AUTHOR=Lopez Chiloeches Maria , Bergonzini Anna , Martin Océane C. B. , Bergstein Nicole , Erttmann Saskia F. , Aung Kyaw Min , Gekara Nelson O. , Avila Cariño Javier F. , Pateras Ioannis S. , Frisan Teresa 

TITLE=Genotoxin-producing Salmonella enterica induces tissue-specific types of DNA damage and DNA damage response outcomes

JOURNAL=Frontiers in Immunology

VOLUME=14

YEAR=2024

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2023.1270449

DOI=10.3389/fimmu.2023.1270449

ISSN=1664-3224

ABSTRACT=<sec><title>Introduction</title><p>Typhoid toxin-expressing <italic>Salmonella enterica</italic> causes DNA damage in the intestinal mucosa <italic>in vivo</italic>, activating the DNA damage response (DDR) in the absence of inflammation. To understand whether the tissue microenvironment constrains the infection outcome, we compared the immune response and DDR patterns in the colon and liver of mice infected with a genotoxigenic strain or its isogenic control strain.</p></sec><sec><title>Methods</title><p><italic>In situ</italic> spatial transcriptomic and immunofluorescence have been used to assess DNA damage makers, activation of the DDR, innate immunity markers in a multiparametric analysis.</p></sec><sec><title>Result</title><p>The presence of the typhoid toxin protected from colonic bacteria-induced inflammation, despite nuclear localization of p53, enhanced co-expression of type-I interferons (<italic>IfnbI</italic>) and the inflammasome sensor <italic>Aim2</italic>, both classic features of DNA-break-induced DDR activation. These effects were not observed in the livers of either infected group. Instead, in this tissue, the inflammatory response and DDR were associated with high oxidative stress-induced DNA damage.</p></sec><sec><title>Conclusions</title><p>Our work highlights the relevance of the tissue microenvironment in enabling the typhoid toxin to suppress the host inflammatory response <italic>in vivo.</italic></p></sec>