The Typhoid Toxin Promotes Host Survival and the Establishment of a Persistent Asymptomatic Infection

Lisa Del Bel Belluz; Riccardo Guidi; Ioannis S. Pateras; Laura Levi; Boris Mihaljevic; Syed Fazle Rouf; Marie Wrande; Marco Candela; Silvia Turroni; Claudia Nastasi; Clarissa Consolandi; Clelia Peano; Toma Tebaldi; Gabriella Viero; Vassilis G. Gorgoulis; Thorbjørn Krejsgaard; Mikael Rhen; Teresa Frisan

doi:10.1371/journal.ppat.1005528

The Typhoid Toxin Promotes Host Survival and the Establishment of a Persistent Asymptomatic Infection

Lisa Del Bel Belluz, Riccardo Guidi, Ioannis S. Pateras, Laura Levi, Boris Mihaljevic, Syed Fazle Rouf, Marie Wrande, Marco Candela, Silvia Turroni, Claudia Nastasi, Clarissa Consolandi, Clelia Peano, Toma Tebaldi, Gabriella Viero, Vassilis G. Gorgoulis, Thorbjørn Krejsgaard, Mikael Rhen, Teresa Frisan^*

^*Corresponding author for this work

28 Citations (Scopus)

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Abstract

Bacterial genotoxins, produced by several Gram-negative bacteria, induce DNA damage in the target cells. While the responses induced in the host cells have been extensively studied in vitro, the role of these effectors during the course of infection remains poorly characterized. To address this issue, we assessed the effects of the Salmonella enterica genotoxin, known as typhoid toxin, in in vivo models of murine infection. Immunocompetent mice were infected with isogenic S. enterica, serovar Typhimurium (S. Typhimurium) strains, encoding either a functional or an inactive typhoid toxin. The presence of the genotoxic subunit was detected 10 days post-infection in the liver of infected mice. Unexpectedly, its expression promoted the survival of the host, and was associated with a significant reduction of severe enteritis in the early phases of infection. Immunohistochemical and transcriptomic analysis confirmed the toxin-mediated suppression of the intestinal inflammatory response. The presence of a functional typhoid toxin further induced an increased frequency of asymptomatic carriers. Our data indicate that the typhoid toxin DNA damaging activity increases host survival and favours long-term colonization, highlighting a complex cross-talk between infection, DNA damage response and host immune response. These findings may contribute to understand why such effectors have been evolutionary conserved and horizontally transferred among Gram-negative bacteria.

Original language	English
Article number	e1005528
Journal	PLoS Pathogens
Volume	12
Issue number	4
Number of pages	25
ISSN	1553-7366
DOIs	https://doi.org/10.1371/journal.ppat.1005528
Publication status	Published - 7 Apr 2016

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The Typhoid Toxin Promotes Host Survival and the Establishment of a Persistent Asymptomatic InfectionFinal published version, 6.62 MBLicence: CC BY

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Del Bel Belluz, L., Guidi, R., Pateras, I. S., Levi, L., Mihaljevic, B., Rouf, S. F., Wrande, M., Candela, M., Turroni, S., Nastasi, C., Consolandi, C., Peano, C., Tebaldi, T., Viero, G., Gorgoulis, V. G., Krejsgaard, T., Rhen, M., & Frisan, T. (2016). The Typhoid Toxin Promotes Host Survival and the Establishment of a Persistent Asymptomatic Infection. PLoS Pathogens, 12(4), [e1005528]. https://doi.org/10.1371/journal.ppat.1005528

Del Bel Belluz, L, Guidi, R, Pateras, IS, Levi, L, Mihaljevic, B, Rouf, SF, Wrande, M, Candela, M, Turroni, S, Nastasi, C, Consolandi, C, Peano, C, Tebaldi, T, Viero, G, Gorgoulis, VG, Krejsgaard, T, Rhen, M & Frisan, T 2016, 'The Typhoid Toxin Promotes Host Survival and the Establishment of a Persistent Asymptomatic Infection', PLoS Pathogens, vol. 12, no. 4, e1005528. https://doi.org/10.1371/journal.ppat.1005528

