F-039. CD11c (+) Cells Are Critical for Early Protection against Pulmonary Infection with Cryptococcus neoformans

J. J. Osterholzer1,2, J. Milam1, N. Falcowski1, G-H. Chen1, R. McDonald1, G. B. Toews1,2, G. B. Huffnagle1, M. A. Olszewski1,2;
1Univ. of Michigan, Ann Arbor, MI, 2VA Med. Ctr., Ann Arbor, MI.

RATIONALE: Murine infection with the pathogenic fungi, Cryptococcus neoformans (Cneo), stimulates an adaptive, T-cell mediated immune response. T1 responses are protective whereas T2 responses are characterized by chronic infection resembling allergic bronchopulmonary pulmonary mycosis. We hypothesized that CD11c(+) cells, {which include lung dendritic cells (DC)}, would be important mediators of this response. To study the role of dendritic cells (DCs) during cryptococcal infection, we systemically depleted CD11c(+) cells immediately prior to Cneo challenge. METHODS: Wild type (C576BL/6) or DC-DTR (transgenic C576BL/6 mice expressing the diphtheria toxin receptor under the control of the CD11 promoter) were inoculated intraperitoneal with diphtheria toxin (DT; 4-6 ng/g body weight) or saline on day -1 and inoculated intratracheal with 104 colony forming units (CFU) of Cneo on day 0. Thereafter, the following experiments were performed to assess the effect of CD11c(+) cell depletion: 1) flow cytometric analysis to confirm depletion of CD11c(+) cells; 2) clinical score assessment; 3) survival analysis; 4) lung Cneo CFU 5) serum Cneo antigen determination; and 6) histologic and serologic comparison of local and systemic pathology. RESULTS: Pulmonary infection with Cneo in mice depleted of CD11c(+) cells results in rapid clinical deterioration and death within 5-6 days from inoculation. Death was not attributable to a significant difference in cryptococcal burden. Histologic analysis of mice depleted of CD11c(+) cells reveals suppurative pneumonia and acute hepatic necrosis. CONCLUSION: CD11c(+) cells are critical for early protection against pulmonary infection with Cneo. This protective effect precedes the recruitment of additional CD11c(+) cells and the development of adaptive immunity. Thus, we propose that endogenous CD11c(+) cells (DC and/or alveolar macrophages) provide protection against the immediate consequences of Cneo infection. Whether protection is mediated by early innate immune responses or the suppression of over-exuberant inflammation and shock is under further investigation.

234/F. Fungal Detection, Clinical Mycology and Drug Resistance

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