Dissecting the role of Lyn kinase in the immune response to virus

Abstract

Influenza A virus is a major human pathogen that is caused by RNA viruses of the Orthomyxoviridae family. It causes respiratory tract infections with a range of clinical outcomes and are a considerable threat to human health. Understanding the mechanisms and the signalling pathways underlying viral infection has become an important goal in respiratory research. During an inflammatory response, immune cells must be able to communicate with one another and such communication mechanisms depend heavily on activating a series of intracellular signalling pathways necessary for removing the pathogen. The majority of intracellular signaling pathways are highly regulated by protein kinases, a family in which the Lyn tyrosine kinase belongs in. Lyn is expressed in most immune cells, except T cells and are key initiators of signal transduction. The studies in this thesis have established a role for the Lyn tyrosine kinase is regulating inflammatory cell recruitment and activation in anti-viral immune responses. Mice deficient in Lyn experienced less weight loss upon infection and show both enhanced innate and adaptive immune responses to influenza (using the influenza A viruses, Mem71 and A/PR8 virus). In addition, Lyn-/- mice also display increased cytokine gene expression. In contrast, influenza infection of mice constitutively expressing Lyn recovered less quickly, show increased morbidity and also displayed delayed immune cell kinetics and T cell responses after infection. The results in this thesis suggest that the Lyn plays an important regulatory role during anti-viral responses. Understanding the Lyn signaling pathway may allow for better understanding of the biological mechanisms controlling the pathogenesis and host immune responses to influenza and may be a target for therapeutic intervention.