Nitric Oxide Is a Key Determinant of Group B Streptococcus–Induced Murine Macrophage Apoptosis

Glen C. Ulett, Elisabeth E. Adderson
2005 Journal of Infectious Diseases  
Group B streptococcus (GBS; Streptococcus agalactiae) induces apoptosis of macrophages, and this may be an important mechanism GBS uses to suppress immune responses. The mechanisms whereby GBS induces apoptosis have not been identified. We studied GBS infection in murine macrophage-like J774A.1 cells and analyzed gene expression before apoptosis. Tumor necrosis factor (TNF)-a, interleukin (IL)-1, and inducible nitric oxide synthase (iNOS) gene expression coincided with apoptosis. Inhibition of
more » ... NOS gene expression by use of N G -monomethyl-L-arginine (NMMA) inhibited apoptosis, whereas inhibition of TNF-a and IL-1 biological activity did not. Macrophages from congenic iNOS-deficient mice were less susceptible to apoptosis than were macrophages from C57BL/6 mice. The NO donor S-nitroso-N-acetylpenicillamine (SNAP) induced apoptosis without infection, confirming its proapoptotic effect. NMMA did not impair the microbicidal activity of macrophages, however, and SNAP was not bactericidal against GBS in vitro. In human monocyte-derived macrophages (HMDMs), NO production was minimal, even after costimulation with IFN-g and lipopolysaccharide. Dose-dependent apoptosis of HMDMs occurred without a significant NO response. Thus, NO is an important mediator of GBS-induced murine macrophage apoptosis but does not contribute to antimicrobial activity or cytotoxicity in HMDMs. HMDMs and murine macrophages are killed by GBS by alternative, NOindependent mechanisms. Future studies of host-cell machinery commandeered by GBS to bring about apoptosis will be important for understanding the role played by apoptosis in defense against this important human pathogen.
doi:10.1086/429693 pmid:15838805 fatcat:pzalpm532fg7zkghcq74lwyp6u