Individualized Constellation of Killer Cell Immunoglobulin-Like Receptors and Cognate HLA Class I Ligands that Controls Natural Killer Cell Antiviral Immunity Predisposes COVID-19

Maruthamuthu, Stalinraja; Rajalingam, Karan; Kaur, Neeraj; Morvan, Maelig; Soto, Jair; Lee, Nancy; Kong, Denice; Hu, Zicheng; Reyes, Kevin; Ng, Dianna; Butte, Atul J.; Chiu, Charles Y.; Rajalingam, Raja

doi:10.3389/fgene.2022.845474

Cited by 21 publications

(13 citation statements)

References 68 publications

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“…found an association between two NK cell immunoglobulin-like receptors (KIR), named KIR2DS4 and KIR3DL1, with an inhibitory and activating function, respectively, and an increased risk of severe disease ( 88 ). Another study reported a significant decrease in the inhibitory KIR receptors in COVID-19 patients compared to healthy controls and a considerable increase in activating KIR receptors in patients with a severe disease ( 89 ) ( Figure 1 ).…”

Section: The Relationship Between the Innate Immune System And The Pr...mentioning

confidence: 96%

“…In recent studies, a significant decrease has been observed in the frequency and the absolute numbers of basophils in patients with severe COVID-19 ( 82 , 92 , 93 ). Moreover, a stronger expression of programmed cell death ligand 1 (PD-L1), an inhibitor of T cell activation, has been found on basophils in severe vs. mild COVID-19, correlating with poor disease outcomes ( 89 ).…”

Section: The Relationship Between the Innate Immune System And The Pr...mentioning

confidence: 99%

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Immune responses in mildly versus critically ill COVID-19 patients

et al. 2023

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The current coronavirus pandemic (COVID-19), caused by SARS-CoV-2, has had devastating effects on the global health and economic system. The cellular and molecular mediators of both the innate and adaptive immune systems are critical in controlling SARS-CoV-2 infections. However, dysregulated inflammatory responses and imbalanced adaptive immunity may contribute to tissue destruction and pathogenesis of the disease. Important mechanisms in severe forms of COVID-19 include overproduction of inflammatory cytokines, impairment of type I IFN response, overactivation of neutrophils and macrophages, decreased frequencies of DC cells, NK cells and ILCs, complement activation, lymphopenia, Th1 and Treg hypoactivation, Th2 and Th17 hyperactivation, as well as decreased clonal diversity and dysregulated B lymphocyte function. Given the relationship between disease severity and an imbalanced immune system, scientists have been led to manipulate the immune system as a therapeutic approach. For example, anti-cytokine, cell, and IVIG therapies have received attention in the treatment of severe COVID-19. In this review, the role of immunity in the development and progression of COVID-19 is discussed, focusing on molecular and cellular aspects of the immune system in mild vs. severe forms of the disease. Moreover, some immune- based therapeutic approaches to COVID-19 are being investigated. Understanding key processes involved in the disease progression is critical in developing therapeutic agents and optimizing related strategies.

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Section: The Relationship Between the Innate Immune System And The Pr...mentioning

confidence: 96%

Section: The Relationship Between the Innate Immune System And The Pr...mentioning

confidence: 99%

Immune responses in mildly versus critically ill COVID-19 patients

et al. 2023

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“…Further protection could derive from interactions between killer-cell immunoglobulin-like receptors (KIRs), expressed on the surface of natural killer (NK) cells and their cognate human leukocyte antigen (HLA) Class I ligands ( 20 , 21 ). A recent study performed on the population of central southern Sardinia showed that KIR2DS2 in combination with HLA-C alleles of the C1 group exerts a potent protective effect against the adverse outcomes of COVID-19 ( 22 ).…”

Section: Introductionmentioning

confidence: 99%

A Protective HLA Extended Haplotype Outweighs the Major COVID-19 Risk Factor Inherited From Neanderthals in the Sardinian Population

et al. 2022

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Sardinia has one of the lowest incidences of hospitalization and related mortality in Europe and yet a very high frequency of the Neanderthal risk locus variant on chromosome 3 (rs35044562), considered to be a major risk factor for a severe SARS-CoV-2 disease course. We evaluated 358 SARS-CoV-2 patients and 314 healthy Sardinian controls. One hundred and twenty patients were asymptomatic, 90 were pauci-symptomatic, 108 presented a moderate disease course and 40 were severely ill. All patients were analyzed for the Neanderthal-derived genetic variants reported as being protective (rs1156361) or causative (rs35044562) for severe illness. The β°39 C>T Thalassemia variant (rs11549407), HLA haplotypes, KIR genes, KIRs and their HLA class I ligand combinations were also investigated. Our findings revealed an increased risk for severe disease in Sardinian patients carrying the rs35044562 high risk variant [OR 5.32 (95% CI 2.53 - 12.01), p = 0.000]. Conversely, the protective effect of the HLA-A*02:01, B*18:01, DRB*03:01 three-loci extended haplotype in the Sardinian population was shown to efficiently contrast the high risk of a severe and devastating outcome of the infection predicted for carriers of the Neanderthal locus [OR 15.47 (95% CI 5.8 – 41.0), p < 0.0001]. This result suggests that the balance between risk and protective immunogenetic factors plays an important role in the evolution of COVID-19. A better understanding of these mechanisms may well turn out to be the biggest advantage in the race for the development of more efficient drugs and vaccines.

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“…Killer cell immunoglobulin–like receptors (KIR) and associated HLA class I ligands are critical regulators of NK cell development and function. Inadequate NK cell maturation and reduced anti-SARS-CoV-2 defense are likely because of a lack of KIR3DL1 + HLA-Bw4 + and KIR3DL2 + HLA-A3 /11 + combinations, which cause COVID-19 (Maruthamuthu et al 2022 ). The KLRC2 gene encodes NKG2C, an activating NK cell receptor that interacts to HLA-E on infected cells to activate NK cells.…”

Section: Hla Associations In Sars-cov-2 Infection and Covid-19 Diseas...mentioning

confidence: 99%

The immunogenetics of COVID-19

Hollenbach

Srivastava

2022

Immunogenetics

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The worldwide coronavirus disease 2019 pandemic was sparked by the severe acute respiratory syndrome caused by coronavirus 2 (SARS-CoV-2) that first surfaced in December 2019 (COVID-19). The effects of COVID-19 differ substantially not just between patients individually but also between populations with different ancestries. In humans, the human leukocyte antigen (HLA) system coordinates immune regulation. Since HLA molecules are a major component of antigen-presenting pathway, they play an important role in determining susceptibility to infectious disease. It is likely that differential susceptibility to SARS-CoV-2 infection and/or disease course in COVID-19 in different individuals could be influenced by the variations in the HLA genes which are associated with various immune responses to SARS-CoV-2. A growing number of studies have identified a connection between HLA variation and diverse COVID-19 outcomes. Here, we review research investigating the impact of HLA on individual responses to SARS-CoV-2 infection and/or progression, also discussing the significance of MHC-related immunological patterns and its use in vaccine design.

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Individualized Constellation of Killer Cell Immunoglobulin-Like Receptors and Cognate HLA Class I Ligands that Controls Natural Killer Cell Antiviral Immunity Predisposes COVID-19

Cited by 21 publications

References 68 publications

Immune responses in mildly versus critically ill COVID-19 patients

Immune responses in mildly versus critically ill COVID-19 patients

A Protective HLA Extended Haplotype Outweighs the Major COVID-19 Risk Factor Inherited From Neanderthals in the Sardinian Population

The immunogenetics of COVID-19

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