Summary To ensure a successful and sustained response to the COVID-19 crisis it becomes imperative that the functional implications of the considerable genotypic and phenotypic variation in natural human immunity are understood. Natural killer (NK) cells have major roles in controlling the innate and adaptive immune response to viral infections, including herpesviruses, HIV-1, influenza, and SARS. NK cells comprise a significant part of the front-line defense against pathogen invasions and are present at large numbers in lung tissues. NK cell effector functions, including cytokine release and cytotoxicity, are modulated by interactions of killer cell immunoglobulin-like receptors (KIR) with class I human leukocyte antigens (HLA) expressed on tissue cells. Across individuals, there is enormous diversity in the number and nature of viable receptor and ligand pairs and within individuals, there is a multitude of NK cell subsets distinguished by their receptors. Previous studies of epidemic diseases have identified clear relationships between this diversity and susceptibility, resistance or control of infection. Likely reflecting exposure throughout human history to multiple, diverse and geographically discrete pathogens, the HLA and KIR genes are highly variable across individuals and population groups. These genetic variations have direct impact on NK cell functions and the response to infection. Allotype-dependent interactions of KIR with HLA inform, modulate and diversify NK cells in their role of identifying and eliminating virus-infected tissue cells. Consideration of the full extent of this variation across human populations is thus critical to understanding, diagnosing and treating SARS-CoV-2 infection, and for developing and testing vaccines. The overarching hypothesis that we will investigate is that genetic variation of HLA and KIR can determine the course of immunity following SARS-CoV-2 infection, leading to severe COVID-19 in some individuals. The first Aim of our study will examine a large multi-ethnic cohort of 11,500 SARS-CoV-2 infected patients, to determine the association of HLA and KIR genetic diversity with severity of disease. The cohorts are drawn from the countries hardest hit by the pandemic, including Brazil, Italy, Spain, UK and the USA. NK cells recognize infected cells through loss of ligands for inhibitory receptors or gain of ligands for activating receptors. Many viruses are known to exploit any or all of these mechanisms to evade immune detection. The second Aim will examine the role of SARS-CoV-2 derived proteins in evading NK cell driven immune responses, and how this varies across all known HLA and KIR allotype interactions. NK cells can be activated by antibodies that are bound to virus segments on the surface of infected cells, and we have shown this activity is also dependent on HLA and KIR diversity. The final Aim will therefore examine the role of antibody-dependent elimination of SARS-CoV-2 infected cells, and the impact of KIR and HLA polymorphism on this response. Validating our approach, our preliminary findings already identified one potential therapeutic target. Our findings will thus have immediate consequence for identifying individuals most at risk for developing severe COVID-19, for developing both universal and personalized treatment, and to aid in vaccine design.

R01AI158410

2021-09-01

2025-08-31