Interferon and Host Response to Pneumococcal Infection

Despite the availability of vaccines and antibiotics, morbidity and mortality due to SPn infection have increased due to the emergence of antibiotic-resistant bacteria and an increasing pool of susceptible hosts with HIV infection and other immunocompromising conditions. Even in immunocompetent patients, the early mortality due to invasive SPn infection is refractory to antibiotic therapy and intensive care support. Immunomodulatory therapies to stimulate natural host defenses may prove valuable adjuncts to improving the outcome from this common and serious infection. We have shown preliminary that interferon-gamma (IFN-G), a key immunomodulator of host defenses against nonviral pathogens, is produced in response to SPn bacteremia in mice and that this cytokine plays a functionally significant role in murine host immunity against this potentially lethal infection. The objective of this proposal is to fully characterize the role of interferon-G (IFN-G) in the early pathogenesis of invasive SPn infection. We specifically propose to: 1. Define the regulation of IFN-G production during SPn infection, by completing preliminary studies characterizing IFN-G levels in serum and lung during invasive SPn infection, defining the cellular source of IFN- G (NK cells, CD4+ and CD8+ cells), defining the bacterial components (cell wall, penumolysin) that stimulate IFN-G production, and characterizing the production of cytokines which stimulate IFN-G production (IL-12) and TH2 cytokines which downregulate IFN-G production (IL-4 AND IL-10). 2. Characterize the mechanism by which IFN-G protects against SPn disease, by demonstrating that IFN-G production is functionally significant in vivo, and by defining lung or splenic NK cells or tissue macrophages as target cells for IFN-G during invasive SPn infection. 3. Determine if immunomodulatory therapy with IFN-G protects against invasive SPn infection, by assessing the effect of IFN- G therapy on survival of mice and on bacterial clearance from lung and blood.