Gender differences in expression of the human caspase-12 long variant determines susceptibility to
            <i>Listeria monocytogenes</i>
            infection

Yeretssian, Garabet; Doiron, Karine; Shao, Wei; Leavitt, Blair R.; Hayden, Michael R.; Nicholson, Donald W.; Saleh, Maya

doi:10.1073/pnas.0813362106

Cited by 54 publications

(44 citation statements)

References 26 publications

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“…Although more narrow in taxonomic scope than our study, Alexander's quantitative PCR study (Alexander et al, 2006) detected gender-specific differences in only two species of the altered Schaedler's flora (species of Firmicutes and Clostridium). Moreover, expression of a human caspase conferred differential susceptibility to Listeria monocytogenes infection in male and female transgenic mice, apparently due to estrogen interactions (Yeretssian et al, 2009). However, Kovacs et al (2011) found no gender differences in the CC mice of their study.…”

Section: Discussionmentioning

confidence: 86%

Host genetic and environmental effects on mouse intestinal microbiota

et al. 2012

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The mammalian gut harbors complex and variable microbial communities, across both host phylogenetic space and conspecific individuals. A synergy of host genetic and environmental factors shape these communities and account for their variability, but their individual contributions and the selective pressures involved are still not well understood. We employed barcoded pyrosequencing of V1-2 and V4 regions of bacterial small subunit ribosomal RNA genes to characterize the effects of host genetics and environment on cecum assemblages in 10 genetically distinct, inbred mouse strains. Eight of these strains are the foundation of the Collaborative Cross (CC), a panel of mice derived from a genetically diverse set of inbred founder strains, designed specifically for complex trait analysis. Diversity of gut microbiota was characterized by complementing phylogenetic and distance-based, sequence-clustering approaches. Significant correlations were found between the mouse strains and their gut microbiota, reflected by distinct bacterial communities. Cohabitation and litter had a reduced, although detectable effect, and the microbiota response to these factors varied by strain. We identified bacterial phylotypes that appear to be discriminative and strainspecific to each mouse line used. Cohabitation of different strains of mice revealed an interaction of host genetic and environmental factors in shaping gut bacterial consortia, in which bacterial communities became more similar but retained strain specificity. This study provides a baseline analysis of intestinal bacterial communities in the eight CC progenitor strains and will be linked to integrated host genotype, phenotype and microbiota research on the resulting CC panel.

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Section: Discussionmentioning

confidence: 86%

Host genetic and environmental effects on mouse intestinal microbiota

et al. 2012

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“…Quantitative PCR (qPCR) was performed using iTaq SYBR Green Supermix (Bio-Rad, Philadelphia, PA) with primers as in Ref. 9. Fold induction was calculated over uninfected levels using the DD-Ct method.…”

Section: Quantitative Reverse Transcription-polymerase Chain Reactionmentioning

confidence: 99%

“…They trigger inflammation by activating caspase-1, which cleaves pro-IL-1b and pro-IL-18 into their mature active forms. We have previously shown that a second member of the caspase-1 subfamily, caspase-12, which is catalytically inactive in humans and attenuated in rodents (6), acts as an inhibitor of both the inflammasome and NF-kB pathways (7)(8)(9). Expression of human caspase-12 is predominately confined to African descendents and is associated with dampened proinflammatory cytokine production and sepsisrelated mortality (8).…”

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confidence: 99%

Caspase-12 Dampens the Immune Response to Malaria Independently of the Inflammasome by Targeting NF-κB Signaling

Labbé¹,

Miu²,

Yeretssian

et al. 2010

The Journal of Immunology

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Pathogen sensing by the inflammasome activates inflammatory caspases that mediate inflammation and cell death. Caspase-12 antagonizes the inflammasome and NF-κB and is associated with susceptibility to bacterial sepsis. A single-nucleotide polymorphism (T125C) in human Casp12 restricts its expression to Africa, Southeast Asia, and South America. Here, we investigated the role of caspase-12 in the control of parasite replication and pathogenesis in malaria and report that caspase-12 dampened parasite clearance in blood-stage malaria and modulated susceptibility to cerebral malaria. This response was independent of the caspase-1 inflammasome, as casp1−/− mice were indistinguishable from wild-type animals in response to malaria, but dependent on enhanced NF-κB activation. Mechanistically, caspase-12 competed with NEMO for association with IκB kinase-α/β, effectively preventing the formation of the IκB kinase complex and inhibiting downstream transcriptional activation by NF-κB. Systemic inhibition of NF-κB or Ab neutralization of IFN-γ reversed the increased resistance of casp12−/− mice to blood-stage malaria infection.

