| Summary: | <p>This thesis investigates the role of monocytes in mouse and human influenza A virus (IAV) infection and questions how they contribute to immunopathology. I first show in mice that Ly6C<sup>hi</sup> monocytes are dominant immune cells in the lungs during severe IAV infection. Comparison of the gene expression profiles in lungs of severe or mild IAV infection revealed enrichment of genes related to monocyte recruitment in severe disease, which were more rapidly expressed than in mild infection. There was also less representation of M2 macrophage polarisation genes in lungs during severe disease.</p> <p>In human IAV infection, inflammatory monocytes and neutrophilic MDSCs were higher in fresh blood samples in severe compared to mild disease; but only monocyte frequency was specific to IAV infection. There were less IL-10 producing monocytes and more IL-6<sup>+</sup>TNFα<sup>-</sup> producing monocytes in severe compared to mild infection, and HLA-DR was markedly reduced on these monocytes. Increase in monocytes, but not neutrophilic MDSC, was sustained throughout infection and into recovery. Frequency of monocytes correlated with differentiation states of CD8<sup>+</sup> T cells, and there was a negative association between iNKT cells and inflammatory monocytes in blood.</p> <p>Focusing on the interaction between iNKT cells and monocytes, I questioned if monocyte number and function were regulated by iNKT cells. Using iNKT deficient mice (Jα18<sup>-/-</sup>) and deriving monocytes from blood and lungs following IAV infection and comparing to wild-type mice, I showed that iNKT cells influenced diverse monocyte characteristics including apoptosis, M1/M2 polarisation and inflammasome activation. Induction of monocyte apoptosis by activated iNKT cells was investigated in vitro as a possible mechanism by which activated iNKT cells controlled monocyte numbers.</p> <p>This thesis established the role of monocytes in IAV immunopathology and provides a rationale for further studies in amelioration of monocyte number in severe IAV infection.</p>
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