TNF‐α, nitric oxide and IFN‐γ are all critical for development of necrosis in the small intestine and early mortality in genetically susceptible mice infected perorally with Toxoplasma gondii

Abstract

We previously reported that genetic susceptibility of mice to peroral infection with T. gondii is associated with CD4+ T cell-dependent, interferon (IFN)-gamma-mediated necrosis of their small intestine. We examined the role of tumour necrosis factor (TNF)-alpha and nitric oxide (NO), in addition to IFN-gamma. At 7 days after infection, a marked increase in CD4+ T cells was observed in lamina propria mononuclear cells (LPC) of the small intestine as compared with normal mice, and significantly greater amounts of mRNA for IFN-gamma, TNF-alpha, and inducible NO synthase (iNOS) were detected in LPC of the small intestine of infected than uninfected animals. Treatment of infected mice with anti-TNF-alpha monoclonal antibody (mAb) or the iNOS inhibitor, aminoguanidine, prevented necrosis and prolonged time to death. Infected iNOS-targeted mutant mice did not develop the disease whereas infected, control mice did. Treatment with anti-TNF-alpha mAb did not affect the expression of IFN-gamma in the LPC but inhibited expression of iNOS in the infected mice, indicating the role of TNF-alpha in the induction of iNOS. These results suggest that NO induced by a combination of IFN-gamma and TNF-alpha through activation of iNOS is a critical mediator of intestinal pathology and contributes to early mortality in genetically susceptible mice.

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.…”

Partial depletion of CD4+CD25+Foxp3+ T regulatory cells significantly increases morbidity during acute phase Toxoplasma gondii infection in resistant BALB/c mice

“…Inadequately regulated inflammatory responses that cause tissue destruction have been suggested to increase susceptibility to T. gondii infection [7,34]. However, there is no evidence that high levels of intestinal IFN-g favour T. gondii replication and TNF-a, despite its detrimental role in the intestinal mucosa of T. gondii infected mice, has been reported to prevent tachyzoite replication in the small intestine [8]. IL-6, on the other hand, is the only cytokine which has previously shown to enhance T. gondii replication in macrophages [9].…”

“…In C57BL/6 (B6) mice acute phase mortality following peroral infection was demonstrated to be due to necrosis of the small intestine mediated by IFN-g produced by CD4 þ T cells whilst in genetically resistant BALB/c mice this very same mediator was shown to be required for survival [7]. Subsequent reports also provided evidence for the participation of TNF-a and IL-6 in the deleterious acute phase response to peroral T. gondii infection in B6 mice [8,9] however, the role of these cytokines in BALB/c mice remains unknown.…”

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

“…In this model system, acute inflammation is associated with a strong Th1 response characterized by an increased expression of cytokines IFN-+ and TNF- § by CD4 + T cells from the lamina propria (LP) [15,16]. Mice deficient in inducible NO-synthase (iNOS), IL-12, CD40, IFN-+ or CD4 + cells fail to develop lethal ileitis despite a detectable parasite burden [15][16][17], suggesting that this parasite-driven ileitis is T cell dependent.…”