Coinfection with an Intestinal Helminth Impairs Host Innate Immunity against Salmonella enterica Serovar Typhimurium and Exacerbates Intestinal Inflammation in Mice

Abstract

c Salmonella enterica serovar Typhimurium is a Gram-negative food-borne pathogen that is a major cause of acute gastroenteritis in humans. The ability of the host to control such bacterial pathogens may be influenced by host immune status and by concurrent infections. Helminth parasites are of particular interest in this context because of their ability to modulate host immune responses and because their geographic distribution coincides with those parts of the world where infectious gastroenteritis is most problematic. To test the hypothesis that helminth infection may negatively regulate host mucosal innate immunity against bacterial enteropathogens, a murine coinfection model was established by using the intestinal nematode Heligmosomoides polygyrus and S. Typhimurium. We found that mice coinfected with S. Typhimurium and H. polygyrus developed more severe intestinal inflammation than animals infected with S. Typhimurium alone. The enhanced susceptibility to Salmonella-induced intestinal injury in coinfected mice was found to be associated with diminished neutrophil recruitment to the site of bacterial infection that correlated with decreased expression of the chemoattractants CXCL2/macrophage inflammatory protein 2 (MIP-2) and CXCL1/keratinocyte-derived chemokine (KC), poor control of bacterial replication, and exacerbated intestinal inflammation. The mechanism of helminth-induced inhibition of MIP-2 and KC expression involved interleukin-10 (IL-10) and, to a lesser extent, IL-4 and IL-13. Ly6G antibody-mediated depletion of neutrophils reproduced the adverse effects of H. polygyrus on Salmonella infection. Our results suggest that impaired neutrophil recruitment is an important contributor to the enhanced severity of Salmonella enterocolitis associated with helminth coinfection.

A single-cell survey of the small intestinal epithelium

“…H. polygyrus was propagated as previously described 44 . Mice were sacrificed 3 and 10 days after H. polygyrus infection.…”

“…Mice were sacrificed 3 and 10 days after H. polygyrus infection. For Salmonella enterica , mice were infected with a naturally streptomycin-resistant SL1344 strain of S. Typhimurium (10 8 cells) as described 44 and were sacrificed 48 hours after infection.…”

Spatial regulation of IL-4 signalling in vivo

“…Intriguingly, alternatively activated macrophages were also recently proposed to explain reduced viral clearance in an intestinal helminth-viral co-infection model [102]. IL-4 can also inhibit the protective action of other cell types: injection of Schistosoma haematobium eggs into the bladder wall triggered IL-4 production that compromised NKT cell-mediated control of uropathogenic Escheria coli [103], and the severe intestinal inflammation and higher bacterial burdens that occurred in mice co-infected with the gastrointestinal nematode Heligmosomoides polygyrus and Salmonella enterica serovar Typhimurium were attributed to IL-4-mediated suppression of neutrophil recruitment [104]. IL-4 can also directly modify pathogen behaviour.…”

Metabolism at the centre of the host–microbe relationship

“…Chronic helminth infections are associated with increased occurrence of co-infections with a range of bacterial and viral pathogens [117][118][119][120]. Chronic helminth infections are associated with increased occurrence of co-infections with a range of bacterial and viral pathogens [117][118][119][120].…”