Pulmonary inflammation and injury is a frequent (and, in some instances, lethal) outcome of virus infections of the respiratory tract. Respiratory virus infection triggers a coordinated response from the host innate and adaptive immune systems. The host response is essential for virus clearance and recovery, but is also a significant cause of pulmonary injury that can accompany virus elimination. Relevant recent examples of this are the immune-mediated lung inflammation/injury observed in human infections with the SARS coronavirus and the H5N1 avian influenza viruses. The long-term goal of our ongoing research program is to understand the contribution of one component of the adaptive host response, the activated virus-specific effector T cells (Te), to virus clearance from the respiratory tract and role of Te in producing and controlling pulmonary injury. The foundation of this renewal application is the recent and unexpected findings in the murine influenza infection model that anti-viral effector T-cells (both CD4+ Te and more prominently and unexpected CD8+ Te) infiltrating the infected lungs produce high levels of the anti-inflammatory cytokine IL-10 in the respiratory tract during virus elimination and that blocking the effect of Te-derived IL-10 during infection results in increased pulmonary inflammation and lethal injury. We now want to build on these provocative observations on IL-10 production and action in the pulmonary infection and also extend this analysis to a model of direct CD8+ Te mediated pulmonary injury. This renewal application is designed to accomplish two Aims: 1. To identify the site(s) within the infected respiratory tract where Te produce IL-10, the cell type(s) stimulating Te-derived IL-10 production and the relationship between lung inflammation and IL-10 production;2. To define the mechanism through which Te-derived IL-10 regulates pulmonary inflammation and injury.
We believe that through this analysis we will gain insight into the control of pulmonary injury during virus infection of the respiratory tract. These studies may pave the way for the development of new therapeutic approaches to prevent and limit pulmonary injury produced by the host immune system.
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