Intraspecies competition for niches in the distal gut dictate transmission during persistent Salmonella infection.

Lilian H Lam,Denise M Monack,Mary O'Riordan

doi:10.1371/journal.ppat.1004527

Abstract

In order to be transmitted, a pathogen must first successfully colonize and multiply within a host. Ecological principles can be applied to study host-pathogen interactions to predict transmission dynamics. Little is known about the population biology of Salmonella during persistent infection. To define Salmonella enterica serovar Typhimurium population structure in this context, 129SvJ mice were oral gavaged with a mixture of eight wild-type isogenic tagged Salmonella (WITS) strains. Distinct subpopulations arose within intestinal and systemic tissues after 35 days, and clonal expansion of the cecal and colonic subpopulation was responsible for increases in Salmonella fecal shedding. A co-infection system utilizing differentially marked isogenic strains was developed in which each mouse received one strain orally and the other systemically by intraperitoneal (IP) injection. Co-infections demonstrated that the intestinal subpopulation exerted intraspecies priority effects by excluding systemic S. Typhimurium from colonizing an extracellular niche within the cecum and colon. Importantly, the systemic strain was excluded from these distal gut sites and was not transmitted to naïve hosts. In addition, S. Typhimurium required hydrogenase, an enzyme that mediates acquisition of hydrogen from the gut microbiota, during the first week of infection to exert priority effects in the gut. Thus, early inhibitory priority effects are facilitated by the acquisition of nutrients, which allow S. Typhimurium to successfully compete for a nutritional niche in the distal gut. We also show that intraspecies colonization resistance is maintained by Salmonella Pathogenicity Islands SPI1 and SPI2 during persistent distal gut infection. Thus, important virulence effectors not only modulate interactions with host cells, but are crucial for Salmonella colonization of an extracellular intestinal niche and thereby also shape intraspecies dynamics. We conclude that priority effects and intraspecies competition for colonization niches in the distal gut control Salmonella population assembly and transmission.

Highlights

The Salmonella enterica serovars are important pathogens that cause disease ranging from a self-limiting gastroenteritis to persistent systemic infections
Salmonella enterica serovars infect various mammalian hosts, causing disease ranging from self-limiting diarrhea to persistent systemic infections such as typhoid fever
In a mouse model of persistent Salmonella infection, we found that distinct subpopulations formed in intestinal and systemic tissues

Summary

Introduction

The Salmonella enterica serovars are important pathogens that cause disease ranging from a self-limiting gastroenteritis to persistent systemic infections. The human-adapted Salmonella enterica Typhi and Paratyphi serovars are the causative agents of typhoid fever, and penetrate the intestinal epithelium to disseminate to systemic tissues [1]. 1–6% of infected patients become chronic carriers and serve as the reservoir of disease, remaining asymptomatic while excreting Salmonella in their stool [1,2]. S. Typhimurium is a major cause of foodborne diarrheal disease in humans, but can cause invasive nontyphoidal Salmonella (NTS) disease in immunocompromised individuals [5,6]. NTS can persist in the gastrointestinal tract and be excreted in feces in certain patients [7], with elevated levels of NTS fecal shedding associated with antibiotic therapy [8]

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