Abstract

Elimination of Pneumocystis carinii, a significant cause of pneumonia in immunocompromised individuals, from the pulmonary environment is the exclusive responsibility of the alveolar macrophage. However, due to P. carinii's inability to be stably cultured in vitro, to date, there has been no high-throughput assay of viability to elucidate innate cell-mediated host defense mechanisms against P. carinii. Using a novel in vitro killing assay, we discovered that recognition and subsequent non-opsonic killing of P. carinii by alveolar macrophages occurs via a newly described receptor for fungal beta-glucans, Dectin-1. Dectin-1 is a 28 kDa, type II transmembrane receptor that contains a single lectin-like carbohydrate recognition domain which recognizes beta 1,3-linked and beta 1,6-linked glucans. We also observed that the alveolar macrophage inflammatory response to P. carinii is mediated by Dectin-1 recognition. We further show that immature lung-derived dendritic cells express high levels of Dectin-1. Based on these studies, we hypothesize that Dectin-1 is required for non-opsonic alveolar macrophage effector function against P. carinii as well as dendritic cell-mediated activation of adaptive T cell responses against P. carinii. We will test this hypothesis with the following specific aims.
Specific Aim 1 : To test the concept that Dectin-1 mediated recognition of P. carinii is critical for alveolar macrophage host defense against P. carinii in vitro.
Specific Aim 2 : To test the concept that beta-glucan recognition is required for P. carinii-induced pulmonary inflammation.
Specific Aim 3 : To test the concept that interruption of Dectin-1 mediated P. carinii recognition increases susceptibility to lung infection with P. carinii. These studies will investigate a new fungal molecular recognition receptor and characterize its role, in vitro as well as in vivo, against the opportunistic fungal organism P. carinii and may provide new insight into how P. carinii is recognized by the immune system, which may lead to novel immunotherapeutic strategies to combat this devastating pulmonary infection.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL080317-01
Application #
6908505
Study Section
Lung Injury, Repair, and Remodeling Study Section (LIRR)
Program Officer
Peavy, Hannah H
Project Start
2005-05-01
Project End
2010-04-30
Budget Start
2005-05-01
Budget End
2006-04-30
Support Year
1
Fiscal Year
2005
Total Cost
$328,300
Indirect Cost

  Institution

Name
Children's Hosp Pittsburgh/Upmc Health Sys
Department
Type
DUNS #
044304145
City
Pittsburgh
State
PA
Country
United States
Zip Code
15224

  Publications

Gessner, Melissa A; Doran, Stephen F; Yu, Zhihong et al. (2013) Chlorine gas exposure increases susceptibility to invasive lung fungal infection. Am J Physiol Lung Cell Mol Physiol 304:L765-73
Nelson, Michael P; Christmann, Benjamin S; Dunaway, Chad W et al. (2012) Experimental Pneumocystis lung infection promotes M2a alveolar macrophage-derived MMP12 production. Am J Physiol Lung Cell Mol Physiol 303:L469-75
Faro-Trindade, Inês; Willment, Janet A; Kerrigan, Ann M et al. (2012) Characterisation of innate fungal recognition in the lung. PLoS One 7:e35675
Werner, Jessica L; Gessner, Melissa A; Lilly, Lauren M et al. (2011) Neutrophils produce interleukin 17A (IL-17A) in a dectin-1- and IL-23-dependent manner during invasive fungal infection. Infect Immun 79:3966-77
Nelson, Michael P; Christmann, Benjamin S; Werner, Jessica L et al. (2011) IL-33 and M2a alveolar macrophages promote lung defense against the atypical fungal pathogen Pneumocystis murina. J Immunol 186:2372-81
Tsoni, S Vicky; Kerrigan, Ann M; Marakalala, Mohlopheni J et al. (2009) Complement C3 plays an essential role in the control of opportunistic fungal infections. Infect Immun 77:3679-85
Wozniak, Karen L; Ravi, Sailatha; Macias, Sandra et al. (2009) Insights into the mechanisms of protective immunity against Cryptococcus neoformans infection using a mouse model of pulmonary cryptococcosis. PLoS One 4:e6854
Werner, Jessica L; Metz, Allison E; Horn, Dawn et al. (2009) Requisite role for the dectin-1 beta-glucan receptor in pulmonary defense against Aspergillus fumigatus. J Immunol 182:4938-46
Nelson, Michael P; Metz, Allison E; Li, Shaoguang et al. (2009) The absence of Hck, Fgr, and Lyn tyrosine kinases augments lung innate immune responses to Pneumocystis murina. Infect Immun 77:1790-7
Mattila, Polly E; Metz, Allison E; Rapaka, Rekha R et al. (2008) Dectin-1 Fc targeting of aspergillus fumigatus beta-glucans augments innate defense against invasive pulmonary aspergillosis. Antimicrob Agents Chemother 52:1171-2

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