Background:
Tuberculosis is an international public health crisis, significantly worsened by the COVID-19 pandemic.
Tuberculosis(TB) is the leading cause of death from an infectious agent (mycobacterium tuberculosis:Mtb), causing 1.4 million deaths and over 10 million infections annually. The recent COVID-19 pandemic has created a harmful TB syndemic.
NK cells can kill Mtb but are tightly regulated.
Natural killer(NK) cells are innate immune cells that play a protective role during Mtb infection by directly killing Mtb and lysing Mtb-infected cells. Their effector functions, however, are tightly regulated by activating and inhibitory receptors.
CD49a + NK cells exist in the lung but their role during infection is yet to be defined.
Tissue-resident NK cell subsets, that express different receptors to those in the blood, populate the liver and the lung.We have shown that liver-resident NK cells have an enhanced ability to regulate CD8+ T cell activation yet the role of lung-resident NK cells during respiratory infection is unknown. Lung NK cells express the integrin CD49a which has been shown to functionally differentiate skin-resident T cells into IFN-γ and IL-17 producers in the skin. We hypothesise that a similar dichotomy is at play in the lung with CD49a+ and CD49a- NK cells having distinct roles in the defence against TB.
Hypothesis:CD49a⁺ and CD49a⁻ lung-resident NK cells have distinct immune responses to Mtb infection, and their receptors can be therapeutically targeted to enhance NK-mediated immunity against respiratory diseases such as TB.
Aim:To define how human lung-resident NK cells respond to infection with Mtb.
Objectives:
1.Phenotype NK cell populations in human bronchoalveolar lavage(BAL) samples.
2.Investigate how CD49a influences the metabolism, cytokine production, and cytotoxicity of BAL-NK cells in response to Mtb.
Expected outcome:This project will clarify the functional roles of CD49a-defined NK subsets in the human lung and identify potential NK-directed therapeutic targets for TB.