Independent Bottlenecks Characterize Colonization of Systemic Compartments and Gut Lymphoid Tissue by Salmonella

Abstract

Vaccination represents an important instrument to control typhoid fever in humans and protects mice from lethal infection with mouse pathogenic serovars of Salmonella species. Mixed infections with tagged Salmonella can be used in combination with probabilistic models to describe the dynamics of the infection process. Here we used mixed oral infections with tagged Salmonella strains to identify bottlenecks in the infection process in naïve and vaccinated mice. We established a next generation sequencing based method to characterize the composition of tagged Salmonella strains which offers a fast and reliable method to characterise the composition of genome-tagged Salmonella strains. We show that initial colonization of Salmonella was distinguished by a non-Darwinian selection of few bacteria setting up the infection independently in gut associated lymphoid tissue and systemic compartments. Colonization of Peyer's patches fuels the sustained spread of bacteria into mesenteric lymph nodes via dendritic cells. In contrast, infection of liver and spleen originated from an independent pool of bacteria. Vaccination only moderately reduced invasion of Peyer's patches but potently uncoupled bacterial populations present in different systemic compartments. Our data indicate that vaccination differentially skews the capacity of Salmonella to colonize systemic and gut immune compartments and provide a framework for the further dissection of infection dynamics.

Intracellular Listeria monocytogenes Comprises a Minimal but Vital Fraction of the Intestinal Burden following Foodborne Infection

“…Studies using signature-tagged bacteria have been fundamental in modeling the systemic spread of enteric pathogens by highlighting two routes of spread from the gut (7)(8)(9). One route presumably involves direct invasion of the bloodstream and dissemination via the portal vein since it results in colonization primarily in the liver.…”

“…The mechanisms used by bacteria to promote this invasion are unclear, and it is possible that the use of excessively large inocula or physically traumatic transmission methods can facilitate rapid spread by this route. Bacteria can also reach the spleen and liver after colonizing the draining mesenteric lymph nodes (MLN) (7)(8)(9). Melton-Witt et al showed that this indirect route of spread led to continual seeding of the spleen, presumably due to the flow of efferent lymphatic fluid into the bloodstream via the thoracic duct (9).…”

Contaminated Water Delivery as a Simple and Effective Method of Experimental Salmonella Infection

“…Furthermore, the kinetics of infection followed a similar pattern beginning with bacteria detectable solely in the MLN and then spreading quickly to the spleen and liver, where numbers subsequently increased at similar rates. This kinetic was strikingly similar at higher doses and likely reflects the bottleneck in intestinal entry with high numbers of bacteria [32]. However, the overall kinetics of infection, and the percentage of mice that were infected over time, show greater variability with lower doses using both experimental approaches.…”

“…However, a major drawback to this method is that the gavage needle has the potential to damage the esophageal lining, raising some concern that bacteria could use experimentally-induced abrasions to access the host via an unnatural route [8, 32–34]. In addition, the restraint and manipulation required for effective oral gavage dosing induces significant stress in experimental animals [33, 35, 36], which could potentially impact the immune response [37–40] and/or susceptibility to infection [41–44].…”

A Bioluminescent Francisella tularensis SCHU S4 Strain Enables Noninvasive Tracking of Bacterial Dissemination and the Evaluation of Antibiotics in an Inhalational Mouse Model of Tularemia

“…Additionally, the gastrointestinal microbiota plays a role in regulating bacterial translocation, and treatments that disrupt microbiota dynamics, such as antibiotics, may increase bacterial translocation (57). Further work is needed to determine the spatiotemporal population dynamics during relapse of infection with F. tularensis SCHU S4 and to determine whether different subpopulations of bacteria are responsible for the reemergence of infection in different organs, as noted previously for persistent Salmonella infections (58,59).…”