Project 1

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Project Summary Pneumonic sepsis is a leading cause of morbidity and mortality worldwide and poses a major healthcare burden. Pneumonia is frequently associated with sepsis which is characterized by a non-resolving hyperinflammation. However, specific host components of the pulmonary milieu that regulate the intricate balance between pathogen clearance and perpetuation of inflammation and tissue destruction observed in this immune disorder are not clearly understood. This knowledge is critical for developing effective prevention and/or treatment strategies for this deadly immune disorder. The long term goal of the proposed research is to characterize the functioning of pulmonary innate immune components regulating the pathogen clearance and resolution of initial inflammation in a mouse model of pneumonic sepsis caused by Klebsiella pneumonia (KPn). Phagocytic cells play an important role in pathophysiology of sepsis by regulating the induction of initial protective inflammatory response to infection as well as resolution of this inflammation to restore homeostasis. Uptake and clearance of pathogen by phagocytosis and dead cells by efferocytosis are two important phagocytic cell functions; deregulation of either of these can lead to persistent inflammation as seen in sepsis. Innate immune C-type lectin receptors expressed by phagocytic cells are emerging as major players in immune regulation. Although sepsis has its origin in innate immune derangements, the role of CLRs as innate receptors in modulation of sepsis is largely unexplored. In this regard we have shown: 1) kinetic upregulation of two CLRs Clec4d and Clec4e in the lungs of KPn infected mice undergoing pneumonic sepsis; 2) increased susceptibility of Clec4d-/- and Clec4e-/- mice to KPn infection; 3) hyperinflammatory response and increased local and systemic organs burden in infected Clec4d-/- and Clec4e-/- mice; and 4) a defect in neutrophil mediated bacterial phagocytosis in the absence of Clec4e while an impairment of dead cell uptake in Clec4d deficiency. To elucidate the mechanism by which Clec4d and Clec4e play a protective role in defense against pneumonic sepsis, we are proposing to: Aim 1) Characterize Clec4e-mediated phagocytosis of KPn and the downstream events.; Aim 2) Elucidate the mechanisms of Clec4d-mediated regulation of efferocytosis and inflammation during KPn infection.; and Aim 3) Investigate the mechanism by which the early event (phagocytosis) and the late event (efferocytosis) of Clec4e- and Clec4d-mediated control of infection and inflammation are coordinated. The successful completion of these studies will not only fill a gap in our understanding of innate immune responses in pneumonic sepsis but will have implications in finding successful therapies for other immune disorders as well, where unbridled inflammation is the root cause of disease.