Humanized nonobese diabetic-scid IL2rγnullmice are susceptible to lethalSalmonellaTyphi infection

Libby, Stephen J.; Brehm, Michael A.; Greiner, Dale L.; Shultz, Leonard D.; McClelland, Michael; Smith, Kelly D.; Cookson, Brad T.; Karlinsey, Joyce E.; Kinkel, Traci L.; Porwollik, Steffen; Canals, Rocı́o; Cummings, Lisa A.; Fang, Ferric C.

doi:10.1073/pnas.1005566107

Cited by 120 publications

(115 citation statements)

References 66 publications

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“…It is well known that the restriction against S. typhi in mice is not due to a barrier effect as mice are even resistant to intraperitoneal infection (Collins and Carter, 1978). Recent chimeric humanized mouse models demonstrate that the host restriction in bone marrow derived cells applies to systemically administered S. typhi (Firoz Mian et al, 2011;Libby et al, 2010;Song et al, 2010). Consistent with the infection experiments in culture, S. typhi did not cause infection of wild-type mice whereas the absence of TLR11 led to lethal systemic infection, even with a low dose infection (10 4 CFU per animal), with dissemination of the bacteria to different organs ( Supplementary Fig 6C,D).…”

Section: Infection Of Tlr11 Knockout Mice By S Typhi Is Dependent Onsupporting

confidence: 63%

“…The transplantation of mice with human immune cells can render mice susceptible to S. typhi infection by intraperitoneal inoculation, suggesting that the host-specificity of S. typhi also results from a requirement for human mononuclear cells (Firoz Mian et al, 2011;Libby et al, 2010;Song et al, 2010). Our studies suggest that TLR11 is critical for preventing infection by Salmonella typhi following the normal, oral, transmission route.…”

Section: Infection Of Tlr11 Knockout Mice By S Typhi Is Dependent Onmentioning

confidence: 77%

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Mouse model of Salmonella typhi infection

2010

Science-Business eXchange

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Salmonella spp. are gram-negative flagellated bacteria that can cause food and water-borne gastroenteritis and typhoid fever in humans. We now report that flagellin from Salmonella spp. is recognized in mouse intestine by Toll-like receptor 11 (TLR11). Absence of TLR11 renders mice more susceptible to infection by S. typhimurium, with increased dissemination of the bacteria and enhanced lethality. Unlike S. typhimurium, S. typhi, a human obligatory pathogen that causes typhoid fever, is normally unable to infect mice. TLR11 is expressed in mice but not in humans, and remarkably, we find that tlr11 −/− mice are efficiently infected with orally-administered S. typhi. We also find that tlr11 −/− mice can be immunized against S. typhi. Therefore, tlr11 −/− mice represent the first small animal model for the study of the immune response to S. typhi, and for the development of vaccines against this important human pathogen.

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Section: Infection Of Tlr11 Knockout Mice By S Typhi Is Dependent Onsupporting

confidence: 63%

Section: Infection Of Tlr11 Knockout Mice By S Typhi Is Dependent Onmentioning

confidence: 77%

Mouse model of Salmonella typhi infection

2010

Science-Business eXchange

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“…T6SS variants have been acquired at least three times within the Salmonella lineage, and little is known about their function and mechanism, although most reports have implicated roles for the S. Typhimurium SPI-6 T6SS in the pathogenesis of mice and infection of macrophages (5,9,17,19,24,28,30,38). We found that the disruption of noncore T6SS clusters 2 and 4 caused significant defects in systemic dissemination in mice and that disruption of noncore gene clusters 1 and 3 resulted in a significant intracellular replication defect in macrophages.…”

Section: Discussionmentioning

confidence: 99%

Type VI Secretion System-Associated Gene Clusters Contribute to Pathogenesis of Salmonella enterica Serovar Typhimurium

