Agradecimentos: We also want to thank the Brazilian Biorenewables National Laboratory (LNBR), part of the Brazilian Centre for Research in Energy and Materials (CNPEM), a private non-profit organization under the supervision of the Brazilian Ministry for Science, Technology, and Innovations (MCTI) for their assistance. We thank the Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) grant number 2018-14762-3 (FL), 2019/17324-0 (BB), 2021/04977-5 (GG) and the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) grant numbers 301058/2019-9 and 404735/2018-5 (GG), both from Brazil, and the National Institutes of Health/National Institute of Allergy and Infectious Diseases grants R01AI153356 (GG). AT was funded by a John and Pat Hume PhD Scholarship from Maynooth University. The Science Foundation Ireland provided grants SFI-21/FFP-P/10146 to ÖB and SFI-21/PATH-S/9444 to ÖS-B. Protein mass spectrometry facilities were funded by a competitive award from Science Foundation Ireland (12/RI/2346 (3)) to SD Ver menos

Abstract: 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-1ß, TNF-a, IFN-?, 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 Ver menos