AUTHOR=Preite Nycolas Willian , Borges Bruno Montanari , Kaminski Valéria de Lima , Ayupe Marina Caçador , Gonçalves Leonardo Mandu , dos Santos Bianca Vieira , Fonseca Dennyson Leandro M. , Filgueiras Igor Salerno , Salgado Caio Loureiro , Muxel Sandra Marcia , Cabral-Marques Otavio , da Fonseca Denise Morais , Loures Flávio Vieira , Calich Vera Lúcia Garcia 

TITLE=Blocking the CTLA-4 and PD-1 pathways during pulmonary paracoccidioidomycosis improves immunity, reduces disease severity, and increases the survival of infected mice

JOURNAL=Frontiers in Immunology

VOLUME=Volume 15 - 2024

YEAR=2024

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2024.1347318

DOI=10.3389/fimmu.2024.1347318

ISSN=1664-3224

ABSTRACT=Immune checkpoint pathways, i.e., co-inhibitory pathways expressed as feedback following immune activation, are crucial for controlling excessive immune response. CTLA-4 (Cytotoxic T Lymphocyte Antigen-4) and PD-1 (Programmed Cell Death Protein-1) are the central classical checkpoint inhibitory (CPI) molecules used for the control of neoplasms and some infectious diseases, including some fungal infections. As the immunosuppression of severe paracoccidioidomycosis (PCM), a chronic granulomatous fungal disease, was shown to be associated with the expression of coinhibitory molecules, we hypothesized that inhibition of CTLA-4 and PD-1 could have a beneficial effect on pulmonary PCM. To this end, C57BL/6 mice were infected with Paracoccidioides brasiliensis yeasts and treated in the course of the disease with monoclonal antibodies (mAbs) -CTLA-4, -PD-1, control IgG, or PBS. We verified that the blockade of CTLA-4 and PD-1 reduced the fungal loads in the lungs, its dissemination to the liver and spleen, and diminished the size of pulmonary lesions, resulting in increased survival of mice. Compared with PBS-treated infected mice, significantly increased levels of many pro-and anti-inflammatory cytokines were seen in the lungs of -CTLA-4 treated mice, but a drastic reduction in the liver following PD-1 blockade. In the lungs of -CPI and IgG-treated mice, no changes in the frequency, but a significant reduction of total inflammatory leukocytes were seen. Compared with PBS-treated controls, -CPI and IgG-treated mice showed a reduced pulmonary infiltrate of several myeloid subpopulations and their expression of costimulatory molecules. In addition, a diminished number of TCD4+ and TCD8+ cells but sustained numbers of Th1, Th2, and Th17 T cell subsets were detected. An