COVID-19 News: Study Finds That HLA-DPB1*013:01 Protects Against Developing Severe COVID-19 While KIR2DS4*001 Worsens Infections!

COVID-19 News: The COVID-19 pandemic has affected millions of lives globally, with a wide range of symptoms and disease severity observed among those infected with the SARS-CoV-2 virus. From asymptomatic cases to severe respiratory illness and even death, the outcome of a COVID-19 infection can vary significantly.


 
Recent research conducted by the University of Colorado School of Medicine, USA, in collaboration with the University of Turin, University of Siena, and Azienda Ospedaliera Universitaria in Italy, has shed light on the genetic factors that influence the severity of COVID-19. This groundbreaking study delves into the intricate interplay between two sets of genes, HLA (Human Leukocyte Antigen) and KIR (Killer-Cell Immunoglobulin-Like Receptors), and their impact on immune responses to the SARS-CoV-2 virus.
 
Past COVID-19 News reports have shown that various other HLA Allele polymorphisms also play a role in SARS-CoV-2 infection outcomes.
 
https://www.thailandmedical.news/news/breaking-news-scientist-discover-that-the-common-allele-hla-b-15-01-is-associated-with-asymptomatic-sars-cov-2-infection
 
https://www.thailandmedical.news/news/swiss-study-uncovers-that-hla-variants-and-t-cell-receptor-tcr-diversity-play-a-role-in-covid-19-infection-outcomes
 
https://www.thailandmedical.news/news/covid-19-world%E2%80%99s-first-hla-i-immunopeptidome-study-of-sarscov-2-infected-human-cell-lines-by-harvard-university-reveals-alarming-details
 
HLA and KIR: The Genetic Foundations of Immune Responses
The human immune system is a marvel of complexity and precision, with a multitude of factors at play. The class I and class II HLA molecules, encoded by a highly polymorphic set of genes, play a critical role in guiding immune responses. These molecules present peptide fragments to CD8+ and CD4+ T cells, enabling the immune system to identify and eliminate infected cells while triggering the production of antibodies. Additionally, some HLA alleles interact with KIR, receptors expressed by natural killer (NK) cells and certain T cells, allowing them to detect and target infected cells. HLA and KIR genes are among the most polymorphic genes in the human genome, and their diversity significantly impacts susceptibility to infectious diseases and autoimmunity.
 
NK cells, a type of lymphocyte, are integral to immune responses against viral infections. They have the capacity to identify and eliminate virus-infected cells, influencing both innate and adaptive immunity. The balance of inhibitory and activating signals received by NK cells from various cell surface receptors, particularly inhibitory KIR, significantly influences their function. These inhibitory KIR play a central role in educating NK cells, allowing them to recognize the loss of HLA class I molecules on infected cells. In the context of severe COVID-19, the gene expression profile of NK cells skews towards pro-inflammatory cytokine production. Additionally, the number and function of peripheral NK cells in COVID-19 patients are often reduced, particularly in severe cases. This suggests that the function of NK cells, vital for early immune responses, is compromised in severe COVID-19 patients. The production of pro-inflammatory cytokines, including interferon-α (IFN-α), can also influence NK cell function during SARS-CoV-2 infection, further complicating the immune response.
 
The interplay between HLA and KIR genes is influenced by the combinatorial diversity that arises during genetic inheritance, as HLA and KIR genes are encoded on separate chromosomes. The KIR genomic region is marked by gene presence/absence, copy number variation, allele variability, and haplotypic diversity. Any of these factors can significantly impact NK cell functions. These receptors bind to HLA ligands via their extracellular immunoglobulin-like domains, and the presence of inhibitory or activating KIR transduces signals that modulate NK cell function. Importantly, these interactions can influence a subset of NK cells with notable cytolytic activity and cytokine secretion.
 
COVID-19 Severity and HLA/KIR Polymorphism
Previous research has indicated that the HLA variants associated with COVID-19 severity can vary among different populations. While initial genome-wide association studies (GWAS) did not identify HLA variability in disease susceptibility, more recent studies, particularly in the UK, have shown that certain HLA variants, such as HLA-DRB1*04:01, can protect against severe disease. KIR genes, on the other hand, have been less amenable to GWAS studies.
 
Nevertheless, the presence and absence polymorphism of KIR have been associated with COVID-19 severity, and varying levels of KIR expression by NK cells have been linked to specific clinical outcomes. Due to various limitations, such as HLA genotyping methods, sample size, population diversity, and different clinical outcome assessments, the role of combined HLA and KIR polymorphism in determining COVID-19 severity has remained elusive.
 
In this context, the current study sought to analyze the diversity of HLA and KIR genes in a large Italian cohort, comprising both hospitalized and non-hospitalized COVID-19 patients. The primary objective was to investigate how these genetic variations might impact NK cell function following SARS-CoV-2 infection. Furthermore, the study aimed to assess the presence of autoantibodies against IFN-α, which are associated with COVID-19 severity, in hospitalized patients.
 
HLA-DPB1*013:01: A Shield Against Severe COVID-19
In the analysis of the HLA polymorphism's impact on COVID-19, the researchers considered high-resolution genotyping of 11 HLA genes, encompassing highly polymorphic HLA class I (HLA-A, -B, -C), less polymorphic HLA class I (HLA-E, -F, and -G), and HLA class II (HLA-DPA1, -DPB1, -DQA1, -DQB1, -DRB1) genes. The results revealed the presence of 96 HLA alleles with frequencies exceeding 2% in the cohort.
 
