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Its intracellular levels are dynamically controlled by diguanylate cyclases (DGCs), which synthesize c-di-GMP from GTP, and phosphodiesterases (PDEs), which degrade it into linear pGpG or GMP. The functional effects of cytoplasmic c-di-GMP are mediated through diverse effector proteins, including PilZ domain-containing receptors, transcription factors, and riboswitches. In Leptospira interrogans, a major pathogenic species responsible for leptospirosis, the regulatory roles of c-di-GMP remain poorly understood. Here, we performed a comprehensive bioinformatics and structural analysis of all predicted c-di-GMP related proteins in L. interrogans serovar Copenhageni strain Fiocruz L1-130, a serovar generally associated with severe manifestations of leptospirosis in humans. Our analysis identified seventeen proteins containing GGDEF domain, five proteins containing both GGDEF and EAL domains, four proteins containing EAL domain, five proteins containing HD-GYP domain, twelve proteins containing PilZ domain, and one protein containing an MshEN domain. Comparative analysis with well-characterized bacterial homologs suggests that L. interrogans possess a complex c-di-GMP signaling network, likely involved in modulating biofilm formation, host\u2013pathogen interactions, and environmental survival. These findings provide new insights into the c-di-GMP regulatory network and on signal transduction in Leptospira and lay the foundation for future functional studies aimed at understanding its roles in physiology, virulence, and persistence.<\/jats:p>","DOI":"10.3390\/pathogens15020151","type":"journal-article","created":{"date-parts":[[2026,1,30]],"date-time":"2026-01-30T17:38:34Z","timestamp":1769794714000},"page":"151","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Discovery of Novel c-di-GMP-Related Genes in Leptospira interrogans"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7072-4846","authenticated-orcid":false,"given":"Anielle Salviano de Almeida","family":"Ferrari","sequence":"first","affiliation":[{"name":"Department of Microbiology, Institute of Biomedical Sciences, University of S\u00e3o Paulo, S\u00e3o Paulo 05508-000, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6897-2955","authenticated-orcid":false,"given":"Davi Gabriel Salustiano","family":"Merighi","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Institute of Biomedical Sciences, University of S\u00e3o Paulo, S\u00e3o Paulo 05508-000, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aline Biazola","family":"Visnardi","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Institute of Biomedical Sciences, University of S\u00e3o Paulo, S\u00e3o Paulo 05508-000, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gabriela Roberto","family":"Silva","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Institute of Biomedical Sciences, University of S\u00e3o Paulo, S\u00e3o Paulo 05508-000, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1091-5581","authenticated-orcid":false,"given":"Cau\u00ea Augusto Boneto","family":"Gon\u00e7alves","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Institute of Biomedical Sciences, University of S\u00e3o Paulo, S\u00e3o Paulo 05508-000, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1364-7527","authenticated-orcid":false,"given":"Daniel Enrique","family":"Sanchez-Limache","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Institute of Biomedical Sciences, University of S\u00e3o Paulo, S\u00e3o Paulo 05508-000, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-6610-0068","authenticated-orcid":false,"given":"Bruna Sayuri Cardoso","family":"Ogusku","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Institute of Biomedical Sciences, University of S\u00e3o Paulo, S\u00e3o Paulo 05508-000, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5669-1723","authenticated-orcid":false,"given":"Anacleto Silva de","family":"Souza","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Institute of Biomedical Sciences, University of S\u00e3o Paulo, S\u00e3o Paulo 05508-000, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5284-4630","authenticated-orcid":false,"given":"Robson Francisco","family":"de Souza","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Institute of Biomedical Sciences, University of S\u00e3o Paulo, S\u00e3o Paulo 05508-000, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5664-8055","authenticated-orcid":false,"given":"Cristiane Rodrigues","family":"Guzzo","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Institute of Biomedical Sciences, University of S\u00e3o Paulo, S\u00e3o Paulo 05508-000, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,1,30]]},"reference":[{"key":"ref_1","first-page":"65","article-title":"Leptospirosis in Humans","volume":"387","author":"Haake","year":"2015","journal-title":"Curr. 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