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Infection and Immunity, June 2000, p. 3587-3593, Vol. 68, No. 6
0019-9567/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Cooperation between Reactive Oxygen and Nitrogen Intermediates in Killing of Rhodococcus equi by Activated Macrophages

Patricia A. Darrah,1 Mary K. Hondalus,2 Quiping Chen,3 Harry Ischiropoulos,3 and David M. Mosser1,*

Department of Microbiology and Immunology, Temple University School of Medicine, Philadelphia, Pennsylvania 191401; School of Public Health, Harvard University, Boston, Massachusetts2; and the Stokes Research Institute, University of Pennsylvania, Philadelphia, Pennsylvania 191033

Received 7 January 2000/Returned for modification 1 March 2000/Accepted 16 March 2000

Rhodococcus equi is a facultative intracellular bacterium of macrophages which can infect immunocompromised humans and young horses. In the present study, we examine the mechanism of host defense against R. equi by using a murine model. We show that bacterial killing is dependent upon the presence of gamma interferon (IFN-gamma ), which activates macrophages to produce reactive nitrogen and oxygen intermediates. These two radicals combine to form peroxynitrite (ONOO-), which kills R. equi. Mice deficient in the production of either the high-output nitric oxide pathway (iNOS-/-) or the oxidative burst (gp91phox-/-) are more susceptible to lethal R. equi infection and display higher bacterial burdens in their livers, spleens, and lungs than wild-type mice. These in vivo observations, which implicate both nitric oxide (NO) and superoxide (O2-) in bacterial killing, were reexamined in cell-free radical-generating assays. In these assays, R. equi remains fully viable following prolonged exposure to high concentrations of either nitric oxide or superoxide, indicating that neither compound is sufficient to mediate bacterial killing. In contrast, brief exposure of bacteria to ONOO- efficiently kills virulent R. equi. The intracellular killing of bacteria in vitro by activated macrophages correlated with the production of ONOO- in situ. Inhibition of nitric oxide production by activated macrophages by using NG-monomethyl-L-arginine blocks their production of ONOO- and weakens their ability to control rhodococcal replication. These studies indicate that peroxynitrite mediates the intracellular killing of R. equi by IFN-gamma -activated macrophages.

* Corresponding author. Mailing address: Department of Microbiology and Immunology, Temple University School of Medicine, 3400 N. Broad St., Philadelphia, PA 19140. Phone: (215) 707-8262. Fax: (215) 707-7788. E-mail: dmmosser{at}astro.temple.edu.

Infection and Immunity, June 2000, p. 3587-3593, Vol. 68, No. 6
0019-9567/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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