For the less polymorphic HLA class I genes, there were no significant differences in allele frequencies with respect to disease severity. However, among the highly polymorphic HLA class I genes, HLA-B08:01 and -C07:01 were more common in non-hospitalized patients, while -C*07:02 was more frequent in hospitalized patients. These differences, while not statistically significant after correction for multiple comparisons, suggest a potential role for HLA-B and HLA-C in COVID-19 outcomes.
 
Notably, the analysis of HLA class II alleles revealed a compelling finding. HLA-DPB113:01 was associated with protection from severe COVID-19, with individuals carrying this allele having a significantly reduced risk of hospitalization. The association remained robust even when other variables like sex, age, and ethnicity were taken into account. HLA-DPB113:01 was also linked to less severe outcomes, including a lower likelihood of needing mechanical breathing assistance, intubation, or death. These findings have far-reaching implications, especially for populations where the frequency of HLA-DPB1*13:01 is higher, such as in East Asian and South American Amerindian populations. The protective effect of this allele suggests that certain HLA class II variants can significantly impact the course of SARS-CoV-2 infection.
 
Peptide Binding Properties of HLA-DPβ1*13:01
Antibodies against viral proteins play a crucial role in controlling infections, including SARS-CoV-2. These antibodies are produced in response to viral peptides presented by HLA molecules. HLA-DPβ113:01 was found to be associated with protection against severe COVID-19, prompting further investigation into its unique properties. In silico analysis of peptide binding revealed that HLA-DPβ113:01 demonstrated a preference for peptides derived from viral proteins, including SARS-CoV-2 spike and nucleocapsid proteins.

This observation underscores the significance of the immune response guided by HLA class II molecules, particularly HLA-DPβ113:01. The specific peptides presented by HLA-DPβ113:01 are likely to evoke protective antibody responses, contributing to the decreased risk of severe disease observed in individuals carrying this allele.
 
KIR2DS4*001: A Risk Factor for Severe COVID-19
The genetic diversity of KIR genes, and their interactions with HLA molecules, can significantly influence NK cell function. In the current study, the presence and absence of inhibitory and activating KIR genes were considered in the cohort. The results suggested that individuals with KIR2DS4*001, a specific activating KIR gene, had an increased risk of severe COVID-19. Patients carrying this gene were more likely to be hospitalized and exhibited a higher risk of death.
 
KIR2DS4001 encodes an activating KIR2DS4 receptor, which may enhance NK cell function, potentially leading to increased inflammation and tissue damage in response to SARS-CoV-2 infection. This study highlights that the impact of KIR polymorphism on COVID-19 severity is complex, as other activating KIR genes did not show similar associations. Additional research is needed to fully elucidate the mechanisms through which KIR2DS4001 influences the immune response during COVID-19.
 
Autoantibodies Against IFN-α: A Distinct Pathway to Severe COVID-19
Autoantibodies against interferon-α (IFN-α) have emerged as a crucial factor in COVID-19 severity. These autoantibodies impede the antiviral response by neutralizing IFN-α and other type I interferons, impairing the body's ability to defend against viral infections. The presence of these autoantibodies was detected in hospitalized COVID-19 patients, revealing a statistically significant difference between hospitalized and non-hospitalized individuals.
 
Interestingly, the presence of autoantibodies against IFN-α showed no correlation with either HLA-DPB113:01 or KIR2DS4001. This suggests that the mechanisms underlying the protection associated with HLA-DPB113:01 and the risk linked to KIR2DS4001 are independent of IFN-α autoantibodies. These findings emphasize the multi-faceted nature of COVID-19 pathogenesis and underscore the importance of considering different factors that contribute to severe outcomes.
 
Implications for Future Research and Therapeutics
The findings from this comprehensive study on the genetic foundations of immune responses to COVID-19 have several significant implications. First, the protective role of HLA-DPB113:01 and the risk associated with KIR2DS4001 highlight the impact of HLA class II and KIR polymorphism on disease outcomes.
 
These genetic factors may serve as predictive markers for COVID-19 severity and could inform vaccination strategies and therapeutic approaches. Developing an in-depth understanding of the peptides presented by HLA-DPB1*13:01 may enable the design of vaccines that evoke similar antibody responses, potentially protecting individuals who do not carry this allele.
 
Moreover, the identification of autoantibodies against IFN-α as an independent risk factor for severe COVID-19 further highlights the need for early detection and management of these autoantibodies, especially in hospitalized patients.
 
Therapeutic interventions that target the neutralization of these autoantibodies or boost IFN-α responses may prove beneficial in mitigating disease severity.
 
While the study provides valuable insights into the complex interplay of HLA and KIR genes with COVID-19 outcomes, further research is essential to confirm these associations across diverse populations and to elucidate the mechanisms underlying the observed effects. As we continue to battle the COVID-19 pandemic, understanding the genetic factors influencing disease severity is an essential component in our efforts to develop effective prevention and treatment strategies.
 
The study findings were published in the peer reviewed journal: HLA - Immune Response Genetics (Wiley).
https://onlinelibrary.wiley.com/doi/10.1111/tan.15251
 
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