RESUMO
Background/Objectives: Validated association between COVID-19 and the most obvious candidate genes, e.g. HLA, is still missing. A weak association with class I HLA-C*04:01 was found for infection in Sardinians and for severity in another mixed population. Auto-antibodies to interferon type I have been implicated in the severity of COVID-19 in two studies. Method(s): The binding affinity between HLA molecules and SARS-CoV-2 spike protein and IFNalpha subunits was evaluated in silico. The presence of antibodies against one or more of the 12 IFNalpha subunits was evaluated in 160 hospitalized COVID-19 patients. The 10 most frequent haplotypes in the Italian population were tested in 1.997 SARS-CoV-2 infected patients (hospitalized versus not hospitalized). Result(s): The presence of auto-antibodies against at least one IFNalpha subunit was detected in 26% of patients. The haplotype A*24:02-B*35:02-C*04:01-DRB1*11:04-DQB1*03:01 was found to predispose to severity (p = 0.0018;p = 0.07 after Bonferroni correction) in patients <50 years. The haplotype includes alleles able to bind spike with low affinity (i.e. C*04:01 and DRB1*11:04) and IFNalpha with high affinity (i.e. DRB1*11:04). Conclusion(s): One of the 10 most frequent ancestral haplotype of the Italian population predisposes to severity likely reducing both innate immunity through IFNalpha auto-antibodies induction and adaptive immunity through weaker spike protein presentation.
RESUMO
Extreme polymorphism of HLA and Killer-cell Immunoglobulin-like Receptors (KIR) differentiates immune responses across individuals. Additional to Tcell receptor interactions, subsets of HLA class I act as ligands for inhibitory and activating KIR, allowing natural killer (NK) cells to detect and kill infected cells. We investigated the impact of HLA and KIR polymorphism on the severity of COVID-19. High resolution HLA class I and II and KIR genotypes were determined from 403 non-hospitalized and 1,575 hospitalized SARS-CoV-2 infected patients from Italy collected in 2020. We observed that the activating KIR2DS4*001 allotype is associated with severe disease (OR = 3.74, 95% CI 1.75-9.29, pc = 0.003). KIR2DS4*001 in presence of its specific HLA ligands and inhibitory KIR3DL2*002 in absence its HLA ligand are also enriched in severe COVID-19 patients (OR = 1.64, 95% CI 1.09-2.50, p = 0.019), suggesting this combination acts in tandem to increase risk of developing severe COVID-19. We also observed the HLA class II allotype, HLA-DPB1*13:01 protects SARS-CoV-2 infected patients from hospitalization (OR = 0.49, 95% CI 0.33-0.74, pc = 0.019). These association analyses were replicated using logistic regression with sex and age as covariates. Autoantibodies against IFN-alpha associated with COVID-19 severity were detected in 26% of hospitalized patients. HLA-C*08:02 was more frequent in patients with IFN-alpha autoantibodies than those without, and KIR3DL1*01502 was only present in patients lacking IFN- alpha antibodies. We intend to expand this analysis in Greek and Spanish COVID-19 cohorts. These findings show that KIR and HLA polymorphism may play important roles in determining the clinical outcome following SARS-CoV-2 infection, by influencing the course both of innate and adaptive immunity.