Specific Depletion of Myeloid-Derived Suppressor Cells by the Chemotherapy Agent 5-Fluorouracil Enhances Protective Immune Response in Paracoccidioidomycosis

Autor(es)

Preite, Nycolas Willian ; Kaminski, Valeria de Lima ; Borges, Bruno Montanari ; dos Santos, Bianca Vieira ; Calich, Vera Lucia Garcia ; Loures, Flavio Vieira

• Tipo de documento: Artigo Científico
• Fonte: Journal of Infectious Diseases; v. 230, n. 5, p. 12-pg., 2024-07-11.

Resumo

Background Paracoccidioidomycosis (PCM) is regulated by suppressive mechanisms mediated by plasmacytoid-dendritic cells, regulatory T cells and myeloid-derived suppressor cells (MDSCs). MDSC suppressive activity on Th1/Th17 immunity was shown to be mediated by inhibitory effect of IL-10, IDO-1, and PD-L1. Studies revealed the 5-fluorouracil (5-FU) as a selective MDSC apoptosis-inducing agent, but its in vivo effect on infectious processes remains poorly investigated.Methods MDSCs and other leukocytes were evaluated in the lungs of 5-FU-treated mice after 4, 6, and 8 weeks of Paracoccidioides brasiliensis infection. Disease severity and immunological response were evaluated in MDSCs-depleted mice.Results 5-FU treatment caused a reduction of pulmonary MDSCs and fungal loads. The specific depletion of MDSCs reduced all pulmonary CD4+ T-cell populations resulting in improved tissue pathology and increased survival. This reduction was concomitant with increased frequencies of Th1/Th17 cells and the increased levels of Th1/Th2/Th17 cytokines in the lungs and liver of treated mice, suggesting an early and efficient protective effect of these cells. Furthermore, the immune protection conferred by the 5-FU treatment could be reversed by the MDSC-adoptive transfer.Conclusions 5-FU depletes MDSCs of P. brasiliensis-infected mice, resulting in enhanced immunity. This protective effect can be viewed as a potential immunotherapeutic tool for PCM. The beneficial effect of low-dose chemotherapy drug 5-FU was observed following the selective depletion of MDSCs, leading to improved Th1 and Th17 responses in the infectious disease paracoccidioidomycosis, without adversely affecting other immunological populations. (AU)

• Processo FAPESP: 19/10097-8 - EMU concedido no processo 2018/14762-3: citômetro de fluxo FACS Lyric
• Beneficiário: Flávio Vieira Loures
• Modalidade de apoio: Auxílio à Pesquisa - Programa Equipamentos Multiusuários
• Processo FAPESP: 19/24440-6 - O envolvimento da enzima indolamina 2, 3-dioxigenase 1 (IDO-1) em mecanismos imunossupressores de células supressoras mielóides (MDSCs) na Paracoccidioidomicose Pulmonar Murina
• Beneficiário: Valéria de Lima Kaminski
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado
• Processo FAPESP: 23/08856-3 - Imunoterapia na Paracoccidioidomicose: avaliação de terapia combinada de anticorpos monoclonais anti-CTLA-4 com antifúngicos.
• Beneficiário: Bianca Vieira dos Santos
• Modalidade de apoio: Bolsas no Brasil - Mestrado
• Processo FAPESP: 18/14762-3 - Imunossupressão na paracoccidioidomicose: função reguladora das células supressoras derivadas da linhagem mieloide (MDSC) na imunidade do hospedeiro, na patologia tecidual e adaptação genética das células fúngicas
• Beneficiário: Flávio Vieira Loures
• Modalidade de apoio: Auxílio à Pesquisa - Jovens Pesquisadores - Fase 2
• Processo FAPESP: 19/09278-8 - Imunossupressão na Paracoccidioidomicose Murina: envolvimento das células supressoras mielóides (MDSCs) na imunidade dos hospedeiros
• Beneficiário: Nycolas Willian Preite
• Modalidade de apoio: Bolsas no Brasil - Doutorado Direto
• Processo FAPESP: 21/09962-6 - Perfil transcricional e proteômico de leveduras de Paracoccidioides brasiliensis presentes em lesões granulomatosas crônicas de camundongos C57BL/6
• Beneficiário: Bruno Montanari Borges
• Modalidade de apoio: Bolsas no Brasil - Doutorado Direto