Abstract

Cryptococcus neoformans, the most common cause of fatal fungal infections in patients with AIDS, is acquired via the respiratory tract. Host defense against C. neoformans is dependent upon communication between cells of the innate immune system and T cells. Transport of antigen from the site of initial exposure (lung) to T cell areas of the draining lung associated lymph nodes (LALN) precedes the induction of specific T cell immunity. Transport of antigen via the afferent lymphatics is a specialized function of dendritic cells. Highly controlled movement of monocytic DC precursors from the blood into sites of microbial infection and their subsequent activation/maturation and migration into LALN is crucial for induction of protective immune responses. The molecular signals that regulate the in vivo movement of monocytic DC precursors and DC between different compartments in the lung are poorly understood. Our preliminary studies document that a) CCR2 is crucial to the migration of CD11+ DC; and b) TNF-alpha and IFN-gamma are crucial links between the innate immune response and protective antigen-specific responses to C. neoformans. Hypothesis: CCR2 dependent recruitment of monocytes and/or monocyte-derived DC to the lung is required for generation of a protective T1 immune response to C. neoformans. These phagocytic, uncommitted, immature DC are uniquely capable of high level IL-12 p70 production if early pulmonary TNF-alpha and IFN-gamma drive their maturation.
The specific aims are:
Specific Aim 1 : To determine the cells responsible for transport of antigen from the airspaces to LALN during the development of a specific, protective T cell response to pulmonary Cneo and determine the role of CCR2 in migration of these antigen presenting cells.
Specific Aim 2 : To determine the CCL responsible for CCR2-mediated antigen presenting cell migration during the development of a specific, protective response to pulmonary Cneo infection.
Specific Aim 3 : To determine the role of inflammatory mediators (IFN-gamma, TNF-alpha, PGE2) in regulating Cneo-induced IL-12 production by immature DC.
Specific Aim 4 : To determine the effect of transient lung (TNF-alpha) and IFN-gamma transgene expression on pulmonary antigen-presenting cell phenotype, lymphokine expression, pulmonary clearance, and brain dissemination in Cneo challenged CCR2 -/- mice.
Specific Aim 5 : To determine the effect of adoptive transfer of Cneo pulsed CCR2+/+BMDC into Cneo-infected CCR2 -/- mice.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL051082-14
Application #
7228830
Study Section
Lung Biology and Pathology Study Section (LBPA)
Program Officer
Peavy, Hannah H
Project Start
1993-12-01
Project End
2009-05-31
Budget Start
2007-06-01
Budget End
2009-05-31
Support Year
14
Fiscal Year
2007
Total Cost
$315,954
Indirect Cost

  Institution

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

  Publications

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
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
Jain, Aditya V; Zhang, Yanmei; Fields, W Bradley et al. (2009) Th2 but not Th1 immune bias results in altered lung functions in a murine model of pulmonary Cryptococcus neoformans infection. Infect Immun 77:5389-99
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; 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

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