The influence of MAIT cells and host genomic risk factors on dengue infection

Abstract

Dengue virus (DENV) is a rapidly emerging pathogen causing an estimated 100 million symptomatic infections annually. The clinical spectrum of dengue disease is broad ranging from asymptomatic to death. Factors contributing to differential outcome of DENV disease are not entirely understood. However, variation in host genetics and in the immune response are thought to play an important role in dengue pathogenesis. In this thesis, the influence of host genetics and of a recently discovered unconventional T cell, called Mucosal Associated Invariant T (MAIT) cell, on DENV infection were investigated. MAIT cells are abundant in humans and recognise bacterial ligands. For the first time, activation of MAIT cells was observed during a human viral infection in vivo and in vitro. This activation was TCR independent but dependent on IL-18. Furthermore, levels of IL-18 and MAIT cell activation correlated with disease severity in DENV infected patients. Upon activation, MAIT cells were able to enhance or inhibit DENV infection of various target cells in vitro mediated by IFN-γ. These findings suggest a possible mechanism for how MAIT cell activation may contribute to both antiviral defence and immunopathology during DENV infection. As high viremia is associated with disease severity, the influence of host genetic variants on the susceptibility of two target cells – primary human DCs and macrophages - on DENV infection was investigated using a systems genetics approach. In DCs and macrophages, expression levels of 93 and 3 genes showed strong correlations with the inter-individual variation in infection rates, respectively. These results may lead to the discovery of unknown host genomic risk factors for DENV susceptibility. Overall, understanding the role of MAIT cells during DENV infection as well as identifying new host genomic risk factors for DENV susceptibility are crucial to better understand dengue pathogenesis and may help generate therapeutic agents in the future.

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