Of Mice and Men: Finding appropriate animal models

Questions arise about an attractive mouse model of Salmonella typhi infection.
Of Mice and Men:  Finding appropriate animal models

There is no doubt that the use of animals, especially mouse models, has transformed our ability to ask critical questions about the molecular basis of pathogenesis of many important human infectious diseases. Mouse models also enable us to do important work in testing new vaccines, antimicrobial compounds and treatment regimens. However, mice models have proved challenging for investigating several important pathogens that are restricted to humans and primates. Among these include Shigella species, HIV, Hepatitis C virus, Plasmodium falciparum and the subject of this post: Salmonella enterica serotype typhi (S. Typhi from here on).

S. Typhi is the causative agent of typhoid fever, a scourge of humanity throughout history. Much of the unique aspects of typhoid fever involve macrophage invasion, dissemination throughout the body and secretion of the typhoid toxin. However, S. Typhi does not infect and replicate well in wildtype mice tissues. In contrast, much of the work in understanding Salmonella pathogenesis in mice has utilized enterically localized strains such as S. typhimurium, which while powerful for dissecting factors necessary for intestinal colonization and pathogenesis, do not fully reproduce typhoid fever symptoms. The basis of the S. Typhi host restriction barrier, in work by Galan and colleagues, was traced to the lack of a bacterial effector necessary to subvert a mouse specific trafficking protein, and reintroduction of this protein could now enable S. Typhi to now productively infect a mouse host.

Complementary to altering the pathogen to adapt better to mice, studies have also modified mouse factors to enable wildtype pathogens to gain a foothold. In S. Typhi, these mouse models have included reconstituting mice with humanized hematopoietic cells and deletion of a mouse specific innate immune receptor, TLR11, which was found to recognize and respond to S. Typhi flagella subunits. The TLR11 model was particularly attractive for the study of S. Typhi pathogenesis as adaptive immunity could be kept intact and did not require humanized mice. However, in two recent correspondences in Cell, the usefulness of the TLR11 model of S. Typhi is less clear cut than previously thought. Several groups have been unable to reproduce the phenotype that TLR11 deletion sensitizes mice to S. Typhi, while the original authors find that over time the phenotype has become more variable, suggesting differences in protocols and potentially housing and breeding conditions may make all the difference. Another point of difference between the studies was over the original observation that TLR11 recognized flagellin, a point that could be complicated due to redundant TLR11-independent flagellin-recognition processes in different cell types.

While the debate will continue over the appropriateness of the TLR11 model for the study of S. Typhi, and whether additional factors such as the microbiota could explain the discrepancy between studies, this correspondence is emblematic of the need for deeper understanding of the animal host in microbial pathogenesis research: in addition to interrogating the disease by using animal models, it is important to also better understand the models themselves so that we know whether they can even address the questions that we setting out to answer.

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