Dissemination and proliferation of Salmonella typhimurium in genetically resistant and susceptible mice

Xu, Hong-Ru; Hsu, H. S.

doi:10.1099/00222615-36-6-377

Cited by 20 publications

(22 citation statements)

References 8 publications

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“…Fas-mediated apoptosis has also been implicated in the pathogenicity of Salmonella infection in mice, which is predominantly localized in the liver (36)(37)(38). Consistent with this, treatment with CBLB502 (but not with LPS) improved survival of mice infected with a lethal dose of Salmonella typhimurium (Fig.…”

Section: Metastasis Suppression By Cblb502 Is Mediated By Mobilizatiosupporting

confidence: 66%

“…and function of TLR5 in the liver make biological sense, given that the liver is the primary site of Salmonella residence during infections (36). Our finding that TLR5 and TLR4 are expressed in two different nonoverlapping liver compartments, hepatocytes and Kupffer cells, respectively, further differentiates TLR5 from TLR4, the latter of which is predominantly expressed in cells of the immune system (1).…”

Section: Discussionmentioning

confidence: 85%

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Central role of liver in anticancer and radioprotective activities of Toll-like receptor 5 agonist

Burdelya

Brackett

Kojouharov

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

112

175

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Vertebrate Toll-like receptor 5 (TLR5) recognizes bacterial flagellin proteins and activates innate immune responses to motile bacteria. In addition, activation of TLR5 signaling can inhibit growth of TLR5-expressing tumors and protect normal tissues from radiation and ischemia-reperfusion injuries. To understand the mechanisms behind these phenomena at the organismal level, we assessed nuclear factor kappa B (NF-κB) activation (indicative of TLR5 signaling) in tissues and cells of mice treated with CBLB502, a pharmacologically optimized flagellin derivative. This identified the liver and gastrointestinal tract as primary CBLB502 target organs. In particular, liver hepatocytes were the main cell type directly and specifically responding to systemic administration of CBLB502 but not to that of the TLR4 agonist LPS. To assess CBLB502 impact on other pathways, we created multireporter mice with hepatocytes transduced in vivo with reporters for 46 inducible transcription factor families and found that along with NF-κB, CBLB502 strongly activated STAT3-, phenobarbital-responsive enhancer module (PREM), and activator protein 1 (AP-1-) -driven pathways. Livers of CBLB502-treated mice displayed induction of numerous immunomodulatory factors and massive recruitment of various types of immune cells. This led to inhibition of growth of liver metastases of multiple tumors regardless of their TLR5 status. The changed liver microenvironment was not, however, hepatotoxic, because CBLB502 induced resistance to Fas-mediated apoptosis in normal liver cells. Temporary occlusion of liver blood circulation prevented CBLB502 from protecting hematopoietic progenitors in lethally irradiated mice, indicating involvement of a factor secreted by responding liver cells. These results define the liver as the key mediator of TLR5-dependent effects in vivo and suggest clinical applications for TLR5 agonists as hepatoprotective and antimetastatic agents.breast cancer | colon cancer | neutrophils | natural killer cells | Salmonella T oll-like receptors (TLRs) recognize and are activated by specific patterns in molecules that are produced by a broad range of microbial pathogens but are not present in host molecules. Activation of TLRs by these pathogen-associated molecular patterns leads to induction of infection-fighting innate immune responses (1). Various TLR agonists have been considered for multiple clinical applications, including cancer immunotherapy (2-4), and one, the TLR7 agonist imiquimod, is approved for topical treatment of basal cell carcinoma (5).Although signaling pathways induced by different TLRs all result in mobilization of an innate immune response and involve activation of nuclear factor kappa B (NF-κB), the key regulator of immunity (6, 7), TLR5 is a particularly attractive candidate for therapeutic targeting for several reasons. First, bacterial flagellin, the natural ligand of TLR5, was found to have strong radioprotective effects in rodents and nonhuman primates (8). CBLB502 is a rationally designed derivative of Salmon...

