HLA-C dysregulation as a possible mechanism of immune evasion in SARS-CoV-2 and other RNA-virus infections

Abstract

One of the mechanisms by which viruses can evade the host’s immune system is to modify the host’s DNA methylation pattern. This work aims to investigate the DNA methylation and gene expression profile of COVID-19 patients, divided into symptomatic and asymptomatic, and healthy controls, focusing on genes involved in the immune response. In this study, changes in the methylome of COVID-19 patients’ upper airways cells, the first barrier against respiratory infections and the first cells presenting viral antigens, are shown for the first time. Our results showed alterations in the methylation pattern of genes encoding proteins implicated in the response against pathogens, in particular the HLA-C gene, also important for the T-cell mediated memory response. HLA-C expression significantly decreases in COVID-19 patients, especially in those with a more severe prognosis and without other possibly confounding co-morbidities. Moreover, our bionformatic analysis revealed that the identified methylation alteration overlaps with enhancers regulating HLA-C expression, suggesting an additional mechanism exploited by SARS-CoV-2 to inhibit this fundamental player in the host’s immune response. HLA-C could therefore represent both a prognostic marker and an excellent therapeutic target, also suggesting a preventive intervention that conjugate a virus-specific antigenic stimulation with an adjuvant increasing the T-cell mediated memory response.

Molecular Understanding of ACE-2 and HLA-Conferred Differential Susceptibility to COVID-19: Host-Directed Insights Opening New Windows in COVID-19 Therapeutics

“…The HLA system plays a vital role in the viral antigen presentation pathway, influencing differential viral susceptibility and disease severity. HLA inhibits pathogens, allowing the infected person to trigger an effective immune response against infection [ 62 ].…”

“…In vaccine development, the consequential epitopes of B and T cells of SARS-CoV-2, and their association with HLA alleles, can contribute to the development of protective antibodies against SARS-CoV-2 infection [ 82 ]. HLA-C*01 and HLA-B*44 are potential molecular determinants in evaluating an individual’s risk of COVID-19, and genotyping of class I and II HLA in COVID-19 patients can identify individuals at a higher risk of a cytokine storm [ 62 ]. The HLA-C*01 and B*44 allele pathways can significantly aid in understanding disease transmission, physiopathogenesis, and play a significant role in managing COVID-19 disease, vaccination, and other preventive strategies in terms of clinical management [ 62 ].…”

“…HLA-C*01 and HLA-B*44 are potential molecular determinants in evaluating an individual’s risk of COVID-19, and genotyping of class I and II HLA in COVID-19 patients can identify individuals at a higher risk of a cytokine storm [ 62 ]. The HLA-C*01 and B*44 allele pathways can significantly aid in understanding disease transmission, physiopathogenesis, and play a significant role in managing COVID-19 disease, vaccination, and other preventive strategies in terms of clinical management [ 62 ]. Peptide cocktail vaccines produced by using various epitopes constrained by the HLA-A2 molecule provoke substantial specific CD8+ T cell responses against SARS-CoV-2 in experimental animals [ 83 ].…”