Dectin-1 and Immunity Against Pneumocystis Carinii

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DESCRIPTION (provided by applicant): 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.