Structure-based modeling of SARS-CoV-2 peptide/HLA-A02 antigens

Abstract

11As a first step toward the development of diagnostic and therapeutic tools to fight the Coronavirus 12 disease , it is important to characterize CD8+ T cell epitopes in the SARS-CoV-2 13 peptidome that can trigger adaptive immune responses. Here, we use RosettaMHC, a comparative 14 modeling approach which leverages existing high-resolution X-ray structures from peptide/MHC 15 complexes available in the Protein Data Bank, to derive physically realistic 3D models for high- 16affinity SARS-CoV-2 epitopes. We outline an application of our method to model 439 9mer and 17 279 10mer predicted epitopes displayed by the common allele HLA-A*02:01, and we make our 18 models publicly available through an online database (https://rosettamhc.chemistry.ucsc.edu). As 19 more detailed studies on antigen-specific T cell recognition become available, RosettaMHC 20 models of antigens from different strains and HLA alleles can be used as a basis to understand the 21 link between peptide/HLA complex structure and surface chemistry with immunogenicity, in the 22 context of SARS-CoV-2 infection. 24An ongoing pandemic caused by the novel SARS coronavirus (SARS-CoV-2) has become the 25 focus of extensive efforts to develop vaccines and antiviral therapies (1). Immune modulatory 26 interferons, which promote a widespread antiviral reaction in infected cells, and inhibition of pro-27 inflammatory cytokine function through anti-IL-6/IL-6R antibodies, have been proposed as 28 possible COVID-19 therapies (2, 3). However, stimulating a targeted T cell response against 29 specific viral antigens is hampered by a lack of detailed knowledge of the immunodominant 30 epitopes displayed by common Human Leukocyte Antigen (HLA) alleles across individuals 31 (public epitopes). The molecules of the class I major histocompatibility complex (MHC-I, or HLA 32 in humans) display on the cell surface a diverse pool of 8 to 15 amino acid peptides derived from 33 the endogenous processing of proteins expressed inside the cell (4). This MHC-I restriction of 34 peptide antigens provides jawed vertebrates with an essential mechanism for adaptive immunity: 35 surveillance of the displayed peptide/MHC-I (pMHC-I) molecules by CD8+ cytotoxic T-36 lymphocytes allows detection of aberrant protein expression patterns, which signify viral infection 37 and can trigger an adaptive immune response (5). A recent study has shown important changes in 38 T cell compartments during the acute phase of SARS-CoV-2 infection (6), suggesting that the 39 ability to quantify antigen-specific T cells would provide new avenues for understanding the 40 (which was not certified by peer review) : bioRxiv preprint 2 expansion and contraction of the TCR repertoire in different disease cohorts and clinical settings. 41Given the reduction in breadth and functionality of the naïve T cell repertoire during aging (7), 42 identifying a minimal set of viral antigens that can elicit a protective response will enable the 43 design of diagnostic tools to monitor critical gaps in the T cell repertoir...

Predicting the Immunogenicity of T cell epitopes: From HIV to SARS-CoV-2

“…Only a fraction of SARS-CoV-2 peptides that bind to HLA molecules are immunogenic Many research groups have identified peptides derived from SARS-CoV-2 that can bind with HLA molecules (Ahmed, Quadeer and McKay, 2020;Campbell et al, 2020;Grifoni et al, 2020;Nerli and Sgourakis, 2020;Prachar et al, 2020). Two different approaches were employed.…”

“…In one approach, peptides that bind to different HLA molecules were identified based on experimental assays (Ahmed, Quadeer and McKay, 2020;Prachar et al, 2020). In the other approach, bioinformatic tools were used to identify peptides that bind to HLA molecules (Campbell et al, 2020;Grifoni et al, 2020;Nerli and Sgourakis, 2020). We used our trained classifier to predict the immunogenicity of peptides that were determined to bind to different HLA molecules experimentally, as reported by Ahmed et al (Ahmed, Quadeer and McKay, 2020) and Prachar et al (Prachar et al, 2020).…”

