A dichotomous role for nitric oxide during acuteToxoplasma gondiiinfection in mice

Abstract

Production of nitric oxide by macrophages is believed to be an important microbicidal mechanism for a variety of intracellular pathogens, including Toxoplasma gondii. Mice with a targeted disruption of the inducible nitric oxide synthase gene (iNOS) were infected orally with T. gondii tissue cysts. Time to death was prolonged compared with parental controls. Histologic analysis of tissue from infected mice showed scattered small foci of inf lammation with parasites in various tissues of iNOS؊͞؊ mice, whereas tissue from the parental C57BL͞6 mice had more extensive tissue inf lammation with few visible parasites. In particular, extensive ulceration and necrosis of distal small intestine and fatty degeneration of the liver was seen in the parental mice at day 7 postinfection, as compared with the iNOS؊͞؊ mice where these tissues appeared normal. Serum interferon ␥ and tumor necrosis factor ␣ levels postinfection were equally elevated in both mouse strains. Treatment of the parental mice with a NO synthase inhibitor, aminoguanidine, prevented early death in these mice as well as the hepatic degeneration and small bowel necrosis seen in acutely infected control parentals. These findings indicate that NO production during acute infection with T. gondii can kill intracellular parasites but can be detrimental, even lethal, to the host.

Gram-Negative Bacteria Aggravate Murine Small Intestinal Th1-Type Immunopathology following Oral Infection with Toxoplasma gondii

“…The detection of bacteria in inflamed subepithelial tissue layers by FISH demonstrated that T. gondii-induced ileal inflammation is accompanied by substantial mucosal barrier defects resulting in bacterial translocation. The finding that live E. coli, but not Bacteroides/Prevotella spp., were detected by culture in Ͼ80% of the mesenteric lymph nodes and in 70% of the spleens from mice with severe ileitis (data not shown) suggests that following translocation gut bacteria potentiate tissue destruction and intestinal inflammation by direct cell contact and mediator release (33,68). Such interactions are further supported by decreased IFN-␥ and NO levels after antibiotic treatment and by the elevated intestinal NO levels in gnotobiotic animals monocolonized with E. coli.…”

“…Within 8 days after peroral infection with Toxoplasma gondii, susceptible C57BL/6 mice develop severe ileal inflammation, resulting in necroses of mucosal villi and complete tissue destruction (32,33). Ileitis is caused by a Th1-type immunopathology, characterized by a CD4 ϩ T cell-mediated increase in proinflammatory mediators including IFN-␥, TNF-␣, and NO.…”

Lack of IL-15 results in the suboptimal priming of CD4+T cell response against an intracellular parasite

“…Sections of small bowel and liver from infected parental mice showed the patchy epithelial necrosis and scattered hepatic inflammatory nodules ( Fig. 2 A and B) typical of the hyperimmune response to T. gondii infection (11,26). IL-15 Ϫ/Ϫ mice showed similar changes, with perhaps more inflammation than the controls, but the affected segments of bowel were minimal and most gut epithelia were intact (Fig.…”

Intestinal intraepithelial lymphocytes prevent pathogen‐driven inflammation and regulate the Smad/T‐bet pathway of lamina propria CD4+ T cells

“…In response to the infection, LP CD4 + T lymphocytes secrete INF-+ and TNF- § , which are microbicidal compounds and are associated with the induction of iNOS and subsequent expression of NO [19]. Although essential for limiting parasite invasiveness, the overproduction of these molecules is disruptive to normal intestinal homeostasis [20]. The decreased production of IFN-+ and TNF- § observed after the adoptive transfer of P IEL would then result in decreased inflammation and an increase in the survival of the recipient mice.…”