Inflammation-associated alterations to the intestinal microbiota reduce colonization resistance against non-typhoidal Salmonella during concurrent malaria parasite infection.

Jason P Mooney,Rashaun Potts,Franziska Faber,Caitlin Tiffany,Mohamed M Ali,Kristen L Lokken,Mariana X Byndloss,Renée M Tsolis,Michael D George,Brian P Butler,Brian M M Ahmer,Shirley Luckhart,Eric M Velazquez,Gregory T Walker

doi:10.1038/srep14603

Abstract

Childhood malaria is a risk factor for disseminated infections with non-typhoidal Salmonella (NTS) in sub-Saharan Africa. While hemolytic anemia and an altered cytokine environment have been implicated in increased susceptibility to NTS, it is not known whether malaria affects resistance to intestinal colonization with NTS. To address this question, we utilized a murine model of co-infection. Infection of mice with Plasmodium yoelii elicited infiltration of inflammatory macrophages and T cells into the intestinal mucosa and increased expression of inflammatory cytokines. These mucosal responses were also observed in germ-free mice, showing that they are independent of the resident microbiota. Remarkably, P. yoelii infection reduced colonization resistance of mice against S. enterica serotype Typhimurium. Further, 16S rRNA sequence analysis of the intestinal microbiota revealed marked changes in the community structure. Shifts in the microbiota increased susceptibility to intestinal colonization by S. Typhimurium, as demonstrated by microbiota reconstitution of germ-free mice. These results show that P. yoelii infection, via alterations to the microbial community in the intestine, decreases resistance to intestinal colonization with NTS. Further they raise the possibility that decreased colonization resistance may synergize with effects of malaria on systemic immunity to increase susceptibility to disseminated NTS infections.

Highlights

Childhood malaria is a risk factor for disseminated infections with non-typhoidal Salmonella (NTS) in sub-Saharan Africa
We used a murine model of concurrent malaria and NTS infection to examine the effect of infection with the rodent malaria parasite P. yoelii nigeriensis (P. yoelii) on the initial phase of intestinal colonization by S. enterica serotype Typhimurium
To study effects of acute malaria parasite infection on the intestine, C57BL/6 mice were inoculated with P. yoelii

Summary

Introduction

Childhood malaria is a risk factor for disseminated infections with non-typhoidal Salmonella (NTS) in sub-Saharan Africa. Recent studies have identified multiple factors that may underlie this association, including hemolysis-induced defects in neutrophil function[10], immunosuppressive effects of malaria on macrophage function[11], and blunting of inflammatory responses to tissue invasion by NTS11–13 While all of these effects of malaria on the immune response to NTS are observed subsequent to bacterial tissue invasion, it is not known whether malaria affects host resistance to intestinal colonization with NTS upon bacterial ingestion. It has been hypothesized that effects of malaria on the intestine could be secondary to parasite sequestration in the tissue microvasculature, as sequestration has been observed throughout the gastrointestinal tract in malaria patients[17,18,19] These findings raised the question, whether effects of malaria on the intestinal microenvironment could affect colonization resistance of the host to NTS.

Methods

Results

Conclusion