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Infection and Immunity, November 2008, p. 4913-4923, Vol. 76, No. 11
0019-9567/08/$08.00+0     doi:10.1128/IAI.00569-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Temporal Delay of Peak T-Cell Immunity Determines Chlamydia pneumoniae Pulmonary Disease in Mice ^,

Chengming Wang,¹ Frederik W. van Ginkel,¹ Teayoun Kim,¹ Dan Li,¹ Yihang Li,¹ John C. Dennis,² and Bernhard Kaltenboeck^1*

Department of Pathobiology,¹ Department of Anatomy, Physiology, and Pharmacology, College of Veterinary Medicine, Auburn University, Auburn, Alabama 36849-5519²

Received 9 May 2008/ Returned for modification 25 June 2008/ Accepted 14 August 2008

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 responses to repeated Chlamydia pneumoniae lung infection by multivariate modeling with four dichotomous effects: mouse strain (A/J or C57BL/6), dietary protein content (14% protein and 0.3% L-cysteine-0.9% L-arginine, or 24% protein and 0.5% L-cysteine-2.0% L-arginine), dietary antioxidant content (90 IU -tocopherol/kg body weight versus 450 IU -tocopherol/kg and 0.1% g L-ascorbate), and time course (3 or 10 days postinfection). Following intranasal C. pneumoniae challenge, C57BL/6 mice on a low-protein/low-antioxidant diet, but not C57BL/6 mice on other diets or A/J mice, exhibited profoundly suppressed early lung inflammatory and pan-T-cell (CD3⁺) and helper T-cell (CD45) responses on day 3 but later strongly exacerbated disease on day 10. Contrast analyses characterized severe C. pneumoniae disease as being a delayed-type hypersensitivity (DTH) response with increased lung macrophage and Th1 cell marker transcripts, increased Th1:Th2 ratios, and Th1 cytokine-driven inflammation. Results from functional analyses by DTH, enzyme-linked immunospot, 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.

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* Corresponding author. Mailing address: Department of Pathobiology, College of Veterinary Medicine, Auburn University, 264 Greene Hall, Auburn, AL 36849-5519. Phone: (334) 844-2665. Fax: (334) 844-2652. E-mail: kaltebe{at}auburn.edu

Published ahead of print on 25 August 2008.

Supplemental material for this article may be found at http://iai.asm.org/.

Editor: R. P. Morrison

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Infection and Immunity, November 2008, p. 4913-4923, Vol. 76, No. 11
0019-9567/08/$08.00+0     doi:10.1128/IAI.00569-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.