor peptides, 24 previously processed in the cytoplasm by the proteasome, so as to generate antigenic peptides of 8-9 amino acid 25 residues, which perfectly accommodate within the binding groove of MHC I molecules. These two proteins act in concert but their activity is not redundant as they maintain marked differences in their 27 enzymatic specificity. ERAP1 preferentially cleaves peptides with lysine, leucine, asparagine and tyrosine residues 28 (Serwold et al., 2001) and shows a strong tendency to cut 9-16 amino acids peptides into pieces of 8-9 amino indirect, yet crucial involvement in the anti-microbial response ( Figure 1) immune responses against viral proteome in its entirety (Gilbert, 2012) . In addition, a recent study states that 22 robust cellular immunity against SARS-CoV-2 is likely to be present within the great majority of adults at six 23 months following asymptomatic and mild to moderate infection. 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