Both inducible nitric oxide synthase and NADPH oxidase contribute to the control of virulent phase I Coxiella bumetii infections

Host control of Coxiella burnetii infections is believed to be mediated primarily by activated monocytes/macrophages. The activation of macrophages by cytokines leads to the production of reactive oxygen intermediates (ROI) and reactive nitrogen intermediates (RNI) that have potent antimicrobial activities. The contributions of ROI and RNI to the inhibition of C burnetti replication were examined in vitro by the use of murine macrophage-like cell lines and primary mouse macrophages. A gamma interferon (IFN-gamma) treatment of infected cell lines and primary macrophages resulted in an increased production of nitric oxide (NO) and hydrogen peroxide (H2O2) and a significant inhibition of C. burnetii replication. The inhibition of replication was reversed in the murine cell line J774.16 upon the addition of either the inducible nitric oxide synthase (iNOS) inhibitor N-G-monomethyl-L-arginine (N(G)MMLA) or the H2O2 scavenger catalase. IFN-T-treated primary macrophages from iNOS(-/-) and p47(phox-/-) Mice significantly inhibited replication but were less efficient at controlling infection than IFN-T-treated wild-type macrophages. To investigate the contributions of ROI and RNI to resistance to infection, we performed in vivo studies, using C57BL/6 wild-type mice and knockout mice lacking iNOS or p47(phox). Both iNOS(-/-) and p47(phox-/-) mice were attenuated in the ability to control C. burnetii infection compared to wild-type mice. Together, these results strongly support a role for both RNI and ROI in the host control of C. burnetti infection.