Inflammatory monocytes provide a niche for Salmonella expansion in the lumen of the inflamed intestine

Salmonella exploit host-derived nitrate for growth in the lumen of the inflamed intestine. The generation of host-derived nitrate is dependent on Nos2, which encodes inducible nitric oxide synthase (iNOS), an enzyme that catalyzes nitric oxide (NO) production. However, the cellular sources of iNOS and, therefore, NO-derived nitrate used by Salmonella for growth in the lumen of the inflamed intestine remain unidentified. Here, we show that iNOS-producing inflammatory monocytes infiltrate ceca of mice infected with Salmonella. In addition, we show that inactivation of type-three secretion system (T3SS)-1 and T3SS-2 renders Salmonella unable to induce CC- chemokine receptor-2- and CC-chemokine ligand-2-dependent inflammatory monocyte recruitment. Furthermore, we show that the severity of the pathology of Salmonella- induced colitis as well as the nitrate-dependent growth of Salmonella in the lumen of the inflamed intestine are reduced in mice that lack Ccr2 and, therefore, inflammatory monocytes in the tissues. Thus, inflammatory monocytes provide a niche for Salmonella expansion in the lumen of the inflamed intestine.Author summary: Salmonella exploit gut inflammation to edge out competing microbes in the intestinal lumen and establish infection. Notably, Salmonella use inflammation-derived nitrate for growth in the intestinal lumen. The generation of inflammation-derived nitrate is dependent on Nos2, which encodes inducible nitric oxide synthase (iNOS), an enzyme that catalyzes nitric oxide production. However, the cellular sources of iNOS and, therefore, the nitric oxide-derived nitrate used by Salmonella for growth in the inflamed intestine remain unidentified, presenting an important, long-standing open question. Here, we show that iNOS-producing inflammatory monocytes, which are phagocyte precursors that play a critical role in immunity and host defense, promote nitrate-dependent Salmonella expansion in the inflamed intestine, providing new insights into how Salmonella exploit gut inflammation to establish infection.