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“…25 Secondly, it has been suggested that females may have a more effective immune response than males as a result of estrogen-mediated inhibition of caspase-12 expression. 26 We suggest that both these mechanisms may be operational, protecting against infections and also contributing to women's better response to treatment through either improved cytotoxicity or enhanced immune function.It is of interest that female sex has emerged recently as a predictor of better outcomes not only in CLL but also, for example, in cutaneous head and neck melanoma. 27 Another recent report, in chronic myeloid leukemia, included female sex as one of the two more significant predictors of stable molecular response after long-term imatinib therapy.…”

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confidence: 99%

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The clinical significance of patients' sex in chronic lymphocytic leukemia

Catovsky¹,

Wade

Else³

2014

Haematologica

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© F e r r a t a S t o r t i F o u n d a t i o nwhere. 2,9,10 Briefly, chlorambucil was one of the arms in every trial. 11The comparators were the combination of COP (cyclophosphamide, oncovin and prednisolone) and splenic irradiation in CLL1, chlorambucil plus prednisolone and splenic irradiation in CLL2, chlorambucil plus epirubicin in CLL3, and fludarabine with or without cyclophosphamide in LRF CLL4. Biological, cytogenetic and molecular markers were available from patients entered in the LRF CLL4 trial and have been reported elsewhere, together with a full description of the cutoffs used to define positivity. 12,13 Causes of death were centrally categorized using the patients' death certificates and/or reports from the participating centers. Follow-up (overall survival only) was to June 2012 for the trials and June 2010 for the registration series, with a median follow-up for each trial of at least 9 years.Statistical analyses used the chi square test for comparisons of incidence, response to therapy and toxicities. Kaplan-Meier survival curves were calculated and compared by the log-rank test. Overall survival was calculated from randomization to death from any cause. Progression-free survival in the LRF CLL4 trial was defined as the time from randomization to relapse needing further treatment, progression, or death from any cause. For non-responders and progressive disease, date of progression was when no response or progressive disease was recorded. Multivariate analyses of variables significantly associated with response and overall survival in univariate tests were performed by means of stepwise generalized linear modeling and the Cox proportional hazards model respectively. Values of P≤0.05 (two sided) were considered statistically significant. Analyses were performed using the STA-TISTICA software from StatSoft, a wholly owned subsidiary of Dell, Inc.The LRF CLL4 trial was registered as an International Standard Randomized Trial, number ISRCTN58585610 and was approved by the UK multicenter research ethics committee (MREC). All four trials followed the UK Medical Research Council guidelines for good clinical practice. All patients provided informed consent. All authors had access to the primary clinical trial data. The main trial endpoints have been previously reported. 2,9,10 ResultsThe main characteristics of the patients in both series are shown in Table 1. The proportion of females was significantly higher in the registration series than in the randomized series. Women were more likely than men to be aged ≥70 years in both series. They were more likely to have Binet stage A-progressive disease than stage B or C in the randomized series and slightly more likely to have Rai stage 0 disease than Rai stages I-II in the registration series.Overall survival was significantly longer in women both in the randomized series [hazard ratio (HR): 0.72, 95% confidence interval (CI): 0.64-0.81, P<0.0001; Figure 2A Figure 2B). At 10 years, the overall survival rate in the randomized series was 27% (95% CI...

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Gender differences in expression of the human caspase-12 long variant determines susceptibility to Listeria monocytogenes infection

Cited by 54 publications

References 26 publications

Host genetic and environmental effects on mouse intestinal microbiota

Host genetic and environmental effects on mouse intestinal microbiota

Caspase-12 Dampens the Immune Response to Malaria Independently of the Inflammasome by Targeting NF-κB Signaling

The clinical significance of patients' sex in chronic lymphocytic leukemia

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