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A previous comparative transcriptomic analysis showed that the Cpx pathway of\n              <jats:italic>Y. pestis<\/jats:italic>\n              is up-regulated in infected fleas. The CpxAR two-component system is a component of the envelope stress response and is critical for maintaining the integrity of the cell. Here, a phenotypic screening revealed a survival defect of the\n              <jats:italic>cpxAR<\/jats:italic>\n              mutant to oxidative stress and copper. The measured copper concentration in the digestive tract contents of fed fleas increased fourfold during the digestive process. By direct analysis of phosphorylation of CpxR by a Phos-Tag gel approach, we demonstrated that biologically relevant concentrations of copper triggered the system. Then, a competitive challenge highlighted the role of the CpxAR system in bacterial fitness during flea infection. Lastly, an\n              <jats:italic>in vitro<\/jats:italic>\n              sequential exposure to copper and then H\n              <jats:sub>2<\/jats:sub>\n              O\n              <jats:sub>2<\/jats:sub>\n              to mimic the flea suggests a model in which, within the insect digestive tract, the CpxAR system would be triggered by copper, establishing an oxidative stress response.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>IMPORTANCE<\/jats:title>\n            <jats:p>\n              The bacterium\n              <jats:italic>Yersinia pestis<\/jats:italic>\n              is the agent of flea-borne plague. Our knowledge of the mechanisms used by the plague bacillus to infect the flea vector is limited. The up-regulation of the envelope stress response under the control of the Cpx signaling pathway was previously shown in a transcriptomic study. Here, our\n              <jats:italic>in vivo<\/jats:italic>\n              and\n              <jats:italic>in vitro<\/jats:italic>\n              approaches suggest a model in which\n              <jats:italic>Y. pestis<\/jats:italic>\n              uses the CpxAR phosphorelay system to sense and respond to the copper present in the flea gut, thereby optimizing the flea gut colonization. In other words, the system is essential for bacterial fitness in the flea.\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1128\/jb.00173-24","type":"journal-article","created":{"date-parts":[[2024,8,19]],"date-time":"2024-08-19T13:00:29Z","timestamp":1724072429000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":4,"title":["The CpxAR signaling system confers a fitness advantage for flea gut colonization by the plague bacillus"],"prefix":"10.1128","volume":"206","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5851-3744","authenticated-orcid":false,"given":"Brandon","family":"Robin","sequence":"first","affiliation":[{"name":"Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019 - UMR 9017 - CIIL - Center for Infection and Immunity of Lille, Lille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Am\u00e9lie","family":"Dewitte","sequence":"additional","affiliation":[{"name":"Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019 - UMR 9017 - CIIL - Center for Infection and Immunity of Lille, Lille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9503-8655","authenticated-orcid":false,"given":"V\u00e9ronique","family":"Alaimo","sequence":"additional","affiliation":[{"name":"Univ. Lille, CNRS, UMR 8516 \u2013 LASIRE, Laboratoire de Spectroscopie pour les Interactions, la R\u00e9activit\u00e9 et l'Environnement, Lille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cecile","family":"Lecoeur","sequence":"additional","affiliation":[{"name":"Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019 - UMR 9017 - CIIL - Center for Infection and Immunity of Lille, Lille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fran\u00e7ois","family":"Pierre","sequence":"additional","affiliation":[{"name":"Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019 - UMR 9017 - CIIL - Center for Infection and Immunity of Lille, Lille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4693-5106","authenticated-orcid":false,"given":"Gabriel","family":"Billon","sequence":"additional","affiliation":[{"name":"Univ. Lille, CNRS, UMR 8516 \u2013 LASIRE, Laboratoire de Spectroscopie pour les Interactions, la R\u00e9activit\u00e9 et l'Environnement, Lille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3811-9691","authenticated-orcid":false,"given":"Florent","family":"Sebbane","sequence":"additional","affiliation":[{"name":"Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019 - UMR 9017 - CIIL - Center for Infection and Immunity of Lille, Lille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1834-5416","authenticated-orcid":true,"given":"S\u00e9bastien","family":"Bontemps-Gallo","sequence":"additional","affiliation":[{"name":"Univ. 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