{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T16:48:58Z","timestamp":1788367738414,"version":"build-2803163510"},"update-to":[{"DOI":"10.1371\/journal.ppat.1009630","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2021,6,10]],"date-time":"2021-06-10T00:00:00Z","timestamp":1623283200000}}],"reference-count":116,"publisher":"Public Library of Science (PLoS)","issue":"5","license":[{"start":{"date-parts":[[2021,5,28]],"date-time":"2021-05-28T00:00:00Z","timestamp":1622160000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003141","name":"Consejo Nacional de Ciencia y Tecnolog\u00eda","doi-asserted-by":"publisher","award":["M\u00e9xico 254531"],"award-info":[{"award-number":["M\u00e9xico 254531"]}],"id":[{"id":"10.13039\/501100003141","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100006087","name":"Direcci\u00f3n General de Asuntos del Personal Acad\u00e9mico, Universidad Nacional Aut\u00f3noma de M\u00e9xico","doi-asserted-by":"crossref","award":["IN202418"],"award-info":[{"award-number":["IN202418"]}],"id":[{"id":"10.13039\/501100006087","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100003141","name":"Consejo Nacional de Ciencia y Tecnolog\u00eda","doi-asserted-by":"publisher","award":["256263"],"award-info":[{"award-number":["256263"]}],"id":[{"id":"10.13039\/501100003141","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000009","name":"Foundation for the National Institutes of Health","doi-asserted-by":"publisher","award":["GM059969"],"award-info":[{"award-number":["GM059969"]}],"id":[{"id":"10.13039\/100000009","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100007350","name":"Consejo Nacional de Ciencia y Tecnolog\u00eda","doi-asserted-by":"publisher","award":["M\u00e9xico 429934"],"award-info":[{"award-number":["M\u00e9xico 429934"]}],"id":[{"id":"10.13039\/501100007350","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plospathogens.org"],"crossmark-restriction":false},"short-container-title":["PLoS Pathog"],"abstract":"<jats:p>An intricate regulatory network controls the expression of<jats:italic>Salmonella<\/jats:italic>virulence genes. The transcriptional regulator HilD plays a central role in this network by controlling the expression of tens of genes mainly required for intestinal colonization. Accordingly, the expression\/activity of HilD is highly regulated by multiple factors, such as the SirA\/BarA two-component system and the Hcp-like protein HilE. SirA\/BarA positively regulates translation of<jats:italic>hilD<\/jats:italic>mRNA through a regulatory cascade involving the small RNAs CsrB and CsrC, and the RNA-binding protein CsrA, whereas HilE inhibits HilD activity by protein-protein interaction. In this study, we show that SirA\/BarA also positively regulates translation of<jats:italic>hilE<\/jats:italic>mRNA through the same mentioned regulatory cascade. Thus, our results reveal a paradoxical regulation exerted by SirA\/BarA-Csr on HilD, which involves simultaneous opposite effects, direct positive control and indirect negative control through HilE. This kind of regulation is called an incoherent type-1 feedforward loop (I1-FFL), which is a motif present in certain regulatory networks and represents a complex biological problem to decipher. Interestingly, our results, together with those from a previous study, indicate that HilE, the repressor component of the I1-FFL reported here (I1-FFL<jats:sub>SirA\/BarA-HilE-HilD<\/jats:sub>), is required to reduce the growth cost imposed by the expression of the genes regulated by HilD. Moreover, we and others found that HilE is necessary for successful intestinal colonization by<jats:italic>Salmonella<\/jats:italic>. Thus, these findings support that I1-FFL<jats:sub>SirA\/BarA-HilE-HilD<\/jats:sub>cooperates to control the precise amount and activity of HilD, for an appropriate balance between the growth cost and the virulence benefit generated by the expression of the genes induced by this regulator. I1-FFL<jats:sub>SirA\/BarA-HilE-HilD<\/jats:sub>represents a complex regulatory I1-FFL that involves multiple regulators acting at distinct levels of gene expression, as well as showing different connections to the rest of the regulatory network governing<jats:italic>Salmonella<\/jats:italic>virulence.<\/jats:p>","DOI":"10.1371\/journal.ppat.1009630","type":"journal-article","created":{"date-parts":[[2021,5,28]],"date-time":"2021-05-28T19:58:05Z","timestamp":1622231885000},"page":"e1009630","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":17,"title":["An incoherent feedforward loop formed by SirA\/BarA, HilE and HilD is involved in controlling the growth cost of virulence factor expression by Salmonella Typhimurium"],"prefix":"10.1371","volume":"17","author":[{"given":"Deyanira","family":"P\u00e9rez-Morales","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessica","family":"Nava-Galeana","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9519-8766","authenticated-orcid":true,"given":"Roberto","family":"Rosales-Reyes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0496-6366","authenticated-orcid":true,"given":"Paige","family":"Teehan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helen","family":"Yakhnin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8243-988X","authenticated-orcid":true,"given":"Erika I.","family":"Melchy-P\u00e9rez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4040-4256","authenticated-orcid":true,"given":"Yvonne","family":"Rosenstein","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6909-2941","authenticated-orcid":true,"given":"Miguel A.","family":"De la Cruz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul","family":"Babitzke","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8852-150X","authenticated-orcid":true,"given":"V\u00edctor H.","family":"Bustamante","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2021,5,28]]},"reference":[{"issue":"1","key":"ppat.1009630.ref001","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1038\/nrmicro1788","article-title":"Salmonellae interplay with host cells","volume":"6","author":"A Haraga","year":"2008","journal-title":"Nat Rev Microbiol"},{"issue":"2","key":"ppat.1009630.ref002","doi-asserted-by":"crossref","first-page":"308","DOI":"10.1128\/CMR.00066-12","article-title":"Salmonella enterica serovar Typhimurium skills to succeed in the host: virulence and regulation","volume":"26","author":"A F\u00e0brega","year":"2013","journal-title":"Clin Microbiol Rev"},{"issue":"6","key":"ppat.1009630.ref003","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1038\/nrmicro.2017.20","article-title":"Assembly, structure, function and regulation of type III secretion 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