PMID- 37868350 OWN - NLM STAT- MEDLINE DCOM- 20231031 LR - 20240216 IS - 2235-2988 (Electronic) IS - 2235-2988 (Linking) VI - 13 DP - 2023 TI - Transcriptional profiling of a fungal granuloma reveals a low metabolic activity of Paracoccidioides brasiliensis yeasts and an actively regulated host immune response. PG - 1268959 LID - 10.3389/fcimb.2023.1268959 [doi] LID - 1268959 AB - Granulomas are important immunological structures in the host defense against the fungus Paracoccidioides brasiliensis, the main etiologic agent of Paracoccidioidomycosis (PCM), a granulomatous systemic mycosis endemic in Latin America. We have performed transcriptional and proteomic studies of yeasts present in the pulmonary granulomas of PCM aiming to identify relevant genes and proteins that act under stressing conditions. C57BL/6 mice were infected with 1x10(6) yeasts and after 8- and 12-weeks of infection, granulomatous lesions were obtained for extraction of fungal and murine RNAs and fungal proteins. Dual transcriptional profiling was done comparing lung cells and P. brasiliensis yeasts from granulomas with uninfected lung cells and the original yeast suspension used in the infection, respectively. Mouse transcripts indicated a lung malfunction, with low expression of genes related to muscle contraction and organization. In addition, an increased expression of transcripts related to the activity of neutrophils, eosinophils, macrophages, lymphocytes as well as an elevated expression of IL-1beta, TNF-alpha, IFN-gamma, IL-17 transcripts were observed. The increased expression of transcripts for CTLA-4, PD-1 and arginase-1, provided evidence of immune regulatory mechanisms within the granulomatous lesions. Also, our results indicate iron as a key element for the granuloma to function, where a high number of transcripts related to fungal siderophores for iron uptake was observed, a mechanism of fungal virulence not previously described in granulomas. Furthermore, transcriptomics and proteomics analyzes indicated a low fungal activity within the granuloma, as demonstrated by the decreased expression of genes and proteins related to energy metabolism and cell cycle. CI - Copyright (c) 2023 Borges, Ramos, Preite, Kaminski, Alves de Castro, Camacho, Maximo, Fill, Calich, Traynor, Sarikaya-Bayram, Doyle, Bayram, de Campos, Zelanis, Goldman and Loures. FAU - Borges, Bruno Montanari AU - Borges BM AD - Institute of Science and Technology (ICT), Federal University of Sao Paulo (UNIFESP), Sao Jose dos Campos, SP, Brazil. FAU - Ramos, Rafael Berton Correia AU - Ramos RBC AD - Institute of Science and Technology (ICT), Federal University of Sao Paulo (UNIFESP), Sao Jose dos Campos, SP, Brazil. FAU - Preite, Nycolas Willian AU - Preite NW AD - Institute of Science and Technology (ICT), Federal University of Sao Paulo (UNIFESP), Sao Jose dos Campos, SP, Brazil. FAU - Kaminski, Valeria de Lima AU - Kaminski VL AD - Institute of Science and Technology (ICT), Federal University of Sao Paulo (UNIFESP), Sao Jose dos Campos, SP, Brazil. FAU - Alves de Castro, Patricia AU - Alves de Castro P AD - Faculty of Pharmaceutical Science of Ribeirao Preto (FCFRP), University of Sao Paulo (USP), Ribeirao Preto, SP, Brazil. FAU - Camacho, Mauricio AU - Camacho M AD - Institute of Science and Technology (ICT), Federal University of Sao Paulo (UNIFESP), Sao Jose dos Campos, SP, Brazil. FAU - Maximo, Marina Ferreira AU - Maximo MF AD - Institute of Chemistry, Universidade Estadual de Campinas, Campinas, SP, Brazil. FAU - Fill, Taicia Pacheco AU - Fill TP AD - Institute of Chemistry, Universidade Estadual de Campinas, Campinas, SP, Brazil. FAU - Calich, Vera Lucia Garcia AU - Calich VLG AD - Department of Immunology, Institute of Biomedical Sciences, University of Sao Paulo (USP), Sao Paulo, Brazil. FAU - Traynor, Aimee M AU - Traynor AM AD - Department of Biology, Maynooth University, Maynooth, County Kildare, Ireland. FAU - Sarikaya-Bayram, Ozlem AU - Sarikaya-Bayram O AD - Department of Biology, Maynooth University, Maynooth, County Kildare, Ireland. FAU - Doyle, Sean AU - Doyle S AD - Department of Biology, Maynooth University, Maynooth, County Kildare, Ireland. FAU - Bayram, Ozgur AU - Bayram O AD - Department of Biology, Maynooth University, Maynooth, County Kildare, Ireland. FAU - de Campos, Claudia Barbosa Ladeira AU - de Campos CBL AD - Institute of Science and Technology (ICT), Federal University of Sao Paulo (UNIFESP), Sao Jose dos Campos, SP, Brazil. FAU - Zelanis, Andre AU - Zelanis A AD - Institute of Science and Technology (ICT), Federal University of Sao Paulo (UNIFESP), Sao Jose dos Campos, SP, Brazil. FAU - Goldman, Gustavo H AU - Goldman GH AD - Faculty of Pharmaceutical Science of Ribeirao Preto (FCFRP), University of Sao Paulo (USP), Ribeirao Preto, SP, Brazil. FAU - Loures, Flavio Vieira AU - Loures FV AD - Institute of Science and Technology (ICT), Federal University of Sao Paulo (UNIFESP), Sao Jose dos Campos, SP, Brazil. LA - eng GR - R01 AI153356/AI/NIAID NIH HHS/United States PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20231005 PL - Switzerland TA - Front Cell Infect Microbiol JT - Frontiers in cellular and infection microbiology JID - 101585359 RN - E1UOL152H7 (Iron) SB - IM MH - Animals MH - Mice MH - *Paracoccidioides/genetics MH - Proteomics MH - Mice, Inbred C57BL MH - *Paracoccidioidomycosis MH - Iron/metabolism MH - Immunity MH - Granuloma PMC - PMC10585178 OTO - NOTNLM OT - fungal infection OT - granuloma OT - paracoccidioidomycosis OT - proteomic OT - transcriptomic COIS- The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision. EDAT- 2023/10/23 06:46 MHDA- 2023/10/31 06:42 PMCR- 2023/01/01 CRDT- 2023/10/23 04:37 PHST- 2023/07/28 00:00 [received] PHST- 2023/09/11 00:00 [accepted] PHST- 2023/10/31 06:42 [medline] PHST- 2023/10/23 06:46 [pubmed] PHST- 2023/10/23 04:37 [entrez] PHST- 2023/01/01 00:00 [pmc-release] AID - 10.3389/fcimb.2023.1268959 [doi] PST - epublish SO - Front Cell Infect Microbiol. 2023 Oct 5;13:1268959. doi: 10.3389/fcimb.2023.1268959. eCollection 2023.