Klebsiella pneumoniae is a leading cause of community-acquired and nosocomial infections. Moreover, K pneumoniae is the second leading cause of nosocomial gram negative bacteremia. The recent emergence of multi-antibiotic resistant strains of K pneumoniae due to extended-spectrum B-lactamase (ESBL) production is cause for significant clinical concern. Interestingly, antibiotic resistance appears to be more prevalent in blood isolates than from other sources. While the innate host response towards gram-negative bacterial infections has been characterized, little is known about gamma delta-T cells and their role in these infections. Our preliminary studies indicate that gamma delta-T cell knockout (KO) mice have significantly impaired early expression of pulmonary and hepatic IFN-gamma and TNF-alpha mRNA following intratracheal K. pneumoniae infection, increased blood bacterial dissemination, and increased hepatic bacterial burden subsequent to the initial pulmonary infection. Additional studies indicate increased mortality following intravenous bacterial inoculation in gamma delta-T cell KO mice and uncontrolled blood bacterial growth. Combined, our preliminary data suggest gamma delta-T cell KO mice succumb from an impaired ability to clear disseminated bacteria rather than from an inability to clear the organism from the primary pulmonary infection. The hypothesis of this proposal is that gamma delta T cells play a critical role in the host acute inflammatory response during gram-negative bacteremia via recognition of heat shock protein 60 expression in the liver following infection. A murine model of blood-borne K pneumoniae infection will be used to perform the following Specific Aims: 1)To contrast the host response in gamma delta T cell knockout and wildtype mice during K pneumoniae bacteremia, 2) To assess the kinetics of gamma delta T cell A) recruitment and activation and B) cytokine production during K pneumonia bacteremia, 3) To reconstitute resistance to K pneumoniae in gamma delta T cell knockout mice by adoptive transfer of gamma delta T cells from wildtype and cytokine deficient (IFN-gamma or TNF-alpha) mice, 4) To confer resistance to K. pneumoniae in gamma delta T cell knockout mice by TNF-alpha or IFN-gamma reconstitution using systemic adenovirus gene therapy, and 5) To assess the requirement of heat shock protein 60 for gamma delta T cell activation during K. pneumoniae bacteremia. These studies will provide insights for the development of therapeutic modalities aimed at augmenting host responses, resulting in enhanced resolution of bacterial infections.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI049448-05
Application #
6847437
Study Section
Immunological Sciences Study Section (IMS)
Program Officer
Taylor, Christopher E,
Project Start
2001-04-01
Project End
2006-08-31
Budget Start
2005-03-01
Budget End
2006-08-31
Support Year
5
Fiscal Year
2005
Total Cost
$260,680
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Cogen, Anna L; Moore, Thomas A (2009) Beta2-microglobulin-dependent bacterial clearance and survival during murine Klebsiella pneumoniae bacteremia. Infect Immun 77:360-6
Lau, Helen Y; Huffnagle, Gary B; Moore, Thomas A (2008) Host and microbiota factors that control Klebsiella pneumoniae mucosal colonization in mice. Microbes Infect 10:1283-90
Lau, Helen Y; Clegg, Steven; Moore, Thomas A (2007) Identification of Klebsiella pneumoniae genes uniquely expressed in a strain virulent using a murine model of bacterial pneumonia. Microb Pathog 42:148-55
Lindell, Dennis M; Moore, Thomas A; McDonald, Roderick A et al. (2006) Distinct compartmentalization of CD4+ T-cell effector function versus proliferative capacity during pulmonary cryptococcosis. Am J Pathol 168:847-55
Lindell, Dennis M; Ballinger, Megan N; McDonald, Roderick A et al. (2006) Immunologic homeostasis during infection: coexistence of strong pulmonary cell-mediated immunity to secondary Cryptococcus neoformans infection while the primary infection still persists at low levels in the lungs. J Immunol 177:4652-61
Lindell, Dennis M; Moore, Thomas A; McDonald, Roderick A et al. (2005) Generation of antifungal effector CD8+ T cells in the absence of CD4+ T cells during Cryptococcus neoformans infection. J Immunol 174:7920-8
Moore, Thomas A; Lau, Helen Y; Cogen, Anna L et al. (2005) Defective innate antibacterial host responses during murine Klebsiella pneumoniae bacteremia: tumor necrosis factor (TNF) receptor 1 deficiency versus therapy with anti-TNF-alpha. Clin Infect Dis 41 Suppl 3:S213-7
Kolodsick, Jill E; Toews, Galen B; Jakubzick, Claudia et al. (2004) Protection from fluorescein isothiocyanate-induced fibrosis in IL-13-deficient, but not IL-4-deficient, mice results from impaired collagen synthesis by fibroblasts. J Immunol 172:4068-76
Moore, Thomas A; Lau, Helen Y; Cogen, Anna L et al. (2003) Anti-tumor necrosis factor-alpha therapy during murine Klebsiella pneumoniae bacteremia: increased mortality in the absence of liver injury. Shock 20:309-15
Zeng, Xianying; Moore, Thomas A; Newstead, Michael W et al. (2003) Intrapulmonary expression of macrophage inflammatory protein 1alpha (CCL3) induces neutrophil and NK cell accumulation and stimulates innate immunity in murine bacterial pneumonia. Infect Immun 71:1306-15

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