TY - JOUR
T1 - Transcriptional profiling of a fungal granuloma reveals a low metabolic activity of Paracoccidioides brasiliensis yeasts and an actively regulated host immune response
AU - Borges, Bruno Montanari
AU - Ramos, Rafael Berton Correia
AU - Preite, Nycolas Willian
AU - Kaminski, Valéria de Lima
AU - Alves de Castro, Patrícia
AU - Camacho, Maurício
AU - Maximo, Marina Ferreira
AU - Fill, Taicia Pacheco
AU - Calich, Vera Lúcia Garcia
AU - Traynor, Aimee M.
AU - Sarikaya-Bayram, Özlem
AU - Doyle, Sean
AU - Bayram, Özgür
AU - de Campos, Claudia Barbosa Ladeira
AU - Zelanis, André
AU - Goldman, Gustavo H.
AU - Loures, Flávio Vieira
N1 - Publisher Copyright:
Copyright © 2023 Borges, Ramos, Preite, Kaminski, Alves de Castro, Camacho, Maximo, Fill, Calich, Traynor, Sarikaya-Bayram, Doyle, Bayram, de Campos, Zelanis, Goldman and Loures.
PY - 2023
Y1 - 2023
N2 - 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 1x106 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-1β, TNF-α, IFN-γ, 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.
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 1x106 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-1β, TNF-α, IFN-γ, 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.
KW - fungal infection
KW - granuloma
KW - paracoccidioidomycosis
KW - proteomic
KW - transcriptomic
UR - http://www.scopus.com/inward/record.url?scp=85174736492&partnerID=8YFLogxK
U2 - 10.3389/fcimb.2023.1268959
DO - 10.3389/fcimb.2023.1268959
M3 - Article
C2 - 37868350
AN - SCOPUS:85174736492
SN - 2235-2988
VL - 13
JO - Frontiers in Cellular and Infection Microbiology
JF - Frontiers in Cellular and Infection Microbiology
M1 - 1268959
ER -