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

Author(s)

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

• Document type: Journal article
• Source: Journal of Infectious Diseases; v. 230, n. 5, p. 12-pg., 2024-07-11.

Abstract

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)

• FAPESP's process: 19/10097-8 - Multi-User Equipment approved in grant 2018/14762-3: flow cytometer FACS lyric
• Grantee: Flávio Vieira Loures
• Support Opportunities: Multi-user Equipment Program
• FAPESP's process: 19/24440-6 - The role of indoleamine 2, 3-dioxygenase 1 (IDO-1) in immunosuppressive mechanisms of myeloid-derived suppressor cells (MDSCs) in Pulmonary Paracoccidioidomycosis
• Grantee: Valéria de Lima Kaminski
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 23/08856-3 - Immunotherapy in PCM: evaluation of combined therapy with monoclonal antibodies targeting CTLA-4 and antifungals drugs.
• Grantee: Bianca Vieira dos Santos
• Support Opportunities: Scholarships in Brazil - Master
• FAPESP's process: 18/14762-3 - Immunosuppression in paracoccidioidomycosis: the regulatory role of myeloid-derived suppressor cells (MDSCs) on host immunity, tissue pathology and genetic adaptation of fungal cells
• Grantee: Flávio Vieira Loures
• Support Opportunities: Research Grants - Young Investigators Grants - Phase 2
• FAPESP's process: 19/09278-8 - The role of Myeloid-Derived Suppressor Cells (MDSCs) in Murine Paracoccidioidomycosis
• Grantee: Nycolas Willian Preite
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• FAPESP's process: 21/09962-6 - Transcriptional and proteomic profile of Paracoccidiodes brasiliensis yeasts present in chronic granulomatous lesions of C57BL/6 WT mice
• Grantee: Bruno Montanari Borges
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)