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We hypothesized that while hijacking processes within mammalian cells, the effectors operate as a robust network that can tolerate substantial contractions. This was tested in vivo using the mouse pathogen\n            <jats:italic>Citrobacter rodentium<\/jats:italic>\n            (encoding 31 effectors). Sequential gene deletions showed that effector essentiality for infection was context dependent and that the network could tolerate 60% contraction while maintaining pathogenicity. Despite inducing very different colonic cytokine profiles (e.g., interleukin-22, interleukin-17, interferon-\u03b3, or granulocyte-macrophage colony-stimulating factor), different networks induced protective immunity. Using data from &gt;100 distinct mutant combinations, we built and trained a machine learning model able to predict colonization outcomes, which were confirmed experimentally. Furthermore, reproducing the human-restricted enteropathogenic\n            <jats:italic>E. coli<\/jats:italic>\n            effector repertoire in\n            <jats:italic>C. rodentium<\/jats:italic>\n            was not sufficient for efficient colonization, which implicates effector networks in host adaptation. These results unveil the extreme robustness of both T3SS effector networks and host responses.\n          <\/jats:p>","DOI":"10.1126\/science.abc9531","type":"journal-article","created":{"date-parts":[[2021,3,11]],"date-time":"2021-03-11T20:05:19Z","timestamp":1615493119000},"source":"Crossref","is-referenced-by-count":120,"title":["Type III secretion system effectors form robust and flexible intracellular virulence networks"],"prefix":"10.1126","volume":"371","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2163-2088","authenticated-orcid":true,"given":"David","family":"Ruano-Gallego","sequence":"first","affiliation":[{"name":"Centre for Molecular Microbiology and Infection, Department of Life Sciences, Imperial College, London, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5847-4167","authenticated-orcid":true,"given":"Julia","family":"Sanchez-Garrido","sequence":"additional","affiliation":[{"name":"Centre for Molecular Microbiology and Infection, Department of Life Sciences, Imperial College, London, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6713-5776","authenticated-orcid":true,"given":"Zuzanna","family":"Kozik","sequence":"additional","affiliation":[{"name":"Functional Proteomics Group, Chester Beatty Laboratories, Institute of Cancer Research, London, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3995-6176","authenticated-orcid":true,"given":"Elena","family":"N\u00fa\u00f1ez-Berrueco","sequence":"additional","affiliation":[{"name":"Laboratorio de Inteligencia Artificial, Departamento de Inteligencia Artificial, Universidad Polit\u00e9cnica de Madrid, Campus de Montegancedo, Boadilla del Monte, Madrid, Spain."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0635-928X","authenticated-orcid":true,"given":"Massiel","family":"Cepeda-Molero","sequence":"additional","affiliation":[{"name":"Centre for Molecular Microbiology and Infection, Department of Life Sciences, Imperial College, London, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8995-7615","authenticated-orcid":true,"given":"Caroline","family":"Mullineaux-Sanders","sequence":"additional","affiliation":[{"name":"Centre for Molecular Microbiology and Infection, Department of Life Sciences, Imperial College, London, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6207-8466","authenticated-orcid":true,"given":"Yasaman","family":"Naemi Baghshomali","sequence":"additional","affiliation":[{"name":"Centre for Molecular Microbiology and Infection, Department of Life Sciences, Imperial College, London, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9990-5624","authenticated-orcid":true,"given":"Sabrina L.","family":"Slater","sequence":"additional","affiliation":[{"name":"Centre for Molecular Microbiology and Infection, Department of Life Sciences, Imperial College, London, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7759-3009","authenticated-orcid":true,"given":"Naama","family":"Wagner","sequence":"additional","affiliation":[{"name":"The Shmunis School of Biomedicine and Cancer Research, George S. 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