Enhanced Virulence of Salmonella enterica Serovar Typhimurium after Passage through Mice

Abstract

The interaction between Salmonella enterica and the host immune system is complex. The outcome of an infection is the result of a balance between the in vivo environment where the bacteria survive and grow and the regulation of fitness genes at a level sufficient for the bacteria to retain their characteristic rate of growth in a given host. Using bacteriological counts from tissue homogenates and fluorescence microscopy to determine the spread, localization, and distribution of S. enterica in the tissues, we show that, during a systemic infection, S. enterica adapts to the in vivo environment. The adaptation becomes a measurable phenotype when bacteria that have resided in a donor animal are introduced into a recipient naïve animal. This adaptation does not confer increased resistance to early host killing mechanisms but can be detected as an enhancement in the bacterial net growth rate later in the infection. The enhanced growth rate is lost upon a single passage in vitro, and it is therefore transient and not due to selection of mutants. The adapted bacteria on average reach higher intracellular numbers in individual infected cells and therefore have patterns of organ spread different from those of nonadapted bacteria. These experiments help in developing an understanding of the influence of passage in a host on the fitness and virulence of S. enterica.Salmonella enterica is a facultative intracellular pathogen capable of causing a spectrum of diseases in humans and animals. Current treatments for S. enterica infections are insufficiently effective, and there is a need to develop novel vaccines and therapeutics. Development of these control strategies would benefit from a more sophisticated evaluation of how the bacteria maintain their growth/survival throughout the infection in the face of changes in the host environment that may also include activation of host immune responses.Infection of mice with Salmonella enterica serovar Typhimurium is an established model of systemic typhoid fever in humans. In systemic infections, S. enterica resides within phagocytes. Early after intravenous (i.v.) infection, a decrease in total viable bacterial numbers is observed in infected livers and spleens, as the result of a high rate of reactive oxygen radical-mediated killing that exceeds the bacterial division rate (6). After this initial phase, killing becomes negligible and the bacteria divide intracellularly at variable rates, depending on both the virulence of the infecting isolate and the level of resistance of the host (6, 7, 18). Growth of virulent S. Typhimurium in vivo is also associated with escape from infected macrophages and dissemination to other uninfected cells (1,18). This is a necessary step for the overall net growth of the bacteria in the organs, results in the formation of new infection foci, and is likely to occur mainly as a consequence of necrosis of infected cells and establishment of new foci of infection by the released bacteria (1, 5).Despite activation of the immune system, S. enterica grows a...

Virulence Gene Profiling and Pathogenicity Characterization of Non-Typhoidal Salmonella Accounted for Invasive Disease in Humans

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