Victoria Hellena Silva Pereira, Gustavo Augusto Fonseca Nogueira, Luana Borges-Fernandes, Silvia Hees de Carvalho, Adelina Machado de Carvalho Nogueira, Argus Leão Araújo, Joaquim Pedro Brito-de-Sousa, Juliana Assunção Rodrigues, João Paulo Resende Magalhães Toledo, Vanessa Caroline Randi Magalhães, Jairo Campos de Carvalho, Livia Fulgencio da Cunha, Jordana Grazziela Alves Coelho-Dos-Reis, Andréa Teixeira-Carvalho, Olindo Assis Martins-Filho, Gabriel Macedo Costa Guimarães, Vanessa Peruhype-Magalhães
MAIT cell frequencies were significantly reduced in VL and VL-HIV, predominantly affecting the CD8+ subset. Fold-change analyses demonstrated increased activation and cytotoxicity signatures in VL and VL-HIV patients, with marked upregulation of CD69, CD38, NKG2D, and CD107A, concomitant with increased expression of inhibitory receptors (PD-1, TIM-3, LAG-3), particularly in CD8+ and CD4-CD8- MAIT cells. In contrast, VL-HIV(T) patients exhibited a decrease in this hyperactivated/exhausted phenotype and partial restoration of central memory-associated features, suggesting immune rebalancing under treatment. Integrative correlation network analysis revealed marked differences of MAIT cell immunological interactions. VL and VL-HIV groups displayed reduced network density, decreased selective axis connectivity, and fragmentation of interactions among activation, cytotoxicity, and memory nodes, consistent with immune disorganization. Conversely, treated VL-HIV(T) patients exhibited increased connectivity and re-establishment of coordinated interactions between functional markers, indicating partial re-establishment of the MAIT cell immunological network architecture.
INTRODUCTION: Mucosal-associated invariant T (MAIT) cells are unconventional T lymphocytes with innate-like antimicrobial responsiveness. Despite their recognized role in bacterial and viral infections, their involvement in protozoal diseases, particularly visceral leishmaniasis (VL) and HIV co-infection, remains poorly understood.
METHODS: A cross-sectional study evaluated the immunophenotypic profile of circulating MAIT cells in visceral leishmaniasis patients (VL, n = 8), VL-HIV co-infection patients (VL-HIV, n = 10), VL-HIV coinfected patients under liposomal amphotericin B prophylactic treatment (VL-HIV(T), n = 9), and reference groups comprising HIV-mono-infected (HIV, n = 11) and non-infected (NI, n = 11) individuals. Multiparameter flow cytometry assessed MAIT cell frequency, subset distribution (CD4+, CD8+ and CD4-CD8-), and the expression of activation, costimulatory, cytotoxic, exhaustion and memory markers. Integrative correlation network analysis was performed to evaluate immunological interactions among MAIT cell markers.
RESULTS: MAIT cell frequencies were significantly reduced in VL and VL-HIV, predominantly affecting the CD8+ subset. Fold-change analyses demonstrated increased activation and cytotoxicity signatures in VL and VL-HIV patients, with marked upregulation of CD69, CD38, NKG2D, and CD107A, concomitant with increased expression of inhibitory receptors (PD-1, TIM-3, LAG-3), particularly in CD8+ and CD4-CD8- MAIT cells. In contrast, VL-HIV(T) patients exhibited a decrease in this hyperactivated/exhausted phenotype and partial restoration of central memory-associated features, suggesting immune rebalancing under treatment. Integrative correlation network analysis revealed marked differences of MAIT cell immunological interactions. VL and VL-HIV groups displayed reduced network density, decreased selective axis connectivity, and fragmentation of interactions among activation, cytotoxicity, and memory nodes, consistent with immune disorganization. Conversely, treated VL-HIV(T) patients exhibited increased connectivity and re-establishment of coordinated interactions between functional markers, indicating partial re-establishment of the MAIT cell immunological network architecture.
DISCUSSION: Together, VL and VL-HIV co-infection are associated with quantitative depletion and qualitative dysregulation of circulating MAIT cells, characterized by concurrent hyperactivation and exhaustion, coupled with immunological network fragmentation, while liposomal amphotericin B treatment appears to promote partial immunological reorganization.