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Infection and Immunity, January 2006, p. 225-238, Vol. 74, No. 1
0019-9567/06/$08.00+0     doi:10.1128/IAI.74.1.225-238.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Comparison of Gamma Interferon-Mediated Antichlamydial Defense Mechanisms in Human and Mouse Cells

Christine Roshick,1 Heidi Wood,1 Harlan D. Caldwell,2 and Grant McClarty1,3*

National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, Manitoba, Canada,1 Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, Montana 51840,2 Department of Medical Microbiology, University of Manitoba, 1015 Arlington Street, Winnipeg, Manitoba, Canada R3E 3R23

Received 2 August 2005/ Returned for modification 12 September 2005/ Accepted 14 October 2005

Gamma interferon (IFN-{gamma})-induced effector mechanisms have potent antichlamydial activities that are critical to host defense. The most prominent and well-studied effectors are indoleamine dioxygenase (IDO) and nitric oxide (NO) synthase. The relative contributions of these mechanisms as inhibitors of chlamydial in vitro growth have been extensively studied using different host cells, induction mechanisms, and chlamydial strains with conflicting results. Here, we have undertaken a comparative analysis of cytokine- and lipopolysaccharide (LPS)-induced IDO and NO using an extensive assortment of human and murine host cells infected with human and murine chlamydial strains. Following cytokine (IFN-{gamma} or tumor necrosis factor alpha) and/or LPS treatment, the majority of human cell lines induced IDO but failed to produce NO. Conversely, the majority of mouse cell lines studied produced NO, not IDO. Induction of IDO in human cell lines inhibited growth of L2 and mouse pneumonitis agent, now referred to as Chlamydia muridarum MoPn equally in all but two lines, and inhibition was completely reversible by the addition of tryptophan. IFN-{gamma} treatment of mouse cell lines resulted in substantially greater reduction of L2 than MoPn growth. However, despite elevated NO production by murine cells, blockage of NO synthesis with the L-arginine analogue N-monomethyl-L-arginine only partially rescued chlamydial growth, suggesting the presence of another IFN-{gamma}-inducible antichlamydial mechanism unique to murine cells. Moreover, NO generated from the chemical nitric oxide donor sodium nitroprusside showed little direct effect on chlamydial infectivity or growth, indicating a natural resistance to NO. Finally, IFN-{gamma}-inducible IDO expression in human HeLa cells was inhibited following exogenous NO treatment, resulting in a permissive environment for chlamydial growth. In summary, cytokine- and LPS-inducible effectors produced by human and mouse cells differ and, importantly, these host-specific effector responses result in chlamydial strain-specific antimicrobial activities.

* Corresponding author. Mailing address: National Microbiology Laboratory, Public Health Agency of Canada, 1015 Arlington Street, Winnipeg, Manitoba, Canada R3E 3R2. Phone: (204) 789-6097. Fax: (204) 789-2097. E-mail: mcclart{at}cc.umanitoba.ca.

Editor: D. L. Burns

Infection and Immunity, January 2006, p. 225-238, Vol. 74, No. 1
0019-9567/06/$08.00+0     doi:10.1128/IAI.74.1.225-238.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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