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Infect. Immun. doi:10.1128/IAI.00569-08
Copyright (c) 2008, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Temporal delay of peak T cell immunity determines Chlamydia pneumoniae pulmonary disease in mice

Department of Pathobiology, and Department of Anatomy, Physiology and Pharmacology, College of Veterinary Medicine, Auburn University, Auburn, AL 36849-5519

^* To whom correspondence should be addressed. Email: kaltebe{at}auburn.edu.

	Abstract

Severe chlamydial disease typically occurs after previous infections, and results from a hypersensitivity response that is also required for chlamydial elimination. Here, we quantitatively dissected the immune and disease response to repeated Chlamydia (C.) pneumoniae lung infection by multivariate modeling at four dichotomous effects: mouse strain (A/J or C57BL/6), dietary protein content (14% protein, 0.3% l-cysteine/0.9% l-arginine or 24% protein, 0.5% l-cysteine/2.0% l-arginine); dietary antioxidant content (90 IU -tocopherol/kg vs. 450 IU -tocopherol/kg & 0.1% g l-ascorbate), and time course (3 or 10 days pi). Following intranasal C. pneumoniae challenge, C57BL/6 mice on low-protein/low-antioxidant diet, but not C57BL/6 mice on other diets or A/J mice, exhibited profoundly suppressed early lung inflammatory, pan T cell (CD3⁺) and helper T cell (CD45) responses on day 3, but later strongly exacerbated disease on day 10. Contrast analyses characterized the severe C. pneumoniae disease as delayed type hypersensitivity response with increased lung macrophage and Th1 cell marker transcripts, increased Th1:Th2 ratio, and Th1 cytokine-driven inflammation. Functional analyses by DTH, ELISPOT, and immunohistofluorescence assays were consistent with the results obtained by transcript analysis. Thus, chlamydial disease after secondary infection is a temporal dysregulation of the T cell response characterized by a profoundly delayed T helper cell response that results in a failure to eliminate the pathogen and provokes later pathological Th1 inflammation. This delayed T cell response is under host genetic control and nutritional influence. The mechanism that temporally and quantitatively regulates the host T cell population is the critical determinant in chlamydial pathogenesis.