Human genetic variation altering anthrax toxin sensitivity

Martchenko, Mikhail; Candille, Sophie I.; Tang, Hua; Cohen, Stanley N.

doi:10.1073/pnas.1121006109

Cited by 27 publications

(36 citation statements)

References 52 publications

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“…Similar approaches have also been applied to other cellular phenotypes, including sensitivity to chemotherapeutic drugs (19,20), HIV infection (21), and sensitivity to a bacterial toxin (22). Lymphoblastoid cell lines (LCLs), collected and genotyped as part of the HapMap Project (23), were assayed for pyroptosis and other quantitative phenotypes of host response.…”

mentioning

confidence: 99%

Functional genetic screen of human diversity reveals that a methionine salvage enzyme regulates inflammatory cell death

Ko¹,

Gamazon

Shukla³

et al. 2012

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

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Genome-wide association studies can identify common differences that contribute to human phenotypic diversity and disease. When genome-wide association studies are combined with approaches that test how variants alter physiology, biological insights can emerge. Here, we used such an approach to reveal regulation of cell death by the methionine salvage pathway. A common SNP associated with reduced expression of a putative methionine salvage pathway dehydratase, apoptotic protease activating factor 1 (APAF1)-interacting protein (APIP), was associated with increased caspase-1-mediated cell death in response to Salmonella. The role of APIP in methionine salvage was confirmed by growth assays with methionine-deficient media and quantitation of the methionine salvage substrate, 5′-methylthioadenosine. Reducing expression of APIP or exogenous addition of 5′-methylthioadenosine increased Salmonellae-induced cell death. Consistent with APIP originally being identified as an inhibitor of caspase-9-dependent apoptosis, the same allele was also associated with increased sensitivity to the chemotherapeutic agent carboplatin. Our results show that common human variation affecting expression of a single gene can alter susceptibility to two distinct cell death programs. Furthermore, the same allele that promotes cell death is associated with improved survival of individuals with systemic inflammatory response syndrome, suggesting a possible evolutionary pressure that may explain the geographic pattern observed for the frequency of this SNP. Our study shows that in vitro association screens of disease-related traits can not only reveal human genetic differences that contribute to disease but also provide unexpected insights into cell biology.HapMap | lymphoblastoid | pyroptosis | quantitative trait | polygenic adaptation

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mentioning

confidence: 99%

Functional genetic screen of human diversity reveals that a methionine salvage enzyme regulates inflammatory cell death

Ko¹,

Gamazon

Shukla³

et al. 2012

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

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“…Analizando los porcentajes de ANTXR1 presente en los monocitos de donantes voluntarios de sangre, encontraron grandes diferencias en la expresión de los receptores específicos, por lo que clasificaron a estas poblaciones en grupos denominados de "baja" o "alta" capacidad de expresión. Estos resultados establecen notables diferencias de sensibilidad hacia la toxina en líneas de células linfoblásticas humanas, como resultado, en parte, de los niveles de expresión de ANTXR2 (Martchenko et al, 2012).…”

Section: Vacuna Sterne: Generación De Respuesta Inmuneunclassified

Carbunco. Prevención de la enfermedad

Bernagozzi¹,

Barragán²,

Anselmino³

et al. 2017

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Resumen:Este trabajo revisa las alternativas para la prevención del carbunco, desde la vacuna desarrollada por Pasteur hasta las actuales. Así, se describen diferentes tipos de vacunas (basadas en el antígeno protector, en esporos inactivados, en plásmidos, entre otras) y los efectos que estas producen. Palabras clave: Bacillus anthracis, factores de patogenicidad, toxinas, inmunopatogenia, vacunasAbstract: This work reviews the alternatives used for prevention of carbunco, from the vaccine developed by Pasteur up to current ones. Thus, different types of vaccines (based on protective antigen, inactivated spores, or plasmids) and their effects are described.

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“…This suggests that human cells have varying ability for exotoxin uptake. Further, a SNP that causes a P357A substitution in the human CMG2 region involved with PA internalization reduces the amount of PA uptake in transgenic RAW264.7 cells [132]. It is likely, however, that AMs are uniquely resistant to LT-mediated death as the AMs in Wu's studies were likely collected from several individuals [204].…”

Section: Immunological Effectsmentioning

confidence: 93%

“…Pathological examination of animals that died from injected exotoxin did not show evidence of fibrin deposits, vasculitis, inflammation, or pleural effusions that are often seen at end stages of anthrax [129,131]. Given the number of mammals that B. anthracis infects and the variable resistance to intoxication within a species, B. anthracis may use the exotoxins primarily as a mechanism to increase bacterial burden and dissemination [132]. However, in order to complete their infection cycle and infect new hosts, the bacteria must kill the host and sporulate [17].…”

Section: Death Of the Hostmentioning

confidence: 99%

“…This might be due to single nucleotide polymorphisms (SNPs) in human macrophages. Genetic susceptibility to exotoxin uptake was explored in an in vitro system where lymphoblastoid cells derived from 234 cohorts in the HapMap Project [132]. Cells were treated with PA and FP59, a heterologous cargo protein for the PA oligomer that rapidly kills lymphocytes in a manner independent from either LT or ET, to assess their relative capacity for intoxication.…”

Section: Immunological Effectsmentioning

confidence: 99%

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Opening moves: early events in anthrax pathogenesis and their consequences for dissemination

Lowe

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Bacillus anthracis is a Gram positive sporulating bacterium that is the causative agent of anthrax. Early steps in dissemination are understudied due to the asymptomatic and asynchronous nature of B. anthracis infections. The goals of these studies are to establish a model of the early steps of B. anthracis infections and examine how the initial site of infection and exotoxin production affect bacterial dissemination. In these studies, a mouse model was used in combination with a bioluminescent signature tagged library to determine how B.anthracis disseminates through the host and the roles of an exotoxin component, lethal factor, in colonization and dissemination. This library allowed for real time observation of dissemination and analysis of bacterial population dynamics. In the first set of experiments, mice were infected via inhalational or subcutaneous routes with the tagged library to determine how the bacterial population changed during dissemination. In inhalational and subcutaneous infections, the disseminated population was comprised of a small subset of the original library.This indicated the presence of a population bottleneck, a random decrease in genetic diversity during the infection. Surprisingly, the diminishment and location of the bottleneck varied depending on the initial site of infection. This suggested B. anthracis exploits multiple host environments and some sites may be more permissive for dissemination than others. In the second set of experiments, mice were infected with a signature tagged library where a portion of clones lacked lethal factor. Lethal factor is known to be an important virulence factor as deletion results in attenuated or complete loss of virulence in most animal models. Host survival increased when < 10% of the library produced lethal factor, but few other differences were observed. Furthermore, decreases in the proportion of lethal factor producing clones led to fewer clones disseminating. These findings suggest that a threshold of lethal factor must be ii produced for colonization and dissemination to occur in vivo. In total, this work provides an understanding of how B. anthracis is able to rapidly disseminate from a several tissues and gives insights in where future therapeutics should be focused to reduce disease incidence.iii

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Human genetic variation altering anthrax toxin sensitivity

Cited by 27 publications

References 52 publications

Functional genetic screen of human diversity reveals that a methionine salvage enzyme regulates inflammatory cell death

Functional genetic screen of human diversity reveals that a methionine salvage enzyme regulates inflammatory cell death

Carbunco. Prevención de la enfermedad

Opening moves: early events in anthrax pathogenesis and their consequences for dissemination

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