Humanized mice are susceptible to Salmonella typhi infection

Abstract

Salmonella enterica serovar Typhi is a pathogen that only infects humans. Currently, there is no animal model for studying this pathogen. Recently, alymphoid RAG-2 2/2 /c c 2/2 mice engrafted with human leukocytes, known as humanized mice, have been successfully utilized to develop experimental models for several human-specific viral infections, including HIV, human-like dengue fever and hepatitis C virus. Little is known about the usefulness and feasibility of the humanized mouse model for the study of human-specific bacterial pathogens, such as S. typhi. The aim of this study was to determine if Salmonella enterica serovar Typhi could establish productive infection in humanized mice. Here we report that intravenous inoculation of S. typhi into humanized mice, but not controls, established S. typhi infections. High bacterial loads were found in the liver, spleen, blood and bone marrow of mice reconstituted with human leukocytes, but not in the unreconstituted control mice. Importantly, S. typhi-infected humanized mice lost significant body weight, and some of the infected mice displayed neurological symptoms. Our data suggest, for the first time, that humanized mice are susceptible to S. typhi challenge and that this model can be utilized to study the pathogenesis of S. typhi to develop novel therapeutic strategies.

Host Specificity of Bacterial Pathogens

“…Engraftment of human hematopoietic stem cells into a different mouse background, Rag2 IL2rg null mice, has also been shown to render mice susceptible to S. Typhi infection. However, although the humanized Rag2 IL2rg null mice show high organism burdens indicative of bacterial replication, their infections do not appear to be as lethal as those observed in hu-SRC-SCID mice (Song et al 2010;Firoz Mian et al 2011). It is not clear whether this is owing to different levels or types of human cell engraftment, or perhaps to contributions of the NOD mutation to typhoid susceptibility.…”

Current advances in humanized mouse models

“…[72][73][74] Humanized models of tuberculosis, salmonellosis, yellow fever and Dengue fever have been investigated. [75][76][77] Animal models appropriate for developing a malaria vaccine are eagerly desired, as malaria is one of the most common infectious diseases worldwide. 78 An interesting human malaria model uses immunodeficient mice with transplanted human liver.…”

Altered IFN-γ–Mediated Immunity and Transcriptional Expression Patterns in N-Ethyl-N-Nitrosourea–Induced STAT4 Mutants Confer Susceptibility to Acute Typhoid-like Disease

“…) and, more recently, Tlr11 2/2 mice, which have been shown to be efficiently colonized by S. Typhi, are providing novel tools to study typhoid fever (22)(23)(24)(25). Following oral infection of mice, Salmonella invade the microfold cells in the intestinal epithelium and are taken up by dendritic cells (DCs) and macrophages in the underlying Peyer's patches before infecting the mesenteric lymph nodes and eventually disseminating via the circulation to replicate in resident phagocytes of the spleen and liver (26,27).…”