Typhoid toxin exhausts the RPA response to DNA replication stress driving senescence and Salmonella infection

Ibler, Angela EM; ElGhazaly, Mohamed; Naylor, Kathryn; Bulgakova, Natalia A.; El‐Khamisy, Sherif F.; Humphreys, Daniel

doi:10.1038/s41467-019-12064-1

Cited by 51 publications

(61 citation statements)

References 59 publications

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“…γH2AX provided consistent, reliable results on isolated myoblasts in vitro following γ‐irradiation and on muscle tissue cross sections (see below). γH2AX is best known as a indicator of DNA damage, and, according to PubMed, γH2AX has been used as an indicator of senescence in nearly 500 manuscripts, including several studies 28,45‐47 that use γH2AX as the sole marker of senescence. However, due to the importance of using multiple markers to quantify senescent cells (reviewed by Ref.…”

Section: Resultsmentioning

confidence: 99%

In vivo analysis of γH2AX+ cells in skeletal muscle from aged and obese humans

et al. 2020

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Over the past 20 years, various identifiers of cellular senescence have been used to quantify the abundance of these cells in different tissues. These include classic markers such as p16, senescence-associated β-gal, and γH2AX, in addition to more recent markers (Sudan Black B and HMGB1). In vivo data on the usefulness of these markers in skeletal muscle are very limited and inconsistent. In the present study, we attempted to identify senescent cells in frozen human skeletal muscle biopsies using these markers to determine the effects of age and obesity on senescent cell burden; however, we were only able to assess the abundance of DNA-damaged nuclei using γH2AX immunohistochemistry. The abundance of γH2AX+ cells, including satellite cells, was not higher in muscle from old compared to young individuals; however, γH2AX+ cells were higher with obesity. Additionally, terminally differentiated, postmitotic myofiber nuclei from obese individuals had elevated γH2AX abundance compared to muscle from lean individuals. Analyses of gene expression support the conclusion that the elevated DNA damage and the senescence-associated secretory phenotype are preferentially associated with obesity in skeletal muscle. These data implicate obesity as a larger contributor to DNA damage in skeletal muscle than aging; however, more sensitive senescence markers for human skeletal muscle are needed to determine if these cells are in fact senescent. K E Y W O R D SDNA damage, postmitotic, satellite cells, senescence, γH2AX | 7019 DUNGAN et Al.

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Section: Resultsmentioning

confidence: 99%

In vivo analysis of γH2AX+ cells in skeletal muscle from aged and obese humans

et al. 2020

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“…While the direct induction of senescence by genotoxins further implicates bacteria in oncogenesis, it is less clear whether senescence is subverted by pathogens to promote infection. One example recently implicated in senescence includes the typhoid toxin [19], which is a unique chrimeric toxin encoded by the serovars of the intracellular pathogen Salmonella that cause enteric fever (e.g., typhoidal serovars S. Typhi, S. Paratyphi) and inflammatory gastroenteritis (e.g., non-typhoidal serovars S. Javiana, S. Montevideo) in humans [101][102][103]. The typhoid toxin has been reported to play important roles during the Salmonella infection of mice and humans including pathogen dissemination and host colonisation, the suppression of inflammatory responses, bacteraemia, typhoid fever and chronic Salmonella carriage [103][104][105][106].…”

Section: Induction Of Senescencementioning

confidence: 99%

“…The typhoid toxin mediates its toxigenic activities through CdtB, which is exocytosed from infected mammalian cells in a chimeric complex with the pertussis toxin subunits PltA and Plt, the latter facilitate toxin endocytosis into bystander cells where CdtB causes DNA damage [102,103,107]. Recent work on the typhoid toxin revealed that senescence is hijacked by S. Typhi and S. Javiana to enhance the intracellular Salmonella infection of macrophage and fibroblast-like cells [19]. A senescent-like phenotype was triggered by two mutually exclusive DDRs in distinct cell populations: ATM-dependent γH2AX foci in G1 or ATR-dependent γH2AX localised at the nuclear periphery in G2/M, referred to as RING (response induced by a bacterial genotoxin).…”