2012

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ABSTRACTThe enteropathogenSalmonella entericaserovar Typhimurium employs a suite of tightly regulated virulence factors within the intracellular compartment of phagocytic host cells resulting in systemic dissemination in mice. A type VI secretion system (T6SS) withinSalmonellapathogenicity island 6 (SPI-6) has been implicated in this process; however, the regulatory inputs and the roles of noncore genes in this system are not well understood. Here we describe four clusters of noncore T6SS genes in SPI-6 based on a comparative relationship with the T6SS-3 ofBurkholderia malleiand report that the disruption of these genes results in defects in intracellular replication and systemic dissemination in mice. In addition, we show that the expression of the SPI-6-encoded Hcp and VgrG orthologs is enhanced during late stages of macrophage infection. We identify six regions that are transcriptionally active during cell infections and that have regulatory contributions from the regulators of virulence SsrB, PhoP, and SlyA. We show that levels of protein expression are very weak underin vitroconditions and that expression is not enhanced upon the deletion ofssrB,phoP,slyA,qseC,ompR, orhfq, suggesting an unknown activating factor. These data suggest that the SPI-6 T6SS has been integrated into theSalmonellaTyphimurium virulence network and customized for host-pathogen interactions through the action of noncore genes.

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“…These studies fail to mimic the essential aspects of immunity induced by S. Typhi [8]. Moreover, the determinants of host defense system to S. Typhimurium and S. Typhi are basically different [9][10][11][12] and earlier studies designate that the host immune interaction in response to S. Typhimurium and S. Typhi are qualitatively diverse.…”

Section: Introductionmentioning

confidence: 99%

“…Moreover, the determinants of host defense system to S. Typhimurium and S. Typhi are basically different [9][10][11][12] and earlier studies designate that the host immune interaction in response to S. Typhimurium and S. Typhi are qualitatively diverse. The lack of a small model has been a foremost hindrance in understanding the virulence mechanisms of S. Typhi [8]. In contrast, there are no reports available on physiological and molecular response of host altered by S. Typhi and S. Typhi Ty21a.…”

Section: Introductionmentioning

confidence: 99%

Physiological and Immunological Regulations in Caenorhabditis elegans Infected with Salmonella enterica serovar Typhi

Sivamaruthi

Balamurugan

2013

Indian J Microbiol

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Studies pertaining to Salmonella enterica serovar Typhimurium infection by utilizing model systems failed to mimic the essential aspects of immunity induced by Salmonella enterica serovar Typhi, as the determinants of innate immunity are distinct. The present study investigated the physiological and innate immune responses of S. Typhi infected Caenorhabditis elegans and also explored the Ty21a mediated immune enhancement in C. elegans. Ty21a is a known live vaccine for typhoidal infection in human beings. Physiological responses of C. elegans infected with S. Typhi assessed by survival and behavioral assays revealed that S. Typhi caused host mortality by persistent infection. However, Ty21a exposure to C. elegans was not harmful. Ty21a pre-exposed C. elegans, exhibited significant resistance against S. Typhi infection. Elevated accumulation of S. Typhi inside the infected host was observed when compared to Ty21a exposures. Transcript analysis of candidate innate immune gene (clec-60, clec-87, lys-7, ilys-3, scl-2, cpr-2, F08G5.6, atf-7, age-1, bec-1 and daf-16) regulations in the host during S. Typhi infection have been assessed through qPCR analysis to understand the activation of immune signaling pathways during S. Typhi infections. Gene silencing approaches confirmed that clec-60 and clec-87 has a major role in the defense system of C. elegans during S. Typhi infection. In conclusion, the study revealed that preconditioning of host with Ty21a protects against subsequent S. Typhi infection.

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Humanized nonobese diabetic-scid IL2rγ^nullmice are susceptible to lethalSalmonellaTyphi infection

Abstract: Salmonella enterica serovar Typhi, the cause of typhoid fever, is host-adapted to humans and unable to cause disease in mice. Here, we show that S.

Cited by 120 publications

References 66 publications

Mouse model of Salmonella typhi infection

Mouse model of Salmonella typhi infection

Type VI Secretion System-Associated Gene Clusters Contribute to Pathogenesis of Salmonella enterica Serovar Typhimurium

Physiological and Immunological Regulations in Caenorhabditis elegans Infected with Salmonella enterica serovar Typhi

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