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A major mechanism through which bacteria sense and respond to stimuli in their surroundings is two-component systems (TCSs). TCSs allow for the detection of multiple stimuli to lead to a highly controlled and rapid change in gene expression. Here, we provide a comprehensive list of TCSs important for the pathogenesis of uropathogenic\n                      <jats:italic>Escherichia coli<\/jats:italic>\n                      (UPEC). UPEC accounts for &gt;75% of urinary tract infections (UTIs) worldwide. UTIs are most prevalent among people assigned female at birth, with the vagina becoming colonized by UPEC in addition to the gut and the bladder. In the bladder, adherence to the urothelium triggers\n                      <jats:italic>E. coli<\/jats:italic>\n                      invasion of bladder cells and an intracellular pathogenic cascade. Intracellular\n                      <jats:italic>E. coli<\/jats:italic>\n                      are safely hidden from host neutrophils, competition from the microbiota, and antibiotics that kill extracellular\n                      <jats:italic>E. coli<\/jats:italic>\n                      . To survive in these intimately connected, yet physiologically diverse niches\n                      <jats:italic>E. coli<\/jats:italic>\n                      must rapidly coordinate metabolic and virulence systems in response to the distinct stimuli encountered in each environment. We hypothesized that specific TCSs allow UPEC to sense these diverse environments encountered during infection with built-in redundant safeguards. Here, we created a library of isogenic TCS deletion mutants that we leveraged to map distinct TCS contributions to infection. We identify\u2014for the first time\u2014a comprehensive panel of UPEC TCSs that are critical for infection of the genitourinary tract and report that the TCSs mediating colonization of the bladder, kidneys, or vagina are distinct.\n                    <\/jats:p>\n                    <jats:sec>\n                      <jats:title>IMPORTANCE<\/jats:title>\n                      <jats:p>\n                        While two-component system (TCS) signaling has been investigated at depth in model strains of\n                        <jats:italic>Escherichia coli<\/jats:italic>\n                        , there have been no studies to elucidate\u2014at a systems level\u2014which TCSs are important during infection by pathogenic\n                        <jats:italic>Escherichia coli<\/jats:italic>\n                        . Here, we report the generation of a markerless TCS deletion library in a uropathogenic\n                        <jats:italic>E. coli<\/jats:italic>\n                        (UPEC) isolate that can be leveraged for dissecting the role of TCS signaling in different aspects of pathogenesis. We use this library to demonstrate, for the first time in UPEC, that niche-specific colonization is guided by distinct TCS groups.\n                      <\/jats:p>\n                    <\/jats:sec>\n                  <\/jats:sec>","DOI":"10.1128\/spectrum.02236-23","type":"journal-article","created":{"date-parts":[[2024,2,22]],"date-time":"2024-02-22T09:02:25Z","timestamp":1708592545000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":7,"title":["Mapping niche-specific two-component system requirements in uropathogenic\n                    <i>Escherichia coli<\/i>"],"prefix":"10.1128","volume":"12","author":[{"given":"John R.","family":"Brannon","sequence":"first","affiliation":[{"name":"Department of Pathology, Microbiology and Immunology, Division of Molecular Pathogenesis, Vanderbilt University Medical Center, Nashville, Tennessee, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7791-1641","authenticated-orcid":true,"given":"Seth A.","family":"Reasoner","sequence":"additional","affiliation":[{"name":"Department of Pathology, Microbiology and Immunology, Division of Molecular Pathogenesis, Vanderbilt University Medical Center, Nashville, Tennessee, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tomas A.","family":"Bermudez","sequence":"additional","affiliation":[{"name":"Department of Pathology, Microbiology and Immunology, Division of Molecular Pathogenesis, Vanderbilt University Medical Center, Nashville, Tennessee, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2530-9840","authenticated-orcid":false,"given":"Sarah L.","family":"Comer","sequence":"additional","affiliation":[{"name":"Department of Pathology, Microbiology and Immunology, Division of Molecular Pathogenesis, Vanderbilt University Medical Center, Nashville, Tennessee, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michelle A.","family":"Wiebe","sequence":"additional","affiliation":[{"name":"Department of Pathology, Microbiology and Immunology, Division of Molecular Pathogenesis, Vanderbilt University Medical Center, Nashville, Tennessee, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Taryn L.","family":"Dunigan","sequence":"additional","affiliation":[{"name":"Department of Pathology, Microbiology and Immunology, Division of Molecular Pathogenesis, Vanderbilt University Medical Center, Nashville, Tennessee, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Connor J.","family":"Beebout","sequence":"additional","affiliation":[{"name":"Department of Pathology, Microbiology and Immunology, Division of Molecular Pathogenesis, Vanderbilt University Medical Center, Nashville, Tennessee, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tamia","family":"Ross","sequence":"additional","affiliation":[{"name":"Department of Pathology, Microbiology and Immunology, Division of Molecular Pathogenesis, Vanderbilt University Medical Center, Nashville, Tennessee, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Adebisi","family":"Bamidele","sequence":"additional","affiliation":[{"name":"Department of Pathology, Microbiology and Immunology, Division of Molecular Pathogenesis, Vanderbilt University Medical Center, Nashville, Tennessee, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4249-8997","authenticated-orcid":true,"given":"Maria","family":"Hadjifrangiskou","sequence":"additional","affiliation":[{"name":"Department of Pathology, Microbiology and Immunology, Division of Molecular Pathogenesis, Vanderbilt University Medical Center, Nashville, Tennessee, USA"},{"name":"Department of 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