Disease in the Absence of Virulence Factors: "Avirulent" (TTSS-1/2-deficient) Salmonella Mutants Induce Colitis in NADPH Oxidase KO-Mice

Infections permanently challenge the intestinal immune system. The production of reactive oxygen species (ROS) by NADPH oxidase is thought to be a key element of defense. This becomes evident in patients lacking one of the subunits of the NADPH oxidase, as these are hyper-susceptible to infections, e.g. have a 10x higher likelihood to suffer from Salmonellosis.
We used NADPH oxidase deficient (Cybb^-/-) mice and Salmonella Typhimurium (S. Typhimurium) infections to assess the microbe handling by the large intestinal mucosa. Wild type S. Typhimurium is known to employ two key virulence factors to cause enteropathy. Thus, a S. Typhimurium mutant lacking these virulence genes (S.Tm^avirulent; invGsseD), cannot cause enteropathy in wild type mice.

Strikingly, in Cybb^-/- mice the same mutant strain can trigger pronounced colitis. These mice showed enteropathy dependent on Myd88 and CD11c⁺CX₃CR1⁺ monocytic phagocytes by day 4 post infection. Surprisingly, a partial reconstitution of Cybb-proficiency in the bone marrow derived compartment was sufficient to reduce disease severity significantly. Thus, we concluded that NADPH oxidase expression is restricting the growth of S.Tm^avirulent in the mucosal lamina propria. The disease is the result of a complex interplay between the pathogen, its virulence factors and the innate defenses of the host's mucosa.