Approved Research

To determine if specific combinations of natural killer cell receptor and ligand allotypes predispose to severe disease following infection with influenza virus.

Lay summary

Influenza is a widespread pathogen resulting in 3 to 5 million infections per year with an estimated 290 - 650K of these infections causing death. Initial infection with viral pathogens is controlled by a fast-acting innate immune response of which natural killer cells (NK-cells) play an important role. Interactions between killer cell immunoglobulin like receptors (KIR), found on NK-cells, and their cognate ligands, the human leukocyte antigens, found on most other cell types, control early viral infections, and trigger a wider immune response. Expression of KIR3DL1 gives NK cells the ability to detect diseased cells that may have lost or altered expression of these HLA class I molecules. In turn when infected cells are identified through interactions between KIR3DL1/S1 and viral epitopes displayed by HLA molecules, these cells are destroyed thus controlling infection. Genes encoding KIR3DL1/S1 and HLA class I are some of the most diverse in the human genome and immunogenetic diversity of KIR3DL1/S1 and HLA class I has been associated with outcomes of viral infections. HLA-A*24:02, for example, has been associated with poor outcomes of influenza infection. Polymorphisms in KIR3DL1 affect the specificity and strength of interactions with HLA. KIR3DL1*005 shows ligand specificity and responsiveness to A*24:02. The contribution of alleles of KIR3DL1/S1 to outcome of influenza remains unknown. The goal of this study is to determine if there are association between alleles of KIR3DL1/S1 and HLA-A and -B with patient outcomes of infection with influenza. Outcome will be measured as hospitalization resulting from the infection. This will be accomplished by conducting a case control study of patients hospitalized with influenza infection and those who are not. We will obtain HLA-A and HLA-B alleles from the UK Biobank. KIR3DL1/S1 alleles will be determined from WG-SNP data using an imputation software called PONG that we have developed and rigorously tested. We anticipate the duration for this project being three months. This work aims to provide a deeper understanding for the contribution of immunogenetic diversity of KIR3DL1/S1 and HLA-A and -B to outcomes of infection with influenza. Knowing genetic factors that contribute to severe infection can be used an assessing the initial aggressiveness of treatment plan for patients upon infection. Also, understanding the genetic contribution of KIR3DL1/S1 and HLA-A and -B to severe infections give us a better insight into how the innate immune system functions to control disease and inflammation.