Host Transmission of Salmonella enterica Serovar Typhimurium Is Controlled by Virulence Factors and Indigenous Intestinal Microbiota

Abstract

Transmission is an essential stage of a pathogen's life cycle and remains poorly understood. We describe here a model in which persistently infected 129X1/SvJ mice provide a natural model of Salmonella enterica serovar Typhimurium transmission. In this model only a subset of the infected mice, termed supershedders, shed high levels (>10 8 CFU/g) of Salmonella serovar Typhimurium in their feces and, as a result, rapidly transmit infection. While most Salmonella serovar Typhimurium-infected mice show signs of intestinal inflammation, only supershedder mice develop colitis. Development of the supershedder phenotype depends on the virulence determinants Salmonella pathogenicity islands 1 and 2, and it is characterized by mucosal invasion and, importantly, high luminal abundance of Salmonella serovar Typhimurium within the colon. Immunosuppression of infected mice does not induce the supershedder phenotype, demonstrating that the immune response is not the main determinant of Salmonella serovar Typhimurium levels within the colon. In contrast, treatment of mice with antibiotics that alter the health-associated indigenous intestinal microbiota rapidly induces the supershedder phenotype in infected mice and predisposes uninfected mice to the supershedder phenotype for several days. These results demonstrate that the intestinal microbiota plays a critical role in controlling Salmonella serovar Typhimurium infection, disease, and transmissibility. This novel model should facilitate the study of host, pathogen, and intestinal microbiota factors that contribute to infectious disease transmission.

Crossing the scale from within-host infection dynamics to between-host transmission fitness: a discussion of current assumptions and knowledge

“…Several studies of transmission in animal hosts have also shown a scaling of transmission fitness with pathogen load, e.g. Salmonella and Clostridium difficile transmission in mice [61,62] and Escherichia coli in cattle [63]. All these examples suggest that for some diseases and under some scenarios, infectiousness might be directly determined by pathogen load.…”

Host Specificity of Bacterial Pathogens

“…A byproduct of oxyradical production is the generation of a new respiratory electron acceptor, tetrathionate, which enables S. Typhimurium to out-compete obligate anaerobic microbes in the gut lumen (Winter et al 2010a) by utilizing carbon sources that cannot be fermented (Thiennimitr et al 2011). The resulting bloom of S. Typhimurium in the intestinal lumen enhances its transmission to the next host by the fecaloral route (Lawley et al 2008). With the onset of adaptive immunity, the pathogen is cleared from intestinal tissues, and bacterial shedding in the feces subsides within a few weeks.…”

“…Large rearrangements that alter chromosomal gene order are commonly associated with a lower growth rate, because inversions may alter gene dosage, replication-transcription conflicts, or chromosome symmetry (Hill and Gray 1988;Rebollo et al 1988;Campo et al 2004). The generalist S. Typhimurium needs to multiply at a maximum growth rate in the intestine because successful transmission requires bacterial numbers in the feces to reach a sufficient threshold (Lawley et al 2008). Thus, the maximum growth rate needed for transmission might place the gene order on the chromosomes of broad-host-range Salmonella serovars under selection.…”

“…These genes are intact in broad-host-range Salmonella serovars because they confer properties that enhance transmission of these pathogens by the fecaloral route during gastroenteritis (Lawley et al 2008), which imposes selective constraints that prevent loss of the encoded functions by mutation. However, these genes are no longer under selection in host-restricted pathogens that cause septicemic infections and transmit from reservoirs in the gall bladder (e.g., S. Typhi), the udder (e.g., S. Dublin), or the ovaries (e.g., S. Gallinarum).…”

Molecular insights into farm animal and zoonoticSalmonellainfections

“…Depletion of intestinal microflora with streptomycin is necessary for Salmonella-induced enteritis in mice (Barthel et al 2003) and the development of a 'super-shedder' phenotype and efficient transmission (Lawley et al 2008). Preparations of intestinal microflora are widely used in commercial broiler production and some have been confirmed to afford protection against Salmonella experimentally (Nakamura et al 2002).…”