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 SPninfection. 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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI042240-03
Application #
6170696
Study Section
Bacteriology and Mycology Subcommittee 2 (BM)
Program Officer
Klein, David L
Project Start
1998-04-01
Project End
2003-03-31
Budget Start
2000-04-01
Budget End
2001-03-31
Support Year
3
Fiscal Year
2000
Total Cost
$97,566
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
168559177
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
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