Section: Induction Of Senescencementioning

confidence: 99%

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Senescence and Host–Pathogen Interactions

Humphreys

ElGhazaly

Frisan

2020

Cells

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Damage to our genomes triggers cellular senescence characterised by stable cell cycle arrest and a pro-inflammatory secretome that prevents the unrestricted growth of cells with pathological potential. In this way, senescence can be considered a powerful innate defence against cancer and viral infection. However, damage accumulated during ageing increases the number of senescent cells and this contributes to the chronic inflammation and deregulation of the immune function, which increases susceptibility to infectious disease in ageing organisms. Bacterial and viral pathogens are masters of exploiting weak points to establish infection and cause devastating diseases. This review considers the emerging importance of senescence in the host–pathogen interaction: we discuss the pathogen exploitation of ageing cells and senescence as a novel hijack target of bacterial pathogens that deploys senescence-inducing toxins to promote infection. The persistent induction of senescence by pathogens, mediated directly through virulence determinants or indirectly through inflammation and chronic infection, also contributes to age-related pathologies such as cancer. This review highlights the dichotomous role of senescence in infection: an innate defence that is exploited by pathogens to cause disease.

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“…One of the consequences of DNA damage in cells exposed in vitro to bacterial genotoxins is 122 the acquisition of senescence (Blazkova et al, 2010;Ibler et al, 2019), which is associated with 123 secretion of a broad panel of mediators, mainly related to a pro-inflammatory effect, such as 124 IL1, IL6, and IL8 (Hernandez-Segura et al, 2018). Induction of the senescent phenotype in in 125 vivo bacterial infection is poorly characterized.…”

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Influence of the microenvironment on the modulation of the host response by the typhoid toxin

Martin

Butter

Paparouna

et al. 2020

Preprint

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30Bacterial genotoxins cause DNA damage in eukaryotic cells, resulting in activation of the DNA 31 damage response (DDR) in vitro. These toxins are produced by Gram negative bacteria, en-32 riched in the microbiota of Inflammatory Bowel Disease (IBD) and colorectal cancer (CRC) 33 patients. However, their role in infection remains poorly characterized. We have addressed the 34 role of the typhoid toxin in the modulation of the host-microbial interaction in health and dis-35 ease. 36Infection with a genotoxigenic Salmonella protected mice from intestinal inflammation. The 37 toxin-induced DNA damage caused senescence in vivo, which was uncoupled from the inflam-38 matory response, and associated with the maintenance of an anti-inflammatory environment. 39This effect was lost when infection occurred in mice suffering from inflammatory conditions 40 that mimic Ulcerative Colitis, a form of IBD. 41These data highlight a complex context-dependent crosstalk between bacterial genotoxins-in-42 duced DDR and the host immune response, underlining an unexpected role for bacterial geno-43 toxins. 44 45 cumulates in the cytoplasm of senescent cells (Evangelou et al., 2017). As shown in Figures 2C 130 and S3A, we detected a significant increase in GL13 epithelial positive cells in the colon and 131 small intestine of mice infected with the MC1 TT and MC71 TT strains compared to the levels 132 detected in mice infected with the control Salmonella, with the most prominent effect observed 133 in the C57BL/6 mouse strain (cp Figure 2C and Figure S3A). In our model, induction of senes-134 cence was uncoupled from the activation of a pro-inflammatory response (Figures 1, 3 and S2). 135 136The typhoid toxin maintains an anti-inflammatory microenvironment 137 Supplementary Information

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Typhoid toxin exhausts the RPA response to DNA replication stress driving senescence and Salmonella infection

Cited by 51 publications

References 59 publications

In vivo analysis of γH2AX+ cells in skeletal muscle from aged and obese humans

In vivo analysis of γH2AX+ cells in skeletal muscle from aged and obese humans

Senescence and Host–Pathogen Interactions

Influence of the microenvironment on the modulation of the host response by the typhoid toxin

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