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abstract = "Bacterial genotoxins, produced by several Gram-negative bacteria, induce DNA damage in the target cells. While the responses induced in the host cells have been extensively studied in vitro, the role of these effectors during the course of infection remains poorly characterized. To address this issue, we assessed the effects of the Salmonella enterica genotoxin, known as typhoid toxin, in in vivo models of murine infection. Immunocompetent mice were infected with isogenic S. enterica, serovar Typhimurium (S. Typhimurium) strains, encoding either a functional or an inactive typhoid toxin. The presence of the genotoxic subunit was detected 10 days post-infection in the liver of infected mice. Unexpectedly, its expression promoted the survival of the host, and was associated with a significant reduction of severe enteritis in the early phases of infection. Immunohistochemical and transcriptomic analysis confirmed the toxin-mediated suppression of the intestinal inflammatory response. The presence of a functional typhoid toxin further induced an increased frequency of asymptomatic carriers. Our data indicate that the typhoid toxin DNA damaging activity increases host survival and favours long-term colonization, highlighting a complex cross-talk between infection, DNA damage response and host immune response. These findings may contribute to understand why such effectors have been evolutionary conserved and horizontally transferred among Gram-negative bacteria.",

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AU - Levi, Laura

AU - Mihaljevic, Boris

AU - Rouf, Syed Fazle

AU - Wrande, Marie

AU - Candela, Marco

AU - Turroni, Silvia

AU - Nastasi, Claudia

AU - Consolandi, Clarissa

AU - Peano, Clelia

AU - Tebaldi, Toma

AU - Viero, Gabriella

AU - Gorgoulis, Vassilis G.

AU - Krejsgaard, Thorbjørn

AU - Rhen, Mikael

AU - Frisan, Teresa

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N2 - Bacterial genotoxins, produced by several Gram-negative bacteria, induce DNA damage in the target cells. While the responses induced in the host cells have been extensively studied in vitro, the role of these effectors during the course of infection remains poorly characterized. To address this issue, we assessed the effects of the Salmonella enterica genotoxin, known as typhoid toxin, in in vivo models of murine infection. Immunocompetent mice were infected with isogenic S. enterica, serovar Typhimurium (S. Typhimurium) strains, encoding either a functional or an inactive typhoid toxin. The presence of the genotoxic subunit was detected 10 days post-infection in the liver of infected mice. Unexpectedly, its expression promoted the survival of the host, and was associated with a significant reduction of severe enteritis in the early phases of infection. Immunohistochemical and transcriptomic analysis confirmed the toxin-mediated suppression of the intestinal inflammatory response. The presence of a functional typhoid toxin further induced an increased frequency of asymptomatic carriers. Our data indicate that the typhoid toxin DNA damaging activity increases host survival and favours long-term colonization, highlighting a complex cross-talk between infection, DNA damage response and host immune response. These findings may contribute to understand why such effectors have been evolutionary conserved and horizontally transferred among Gram-negative bacteria.

AB - Bacterial genotoxins, produced by several Gram-negative bacteria, induce DNA damage in the target cells. While the responses induced in the host cells have been extensively studied in vitro, the role of these effectors during the course of infection remains poorly characterized. To address this issue, we assessed the effects of the Salmonella enterica genotoxin, known as typhoid toxin, in in vivo models of murine infection. Immunocompetent mice were infected with isogenic S. enterica, serovar Typhimurium (S. Typhimurium) strains, encoding either a functional or an inactive typhoid toxin. The presence of the genotoxic subunit was detected 10 days post-infection in the liver of infected mice. Unexpectedly, its expression promoted the survival of the host, and was associated with a significant reduction of severe enteritis in the early phases of infection. Immunohistochemical and transcriptomic analysis confirmed the toxin-mediated suppression of the intestinal inflammatory response. The presence of a functional typhoid toxin further induced an increased frequency of asymptomatic carriers. Our data indicate that the typhoid toxin DNA damaging activity increases host survival and favours long-term colonization, highlighting a complex cross-talk between infection, DNA damage response and host immune response. These findings may contribute to understand why such effectors have been evolutionary conserved and horizontally transferred among Gram-negative bacteria.

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The Typhoid Toxin Promotes Host Survival and the Establishment of a Persistent Asymptomatic Infection

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