Even with currently available antibiotics, bacterial pneumonia is a significant cause of morbidity and mortality in influenza pandemics and epidemics. Influenza infection typically induces IFN production in the lung; however, multiple studies have demonstrated that both type 1 and type 2 IFN are detrimental to innate antibacterial immunity after influenza. The intracellular protein Suppressor Of Cytokine Signaling 1 (SOCS1) is a feedback inhibitor of IFN/STAT1 signaling. Interestingly, preliminary studies show that rather than preventing the detrimental effect of IFNs, SOCS1 enhances host susceptibility to secondary pneumococcal infection. Accordingly, the major goal of this application is to identify cellular and molecular factors directly involved in SOCS1-dependent exacerbation of secondary bacterial infection. The central hypothesis is that after influenza infection, SOCS1 modulation of lung immune environment impairs host innate defense against secondary pneumococcal infection. To test this hypothesis, Specific Aim 1 will determine the impact of influenza-induced SOCS1 on lung cytokine response and antibacterial immunity;
and Specific Aim 2 will determine the role of cellular SOCS1 in T cells and alveolar macrophages during post-influenza pneumococcal infection. The long- term goal of this research is to identify targets and therapeutics to reverse this susceptibility to secondary bacterial pneumonia in humans.
A frequent sequela of influenza infection is secondary bacterial pneumonia. Even with currently available antibiotics, bacterial pneumonia is a significant cause of morbidity and mortality in influenza pandemics and epidemics. The objective of this project is to investigate how SOCS1 protein, a feedback inhibitor of cytokine signaling, exacerbates subsequent bacterial infection, and thereby provide the basis for identifying novel therapeutic targets for prevention of these infectious diseases in humans.