“…Moreover, these shared peptides are associated with a limited set of HLA molecules, thus providing poor coverage of the global population. Ahmed et al (Ahmed, Quadeer and McKay, 2020) and Prachar et al (Prachar et al, 2020), among other groups (Campbell et al, 2020;Nerli and Sgourakis, 2020;Prachar et al, 2020), also identified SARS-CoV-2 peptides that are capable of binding to HLA molecules, either based on MHC binding assay results or bioinformatic methods. By doing this, they identified a large pool of SARS-CoV-2 peptides that are associated with diverse HLA molecules, which cover a broad cross-section of the global population.…”

Computationally validated SARS-CoV-2 CTL and HTL Multi-Patch vaccines, designed by reverse epitomics approach, show potential to cover large ethnically distributed human population worldwide

“…On the other hand, the multi-epitope vaccine involves fusion of multiple epitopes identified from the proteome of the SARS-CoV-2 by short peptide linkers. Several subunit and multi-epitope-based vaccine designs have been published claiming potential to activate CD4 and CD8 T-cell immune response driving long-term robust adaptive immunity in the vast majority of the population (Abdelmageed et al, 2020 ; Ahmed et al, 2020 ; Akhand et al, 2020 ; An et al, 2000 ; Banerjee et al, 2020 ; Baruah & Bose, 2020 ; Bhattacharya et al, 2020 ; Fast & Chen, 2020 ; Gragert et al, 2013 ; Gupta et al, 2020 ; Herst et al, 2020 ; Ismail et al, 2020 ; Khan et al, 2020 ; Lee & Koohy, 2020 ; Liu et al, 2020 ; Lu et al, 2014 ; Mitra et al, 2020 ; Nerli & Sgourakis, 2020 ; Poran et al, 2020 ; Ramaiah & Arumugaswami, 2020 ; Saha & Prasad, 2020 ; Sheikhshahrokh et al, 2020 ; Singh et al, 2020 ; Srivastava et al, 2020a ; 2020b ; Ul Qamar et al, 2020 ; Vashi et al, 2020 ; Yarmarkovich, Farrel et al, 2020; Yazdani et al, 2020 ). Numerous highly antigenic regions have also been reported from SARS-CoV-2 proteins, which have been recognized with a large population coverage by favorable binding with large number of HLA allele distributed among different ethnic human population across the world (Grifoni et al, 2020b ; Yarmarkovich, Warrington, et al, 2020 ).…”

Computationally validated SARS-CoV-2 CTL and HTL Multi-Patch Vaccines designed by reverse epitomics approach, shows potential to cover large ethnically distributed human population worldwide

“…All the three CTL and two HTL MPVs were fitting into the ectodomain region of TLR3 receptor (Figure 7). T cell immune response driving long-term robust adaptive immunity in the vast majority of the population (Abdelmageed et al, 2020;Ahmed et al, 2020;Akhand et al, 2020;An et al, 2000;Banerjee et al, 2020;Baruah et al, 2020;Bhattacharya et al, 2020;Fast et al, 2020;Gragert et al, 2013;Gupta et al, 2020;Herst et al, 2020;Ismail et al, 2020;Khan et al, 2020;Lee et al, 2020;Liu et al, 2020;Lu et al, 2014;Mitra et al, 2020;Nerli et al, 2020;Poran et al, 2020;Ramaiah et al, 2020;Saha et al, 2020;Sheikhshahrokh et al, 2020;Singh et al, 2020;Srivastava et al, 2020a;Srivastava et al, 2020b;ul Qamar et al, 2020;Vashi et al, 2020;Yazdani et al, 2020). Numerous highly antigenic regions have also been reported from SARS-CoV-2 proteins which have been recognized on the basis of large population coverage by favorable binding with large number of HLA allele distributed amongst different ethnic human population worldwide (Grifoni et al, 2020b;Yarmarkovich and Warrington et al, 2020).…”