Cryptococcus neoformans is a common cause of fatal infection in patients with AIDS. The respiratory tract is the portal of entry for C. neoformans. The development of protective Th1 cell-mediated immunity (CMI) is crucial to the eradication of the organism and control of cryptococcal dissemination from the lungs to the brain. However, C. neoformans can also stimulate a Th2 type response, resulting in a non-resolving, chronic pulmonary infection. The production of Th2 type cytokines during C. neoformans infection may allow the organism to establish a chronic pulmonary infection from which dissemination could occur during advance stages of T cell deficiency as found in AIDS. Our preliminary studies indicate that TNF alpha production is critical or the development of Th1 immunity and the interplay between hosts TNF alpha and microbial (melanin) factors is a major determinant for Th1 vs. Th2 immunity to C. neoformans. The hypothesis of this proposal is that alveolar macrophage production of TNF alpha and the onset of infection promotes the development of Th1 CMI, while the cryptococcal virulence factor promotes the switch to Th2 CMI.
The specific aims are to determine: (1) the relationship between the timing of TNF alpha production in the lungs and the induction of Il-12, interferon gamma and Th1 type immunity; (2) whether the protective effect of intratracheally administered TNF alpha peptide during pulmonary C. neoformans infection is due to induction of Th1 type CMI in the lungs; (3) whether depletion of alveolar macrophages prior to C. neoformans infection ablates TNF alpha induction and prevents the development of Th1 type CMI; (4) whether the development of C. neoformans-specific Th1 vs. Th2 cells is dependent on the melanin content of C. neoformans during immunization; and (5) whether the synthesis of melanin in vivo by C. neoformans promotes the development of Th2 type CMI. This proposal will investigate whether TNF alpha production by alveolar macrophages is a critical factor for Th1/Th2 switching in the lungs and functions by promoting a Th1 response. This proposal will also investigate the concept that live microbes are dynamic antigens, such that melanin production modulates the development of Th1 vs. Th2 immunity by altering the microenvironment at the time of immune recognition. One of the potential implications of these studies is that therapies inhibiting melanin biosynthesis or activity may also have an adjuvant effect and promote the development of protective Th1 immunity to C. neoformans.
|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|
|Osterholzer, John J; Chen, Gwo-Hsiao; Olszewski, Michal A et al. (2011) Chemokine receptor 2-mediated accumulation of fungicidal exudate macrophages in mice that clear cryptococcal lung infection. Am J Pathol 178:198-211|
|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|
|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|
|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|
|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|
|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; Ballinger, Megan N; McDonald, Roderick A et al. (2006) Diversity of the T-cell response to pulmonary Cryptococcus neoformans infection. Infect Immun 74:4538-48|
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