Abstract

Cryptococcus neoformans is a common cause of fatal fungal infection in patients with AIDS. The respiratory tract is the portal of entry for this ubiquitous, encapsulated yeast and the development of protective Th1 cell-mediated immunity (CMI) is crucial to eradicate the organism and control cryptococcal dissemination from the lungs to the brain. Production of cytokines and other mediators by cells of the innate immune system direct the development of CMI, but the precise nature of these early cellular and molecular events remains to be determined. CCR2 and other chemokine receptors (CKRs) have recently been identified as important co-factors for HIV infections and therapies aimed at blocking CKR binding are being considered. It is of considerable importance to understand the role of CKRs in host defense against infection by AIDS-associated pathogens because CKR antagonists will likely be used in patients concurrently infected with one or more of these pathogens. We have identified in preliminary studies with CCR2 knockout mice that protective Th1 immunity against C. neoformans cannot develop in the absence of CCR2 even if CD4+ and CD8+ T cell numbers in the lungs, blood, and spleen are normal. Hypothesis: MCP-1 via CCR2 mediates mononuclear cell co-stimulation and recruitment which is required to develop protective Th1 immunity against C. neoformans; deficient CCR2 function results in Th2 immunity and an inability to clear C. neoformans.
Specific Aims : (1) To identify the cells in the lungs that express CCR2 during C. neoformans infection; (2) to determine the role of the CCR2 ligand MCP-1 in the development of Th1 immunity to C. neoformans; (3) to determine the role of CCR2 in the activation and recruitment of macrophages during pulmonary C. neoformans infection; (4) to determine the role of CCR2 in the recruitment and activation of T cells during pulmonary C. neoformans infection; (5) To determine the role of MCP-1 and CCR2 in the development of a Th2 response to C. neoformans.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL063670-03
Application #
6390546
Study Section
Special Emphasis Panel (ZHL1-CSR-H (M2))
Program Officer
Colombini-Hatch, Sandra
Project Start
1999-07-02
Project End
2004-06-30
Budget Start
2001-07-01
Budget End
2002-06-30
Support Year
3
Fiscal Year
2001
Total Cost
$262,795
Indirect Cost

  Institution

Name
University of Michigan Ann Arbor
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
791277940
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109

  Publications

Arora, Shikha; Olszewski, Michal A; Tsang, Tiffany M et al. (2011) Effect of cytokine interplay on macrophage polarization during chronic pulmonary infection with Cryptococcus neoformans. Infect Immun 79:1915-26
Zhang, Yanmei; Wang, Fuyuan; Bhan, Urvashi et al. (2010) TLR9 signaling is required for generation of the adaptive immune protection in Cryptococcus neoformans-infected lungs. Am J Pathol 177:754-65
Zhang, Yanmei; Wang, Fuyuan; Tompkins, Kristin C et al. (2009) Robust Th1 and Th17 immunity supports pulmonary clearance but cannot prevent systemic dissemination of highly virulent Cryptococcus neoformans H99. Am J Pathol 175:2489-500
Osterholzer, John J; Surana, Rishi; Milam, Jami E et al. (2009) Cryptococcal urease promotes the accumulation of immature dendritic cells and a non-protective T2 immune response within the lung. Am J Pathol 174:932-43
Erb-Downward, John R; Noggle, Rachael M; Williamson, Peter R et al. (2008) The role of laccase in prostaglandin production by Cryptococcus neoformans. Mol Microbiol 68:1428-37
Herring, Amy C; Falkowski, Nicole R; Chen, Gwo-Hsiao et al. (2005) Transient neutralization of tumor necrosis factor alpha can produce a chronic fungal infection in an immunocompetent host: potential role of immature dendritic cells. Infect Immun 73:39-49
Chen, Gwo-Hsiao; McDonald, Roderick A; Wells, Jason C et al. (2005) The gamma interferon receptor is required for the protective pulmonary inflammatory response to Cryptococcus neoformans. Infect Immun 73:1788-96
Olszewski, Michal A; Noverr, Mairi C; Chen, Gwo-Hsiao et al. (2004) Urease expression by Cryptococcus neoformans promotes microvascular sequestration, thereby enhancing central nervous system invasion. Am J Pathol 164:1761-71
Noverr, Mairi C; Williamson, Peter R; Fajardo, Ryan S et al. (2004) CNLAC1 is required for extrapulmonary dissemination of Cryptococcus neoformans but not pulmonary persistence. Infect Immun 72:1693-9
Noverr, Mairi C; Erb-Downward, John R; Huffnagle, Gary B (2003) Production of eicosanoids and other oxylipins by pathogenic eukaryotic microbes. Clin Microbiol Rev 16:517-33

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