key: cord-334603-yt2pmxi3 authors: de Sousa, Eric; Ligeiro, Dário; Lérias, Joana R.; Zhang, Chao; Agrati, Chiara; Osman, Mohamed; El-Kafrawy, Sherif A; Azhar, Esam I; Ippolito, Giuseppe; Wang, Fu-Sheng; Zumla, Alimudin; Maeurer, Markus title: Mortality in COVID-19 disease patients: Correlating Association of Major histocompatibility complex (MHC) with severe acute respiratory syndrome 2 (SARS-CoV-2) variants date: 2020-07-18 journal: Int J Infect Dis DOI: 10.1016/j.ijid.2020.07.016 sha: doc_id: 334603 cord_uid: yt2pmxi3 Abstract As the 2019 (COVID-19) pandemic caused by the novel coronavirus, SARS-CoV-2 spreads globally, differences in adverse clinical management outcomes have been associated with associated with age >65years, male gender, and co-morbidities such as smoking, diabetes, hypertension, cardiovascular comorbidity and immunosuppression. Ethnicity has been the focus of attention after data from the United Kingdom showed a disproportionate number of deaths among healthcare workers from black, Asian and other ethnic minority backgrounds (1). In addition to ethnicity, socio-economic factors, prior vaccinations and exposure to other coronaviruses, other factors need to be considered to explain geographical and regional variations in susceptibility, severity of clinical expression of COVID-19 disease and outcomes. In the United States there have been disproportionate COVID-19 death rates among African Americans at around 2.6 times higher than that of other groups. Although these data could be due to multiple cultural and socioeconomic factors an underlying genetic susceptibility to SARS-CoV-2 infection may be a factor. As the 2019 (COVID-19) pandemic caused by the novel coronavirus, SARS-CoV-2 spreads globally, differences in adverse clinical management outcomes have been associated with associated with age >65years, male gender, and co-morbidities such as smoking, diabetes, hypertension, cardiovascular comorbidity and immunosuppression. Ethnicity has been the focus of attention after data from the United Kingdom showed a disproportionate number of deaths among healthcare workers from black, Asian and other ethnic minority backgrounds (1). In addition to ethnicity, socio-economic factors, prior vaccinations and exposure to other coronaviruses, other factors need to be considered to explain geographical and regional variations in susceptibility, severity of clinical expression of COVID-19 disease and outcomes. In the United States there have been disproportionate COVID-19 death rates among African Americans at around 2.6 times higher than that of other groups. Although these data could be due to multiple cultural and socioeconomic factors an underlying genetic susceptibility to SARS-CoV-2 infection may be a factor. Genetic factors were thought to play a causative role in the pathogenesis of the SARS outbreak in 2003 in a group of Taiwanese patients, where the HLA-B*4601 haplotype was associated with severity of SARS infection (2) . In Hong Kong Chinese patients a strong association was shown J o u r n a l P r e -p r o o f between HLAB* 0703 and HLA-DRB1*0301 alleles and an increased susceptibility to SARS infection (3) . In contrast, L-SIGN homozygote individuals seem to have a significantly lower risk of SARS infection (4) . Generally, peripheral blood lymphocytes counts of black Americans show lower neutrophil counts and proportionally higher frequency of lymphocytes compared to the rest of the population (5). HLA-association studies of SARS-CoV-1 with HLA-ligands for SARS-CoV-2 have been compiled (6) . The biological and clinical relevance of immune responses to SARS-CoV-2 requires further discussion: 1. Autoimmune associations with COVID-19. Some individuals with COVID-19 experienced neurological symptoms, e.g. Guillain Barre Syndrome (7), suggesting an autoimmune background, which has been associated with MHC alleles (8) . The role of MHC variants in increased susceptibility to infections or, vice versa, immune protection is well known for a number of viral diseases, e.g. the role of MHC alleles in HIV-control, or increased risk for chronic hepatitis B (9). dampens autoimmune responses and confers protection from type I Diabetes (10) (11) associated with strong IFN-production. HLA-DQB1*06:02 has been selected for increased resistance to Yersinia pestis in immigrants from Africa to Europe, engagement of CD4+ T-cells to HLA-DQB1*06:02 leads to increased, pro-inflammatory IL-17 production, independent of the MHC class II presented peptides (12) and confers increased risk to the development of anti-myelin directed autoimmune responses (13) . The haplotypes HLA-DR2-DQ6, DR4-DQ8, and DR3-DQ2 accommodate peptides from infectious pathogens to CD4+ T-cells from Europeans who survived the bottleneck of different, life-threatening infections prevalent in Europe (9). These alleles have also shown to be associated with increased risk for autoimmune diseases, for instance to dietary antigens (celiac disease) (14) in part due to their intrinsic capacity to stimulate stronger IL-17 production, that facilitates Central Nervous System (CNS)associated disease manifestations (15) . (33) . We used for this prediction a 33 residue peptide with the mutation site in the middle (VNKITYGACPKYVKQNTLKLATGMRNVPEKQTR) and thebest fitting peptide with 15 residues that was predicted to binds to HLA-DRB1*04:01, is exactly the peptide reported earlier (33) recognized by a Flu epitope specific T-cell clone. In contrast, the variant (T314K) peptide does not bind ( Table 1) . (40), type 1 diabetes (41, 42) , and Lyme disease induced arthritis (43) . DRB1*09:01 is associated with early childhood myasthenia gravis (44) . DRB3*02:02 is linked to Grave's disease (44) , serum IgG antibodies to Chlamydia pneumoniae with essential hypertension (45) and acute necrotizing encephalopathy (46) In conclusion, there appears to be no selective pressure from MHC class I alleles for SARS-CoV-2 variants tested. Most likely there is selective pressure from MHC class II alleles in regard to binding of the ORF8 (L84S) variants assuming that this mutation may be biologically relevant (25, 26) . This data underlines the need to examine SARS-CoV-2 variants and MHC-associations along with clinical outcomes, a detailed longtime observation with a particular focus on CNS-associated symptoms, particularly in individuals with increased risk to develop autoimmune responses. Is ethnicity linked to incidence or outcomes of covid-19? Association of HLA class I with severe acute respiratory syndrome coronavirus infection Association of human-leukocyteantigen class I (B*0703) and class II (DRB1*0301) genotypes with susceptibility and resistance to the development of severe acute respiratory syndrome Homozygous L-SIGN (CLEC4M) plays a protective role in SARS coronavirus infection Black/white differences in leukocyte subpopulations in men HLA studies in the context of coronavirus outbreaks Guillain-Barre syndrome associated with SARS-CoV-2 infection: causality or coincidence? 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National Science Review TepiTool: A Pipeline for Computational Prediction of T Cell Epitope Candidates Peptide binding predictions for HLA DR, DP and DQ molecules NetMHCIIpan-3.0, a common pan-specific MHC class II prediction method including all three human MHC class II isotypes Quantitative predictions of peptide binding to any HLA-DR molecule of known sequence: NetMHCIIpan A review of HLA allele and SNP associations with highly prevalent infectious diseases in human populations Chemistry of peptides associated with MHC class I and class II molecules Structure of a complex of the human alpha/beta T cell receptor (TCR) HA1.7, influenza hemagglutinin peptide, and major histocompatibility complex class II molecule, HLA-DR4 (DRA*0101 and DRB1*0401): insight into TCR cross-restriction and alloreactivity Balancing selection and heterogeneity across the classical human leukocyte antigen loci: a meta-analytic review of 497 population studies Association of HLA-DRB1/DQB1 polymorphism with high-risk HPV infection and cervical intraepithelial neoplasia women from Shanghai Impact of Host Molecular Genetic Variations and HIV/HPV Co-infection on Cervical Cancer Progression: A Systematic review DRB1*03/DRB3*0101, and DRB3*0202 are susceptibility genes for Graves' disease in North American Caucasians, whereas DRB1*07 is protective E6 and E7 Gene Polymorphisms in Human Papillomavirus Types-58 and 33 Identified in Southwest China Multiple sclerosis and autoimmune diseases: epidemiology and HLA-DR association in North-east Italy Analysis of HLA DP, DQ, and DR allesles in adult Italian rheumatoid arthritis patients Genes for insulin-dependent diabetes mellitus (IDDM) in the major histocompatibility complex (MHC) of African-Americans HLA-encoded genetic predisposition in IDDM: DR4 subtypes may be associated with different degrees of protection Identification of LFA-1 as a candidate autoantigen in treatment-resistant Lyme arthritis A variant of childhood-onset myasthenia gravis: HLA typing and clinical characteristics in Japan Association of HLA-DRB3*0202 and serum IgG antibodies to Chlamydia pneumoniae with essential hypertension in a highly homogeneous population from Majorca Molecular analysis of HLA class IIassociated susceptibility to neuroinflammatory diseases in Korean children HLA-DPB1 and HLA class I confer risk of and protection from narcolepsy DNA methylation as a mediator of HLA-DRB1*15:01 and a protective variant in multiple sclerosis Professor Ippolito, Sir Zumla and Prof Mohamed Osman are co-investigators investigators of the Pan-African Network on Emerging and Re-emerging Infections (PANDORA-ID-NET) funded by the European and Developing Countries Clinical Trials Partnership the EU Horizon 2020 Framework Programme for Research and Innovation. Sir Zumla is in receipt of as UK-NIHR senior investigatorship. Professor Maeurer is a member of the innate immunity advisory group of the Gates Foundation and his work is funded by the Champalimaud Foundation. All authors are members of the Global Cancer and Infectious Diseases consortium for Host-directed therapies: Weblink: https://fchampalimaud.org/covid19/aci