Humanized mice for<i>Salmonella</i><i>typhi</i>infection: new tools for an old problem

Mian, M. Firoz; Pek, Elisabeth A; Chenoweth, Meghan J.; Coombes, Brian K.; Ashkar, Ali A.

doi:10.4161/viru.2.3.16133

Cited by 27 publications

(19 citation statements)

References 35 publications

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“…Although these humanized mice have proven informative to the study of S. Typhi infection, they are expensive and labor-intensive models and (so far) not widely used. Another limitation of such models is that they are subject to considerable inconsistency as a result of the genetic heterogeneity of donors and the variable degree of engraftment (Libby et al, 2010; Mian et al, 2011). …”

Section: Animal Modelsmentioning

confidence: 99%

Same species, different diseases: how and why typhoidal and non-typhoidal Salmonella enterica serovars differ

2014

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Human infections by the bacterial pathogen Salmonella enterica represent major disease burdens worldwide. This highly ubiquitous species consists of more than 2600 different serovars that can be divided into typhoidal and non-typhoidal Salmonella (NTS) serovars. Despite their genetic similarity, these two groups elicit very different diseases and distinct immune responses in humans. Comparative analyses of the genomes of multiple Salmonella serovars have begun to explain the basis of the variation in disease manifestations. Recent advances in modeling both enteric fever and intestinal gastroenteritis in mice will facilitate investigation into both the bacterial- and host-mediated mechanisms involved in salmonelloses. Understanding the genetic and molecular mechanisms responsible for differences in disease outcome will augment our understanding of Salmonella pathogenesis, host immunity, and the molecular basis of host specificity. This review outlines the differences in epidemiology, clinical manifestations, and the human immune response to typhoidal and NTS infections and summarizes the current thinking on why these differences might exist.

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Section: Animal Modelsmentioning

confidence: 99%

Same species, different diseases: how and why typhoidal and non-typhoidal Salmonella enterica serovars differ

2014

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“…Engrafting such immunodeficient mice with human hematopoietic stem cells (HSC) allows the generation of a “naive” human immune system in the resulting chimeric mice. Multiple human tropic pathogens that are reliant on human hematopoietic cells and their lineages for replication can be studied using this platform, as previously shown for HIV [7,8], Dengue [9] and EBV [10] viruses, and Salmonella typhi [11,12]. HIS mice can, in theory, be used to study human immune responses to any antigen or infectious pathogen.…”

Section: Introductionmentioning

confidence: 99%

Evaluation of the efficiency of human immune system reconstitution in NSG mice and NSG mice containing a human HLA.A2 transgene using hematopoietic stem cells purified from different sources

Patton

Vuyyuru

Siglin

et al. 2015

Journal of Immunological Methods

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Severely immunodeficient mice such as the NOD/SCID/IL2rγnull (NSG) strain can be engrafted with human hematopoietic stem cells (HSCs), resulting in chimeric mice containing many components of the human immune system (Human Immune System mice or HIS mice). HIS mice can both support the replication of and recapitulate much of the immunological response to a variety of pathogens, including ones with strict human tropism, such as HIV-1. In an effort to develop a better mouse model for human infectious pathogen infection and possible immune resolution, we compared the human immune system reconstitution of NSG mice following injection with human CD34+ HSCs purified from either fetal liver (FL) or umbilical cord blood (UCB). We analyzed reconstitution in standard NSG mice as well as a derivative of these mice containing an HLA.A2 encoding transgene (NSG.A2). HSCs from both sources effectively reconstituted hematopoietic lineages when injected into NSG mice. In marked contrast, total CD45+ human hematopoietic cells in NSG.A2 mice were well reconstituted by HSCs from UCB but very poorly by HSCs purified from FL. Moreover, the reconstitution of T cell lineages in NSG.A2 mice by HSCs from UCB was inferior to that obtained using NSG mice. We also found that FL CD34+ HSCs contain a much higher percentage of cells with a phenotype consistent with primitive progenitors than UCB HSCs. We discuss possible explanations for the influence of the HLA.A2 transgene on hematopoietic reconstitution using the two sources of HSCs.

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“…) 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).…”

mentioning

confidence: 99%

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

Eva

Yuki

Dauphinee

et al. 2014

The Journal of Immunology

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Salmonella enterica is a ubiquitous Gram-negative intracellular bacterium that continues to pose a global challenge to human health. The etiology of Salmonella pathogenesis is complex and controlled by pathogen, environmental, and host genetic factors. In fact, patients immunodeficient in genes in the IL-12, IL-23/IFN-γ pathway are predisposed to invasive nontyphoidal Salmonella infection. Using a forward genomics approach by N-ethyl-N-nitrosourea (ENU) germline mutagenesis in mice, we identified the Ity14 (Immunity to Typhimurium locus 14) pedigree exhibiting increased susceptibility following in vivo Salmonella challenge. A DNA-binding domain mutation (p.G418_E445) in Stat4 (Signal Transducer and Activator of Transcription Factor 4) was the causative mutation. STAT4 signals downstream of IL-12 to mediate transcriptional regulation of inflammatory immune responses. In mutant Ity14 mice, the increased splenic and hepatic bacterial load resulted from an intrinsic defect in innate cell function, IFN-γ–mediated immunity, and disorganized granuloma formation. We further show that NK and NKT cells play an important role in mediating control of Salmonella in Stat4Ity14/Ity14 mice. Stat4Ity14/Ity14 mice had increased expression of genes involved in cell–cell interactions and communication, as well as increased CD11b expression on a subset of splenic myeloid dendritic cells, resulting in compromised recruitment of inflammatory cells to the spleen during Salmonella infection. Stat4Ity14/Ity14 presented upregulated compensatory mechanisms, although inefficient and ultimately Stat4Ity14/Ity14 mice develop fatal bacteremia. The following study further elucidates the pathophysiological impact of STAT4 during Salmonella infection.

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Humanized mice forSalmonellatyphiinfection: new tools for an old problem

Abstract: (2011) Humanized mice for Salmonella typhi infection: new tools for an old problem, Virulence, 2:3, 248-252,

Cited by 27 publications

References 35 publications

Same species, different diseases: how and why typhoidal and non-typhoidal Salmonella enterica serovars differ

Same species, different diseases: how and why typhoidal and non-typhoidal Salmonella enterica serovars differ

Evaluation of the efficiency of human immune system reconstitution in NSG mice and NSG mice containing a human HLA.A2 transgene using hematopoietic stem cells purified from different sources

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

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