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Section: Metastasis Suppression By Cblb502 Is Mediated By Mobilizatiosupporting

confidence: 66%

Section: Discussionmentioning

confidence: 85%

Central role of liver in anticancer and radioprotective activities of Toll-like receptor 5 agonist

Burdelya

Brackett

Kojouharov

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

112

175

View full text Add to dashboard Cite

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“…It is clear, however, that IgG2c-switched Ab to LPS or FliC was not induced during the early EF response, even though good IgM responses were detected against both Ag. The induction of the EF response corresponds to the time when the hemogenous spread of the organism in humans and mice peaks, suggesting Ab contributes to curb the bacteremia (32,(45)(46)(47).…”

Section: Discussionmentioning

confidence: 99%

Salmonella Induces a Switched Antibody Response without Germinal Centers That Impedes the Extracellular Spread of Infection

Cunningham

Gaspal

Serre

et al. 2007

The Journal of Immunology

183

235

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T-dependent Ab responses are characterized by parallel extrafollicular plasmablast growth and germinal center (GC) formation. This study identifies that, in mice, the Ab response against Salmonella is novel in its kinetics and its regulation. It demonstrates that viable, attenuated Salmonella induce a massive early T-dependent extrafollicular response, whereas GC formation is delayed until 1 mo after infection. The extrafollicular Ab response with switching to IgG2c, the IgG2a equivalent in C57BL/6 mice, is well established by day 3 and persists through 5 wk. Switching is strongly T dependent, and the outer membrane proteins are shown to be major targets of the early switched IgG2c response, whereas flagellin and LPS are not. GC responses are associated with affinity maturation of IgG2c, and their induction is associated with bacterial burden because GC could be induced earlier by treating with antibiotics. Clearance of these bacteria is not a consequence of high-affinity Ab production, for clearance occurs equally in CD154-deficient mice, which do not develop GC, and wild-type mice. Nevertheless, transferred low- and high-affinity IgG2c and less efficiently IgM were shown to impede Salmonella colonization of splenic macrophages. Furthermore, Ab induced during the infection markedly reduces bacteremia. Thus, although Ab does not prevent the progress of established splenic infection, it can prevent primary infection and impedes secondary hemogenous spread of the disease. These results may explain why attenuated Salmonella-induced B cell responses are protective in secondary, but not primary infections.

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“…In the first laboratory experiments, we infected male mice (MHC haplotypes DD, KK, QQ, DK, DQ, and KQ) with a single LT2 strain (Xu and Hsu 1992). In the second experiment, we infected equal numbers of males and females (haplotypes BB, DD, QQ, BD, BQ, and DQ) first with a single LT2 strain.…”

Section: Methodsmentioning

confidence: 99%

Major Histocompatibility Complex Heterozygosity Reduces Fitness in Experimentally Infected Mice

et al. 2007

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It is often suggested that heterozygosity at major histocompatibility complex (MHC) loci confers enhanced resistance to infectious diseases (heterozygote advantage, HA, hypothesis), and overdominant selection should contribute to the evolution of these highly polymorphic genes. The evidence for the HA hypothesis is mixed and mainly from laboratory studies on inbred congenic mice, leaving the importance of MHC heterozygosity for natural populations unclear. We tested the HA hypothesis by infecting mice, produced by crossbreeding congenic C57BL/10 with wild ones, with different strains of Salmonella, both in laboratory and in large population enclosures. In the laboratory, we found that MHC influenced resistance, despite interacting wild-derived background loci. Surprisingly, resistance was mostly recessive rather than dominant, unlike in most inbred mouse strains, and it was never overdominant. In the enclosures, heterozygotes did not show better resistance, survival, or reproductive success compared to homozygotes. On the contrary, infected heterozygous females produced significantly fewer pups than homozygotes. Our results show that MHC effects are not masked on an outbred genetic background, and that MHC heterozygosity provides no immunological benefits when resistance is recessive, and can actually reduce fitness. These findings challenge the HA hypothesis and emphasize the need for studies on wild, genetically diverse species.

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Dissemination and proliferation of Salmonella typhimurium in genetically resistant and susceptible mice

Cited by 20 publications

References 8 publications

Central role of liver in anticancer and radioprotective activities of Toll-like receptor 5 agonist

Central role of liver in anticancer and radioprotective activities of Toll-like receptor 5 agonist

Salmonella Induces a Switched Antibody Response without Germinal Centers That Impedes the Extracellular Spread of Infection

Major Histocompatibility Complex Heterozygosity Reduces Fitness in Experimentally Infected Mice

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