Cryptococcus neoformans is an opportunistic pathogen. It is a wood rot fungus that is inhaled from the environment (usually early in life) and very likely persists at low levels in the body until a reactivating event occurs (such as AIDS). The vast majority of life-threatening Cryptococcus infections are reactivation diseases. However, the mechanism by which low numbers of fungal organisms can persist in the face of an adaptive immune response is unknown. Recently, our laboratory identified that Cryptococcus and other pathogenic fungi can produce prostaglandins and leukotrienes. These are bioactive lipids derived from the fatty acid arachidonic acid and collectively belong to a larger class of bioactive lipids known as oxylipins (oxygenated fatty acid derivatives). Prostaglandins and leukotrienes are also produced by the host and are well-described modulators of innate and adaptive immune responses. The fact that both the host and fungus can produce similar signal molecules suggests a novel mechanism for low level fungal persistence. The hypothesis of this proposal is that production of oxylipins by both fungi and host modulates the microbiology of the fungus and the host-pathogen interaction in favor of chronic infection or persistence.
The Specific Aims are (1) to determine the effect of exogenous 18 and 20 carbon fatty acids, in the presence or absence of polyphenols, on modulating the biology of Cryptococcus neoformans (growth, melanization, capsule, cAMP production, phase transformation, Mfod activation, antifungal susceptibility); (2) to determine the role of cryptococcal laccase (CNLAC1) in fatty acid utilization and oxylipin production; (3) to determine the role of the fungal oxylipin CnPGEx in cryptococcal biology and pathogenesis; (4) to determine the role of host PGE2 and other prostaglandins in cryptococcal biology and host immunity

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI059201-04
Application #
7172258
Study Section
Special Emphasis Panel (ZRG1-IDM-C (02))
Program Officer
Duncan, Rory A
Project Start
2004-02-15
Project End
2009-01-31
Budget Start
2007-02-01
Budget End
2008-01-31
Support Year
4
Fiscal Year
2007
Total Cost
$316,060
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
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Milam, Jami E; Erb-Downward, John R; Chen, Gwo-Hsiao et al. (2010) CD11c+ cells are required to prevent progression from local acute lung injury to multiple organ failure and death. Am J Pathol 176:218-26
Chen, Gwo-Hsiao; Osterholzer, John J; Choe, Mun Y et al. (2010) Dual roles of CD40 on microbial containment and the development of immunopathology in response to persistent fungal infection in the lung. Am J Pathol 177:2459-71
Osterholzer, John J; Chen, Gwo-Hsiao; Olszewski, Michal A et al. (2009) Accumulation of CD11b+ lung dendritic cells in response to fungal infection results from the CCR2-mediated recruitment and differentiation of Ly-6Chigh monocytes. J Immunol 183:8044-53
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Osterholzer, John J; Milam, Jami E; Chen, Gwo-Hsiao et al. (2009) Role of dendritic cells and alveolar macrophages in regulating early host defense against pulmonary infection with Cryptococcus neoformans. Infect Immun 77:3749-58
Osterholzer, John J; Curtis, Jeffrey L; Polak, Timothy et al. (2008) CCR2 mediates conventional dendritic cell recruitment and the formation of bronchovascular mononuclear cell infiltrates in the lungs of mice infected with Cryptococcus neoformans. J Immunol 181:610-20
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
Milam, Jami E; Herring-Palmer, Amy C; Pandrangi, Raj et al. (2007) Modulation of the pulmonary type 2 T-cell response to Cryptococcus neoformans by intratracheal delivery of a tumor necrosis factor alpha-expressing adenoviral vector. Infect Immun 75:4951-8

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