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Infection and Immunity, December 2001, p. 7374-7379, Vol. 69, No. 12
0019-9567/01/$04.00+0   DOI: 10.1128/IAI.69.12.7374-7379.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Role for Inducible Nitric Oxide Synthase in Protection from Chronic Chlamydia trachomatis Urogenital Disease in Mice and Its Regulation by Oxygen Free Radicals

K. H. Ramsey,^1,* I. M. Sigar,¹ S. V. Rana,¹ J. Gupta,¹ S. M. Holland,² and G. I. Byrne³

Microbiology Department, Chicago College of Osteopathic Medicine, Midwestern University, Downers Grove, Illinois 60515¹; Laboratory of Host Defenses, National Institutes of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892²; and Department of Medical Microbiology and Immunology, University of Wisconsin Medical School, Madison, Wisconsin 53706³

Received 29 May 2001/Returned for modification 23 July 2001/Accepted 20 September 2001

It has been previously reported that although inducible nitric oxide synthase (iNOS) gene knockout (NOS2^/) mice resolve Chlamydia trachomatis genital infection, the production of reactive nitrogen species (RNS) via iNOS protects a significant proportion of mice from hydrosalpinx formation and infertility. We now report that higher in vivo RNS production correlates with mouse strain-related innate resistance to hydrosalpinx formation. We also show that mice with a deletion of a key component of phagocyte NADPH oxidase (p47^phox/) resolve infection, produce greater amounts of RNS in vivo, and sustain lower rates of hydrosalpinx formation than both wild-type (WT) NOS2^+/+ and NOS2^/ controls. When we induced an in vivo chemical block in iNOS activity in p47^phox/ mice using N^G-monomethyl-L-arginine (L-NMMA), a large proportion of these mice eventually succumbed to opportunistic infections, but not before they resolved their chlamydial infections. Interestingly, when compared to WT and untreated p47^phox/ controls, L-NMMA-treated p47^phox/ mice resolved their infections more rapidly. However, L-NMMA-treated p47^phox/ mice lost resistance to chronic chlamydial disease, as evidenced by an increased rate of hydrosalpinx formation that was comparable to that for NOS2^/ mice. We conclude that phagocyte oxidase-derived reactive oxygen species (ROS) regulate RNS during chlamydial urogenital infection in the mouse. We further conclude that while neither phagocyte oxidase-derived ROS nor iNOS-derived RNS are essential for resolution of infection, RNS protect from chronic chlamydial disease in this model.

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^* Corresponding author. Mailing address: Microbiology Department, Chicago College of Osteopathic Medicine, Midwestern University, 555 31st St., Downers Grove, IL 60515. Phone: (630) 515-6165. Fax: (630) 515-7245. E-mail: kramse{at}midwestern.edu.

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Infection and Immunity, December 2001, p. 7374-7379, Vol. 69, No. 12
0019-9567/01/$04.00+0   DOI: 10.1128/IAI.69.12.7374-7379.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

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