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Principal Investigator: Paul John Norman
Organization: UNIVERSITY OF COLORADO DENVER
Fiscal Year: 2024
Award: $706,411
Funding agency: National Institute of Allergy and Infectious Diseases
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.
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