Biology subjects

da Fonseca-Martins, A. M.

Publications and source records attributed to da Fonseca-Martins, A. M..

4 recordsLinked to original sources

bioRxiv2025

Mice Mucosal Leishmaniasis model shown high parasite load, increased cytotoxicity and impaired IL-10+ cells response

Mucosal Leishmaniasis is one of the most aggressive clinical manifestations of Leishmania infection disease, characterized by the destruction of nasal and oral tissues. The mechanisms by which this disease occurs are still not well understood due to the lack of effective experimental models. Mucosal leishmaniasis is associated with inflammatory response, especially Th17 response. Based on that, in this work, the immunopathological aspects of the experimental infection of BALB/c mice by Leishmania amazonensis in the mucosa site were evaluated due to high susceptibility and the disease been associated with Th17 response. Three infection modes were performed and compared according to the injection site. Six weeks post infection, mice presented edema in the nasal and premaxillary region, with progressive growth until twelve weeks. The micro-Computerized Tomography and the histology images demonstrated that the parasite inoculation led to destruction of squamous and transitional tissues in NC and NB groups, with several cells harboring amastigotes. Mice infected in the mucosa tissues had higher parasite load and IgG, IgM antibody levels and increased production of cytotoxic mediators such as CD107, granzyme b and perforin, inflammatory cytokines as IFN-{gamma} and IL-17, but lower frequencies of CD4+ IL-10+ cells compared to ear dermis. Taken together, our data shows that L. amazonensis parasites are more proliferative in nasal mucosa and the infection leads to an increased inflammatory response compared to ear dermis, pointing to this model as an interesting approach to understand some features of MCL immunopathology.

immunology↗

bioRxiv2024

IL-17A/IFN-γ producing γ δ T cell functional dichotomy impacts cutaneous leishmaniasis in mice

{gamma}{delta} T cells are innate-like lymphocytes with pleiotropic roles in immune responses to pathogens, often ascribed to their IL-17A-producing or IFN-{gamma}-producing {gamma}{delta} T cell subsets. Here we investigated the impact of this functional dichotomy on cutaneous leishmaniasis, a set of neglected diseases caused by parasites of the Leishmania genus. We demonstrate that in Sv129 mice susceptible to Leishmania amazonensis, V{gamma}4+ {gamma}{delta} T cells are the main source of IL-17A. Furthermore, in type 1 interferon receptor-deficient (A129) mice presenting increased susceptibility to infection, there is a higher frequency of IL-17A-producing {gamma}{delta} T cells when compared to wild-type mice. Mechanistically, we demonstrate that lipophosphoglycan (LPG) of L. amazonensis induces IL-17A-producing {gamma}{delta} T cells. Importantly, C57Bl/6 mice deficient in {gamma}{delta} T cells or in IL-17 receptor (IL-17RA) show reduced lesion sizes, consistent with a pathogenic role of IL-17A-producing {gamma}{delta} T cells in cutaneous leishmaniasis. Conversely, the adoptive transfer of FACS-sorted {gamma}{delta} T cells led to an accumulation of IFN-{gamma}-producing {gamma}{delta} T cells in various susceptible strains of mice which associated with control of lesion development. These data demonstrate a pathophysiological dichotomy in which IL-17A-producing {gamma}{delta} T cells promote pathogenesis, whereas IFN-{gamma}-producing {gamma}{delta} T cells display therapeutic potential in cutaneous leishmaniasis.

immunology↗

bioRxiv2022

Leishmania amazonensis infection induces PD-L1 expression on dendritic cells in an mTor-dependent manner and impairs Th1 responses in vitro and in vivo

Leishmania amazonensis is one of the etiological agents of diffuse cutaneous leishmaniasis in South America. In murine models of this infection, dysregulated expansion of effector T cells or exhaustion of Th1 responses are known to be related to pathogenesis, while the induction of regulatory T cells (Tregs) promotes lesion resolution. Recent research has identified several important co-stimulator/receptor pairs, including PD-1/PD-L1, for modulating Th1 responses and Treg induction. In this study, we examined the roles of these molecules in L. amazonensis-infected C57BL/6 mice. We found a significant and selective increase in the expression of PD-1 and PD-L1 (20-fold and 5-fold, respectively), in infected footpad tissues, which correlated with an increased percentage of PD-L1+CD11c+ dendritic cells (DCs) and PD-1+CD4+ T cells in the draining lymph nodes. To evaluate the mechanism of parasite-induced PD-L1 expression, we infected bone marrow-derived DCs (BMDCs) with promastigotes and amastigotes in vitro in the presence of small molecular inhibitors of critical signaling pathways. While L. amazonensis infection decreased PD-L2 expression on the surface of BMDCs, infection-mediated PD-L1 up-regulation was consistently detected, which was dependent on mTOR and partially dependent on STAT3, PI3K, and MAPK. Infected BMDCs also significantly inhibited the expansion of Th1 cells, but were more competent in inducing CD25+FoxP3+ Tregs in vitro than the non-infected BMDCs; such effects were PD-L1-dependent, as BMDCs from PD-L1-/- mice failed to do the same. In vivo experiments revealed that infected PD-L1-/- mouse tissues showed increased Th1 responses and IFN-{gamma} production, as well as reduced lesion sizes and parasite loads, without affecting Tregs cell expansion. Together, these results support a protective role for PD-1/PD-L1 signaling in regulating local immune responses during L. amazonensis infection. This study provides new insights on immune regulation in New World cutaneous leishmaniasis.

immunology↗

bioRxiv2019

Protection induced by anti-PD-1 and anti-PD-L1 treatment in Leishmania amazonensis-infected BALB/c mice

Leishmaniasis is a neglected disease, for which current treatment presents numerous issues. Leishmania amazonensis is the etiological agent of cutaneous and diffuse cutaneous leishmaniasis. The roles of the programmed death-1 (PD-1) receptor on lymphocytes and its ligand (PD-L1) on antigen-presenting cells have been well studied in tumor and other infection models; but little is known about their roles in non-healing cutaneous leishmaniasis. Our previous report of L. amazonensis-induced PD-L1 expression on dendritic cells, in combination with decreased IFN-{gamma} production by CD4+ T cells in C57BL/6 mice, led to a hypothesis that the formation of the PD-1/PD-L1 complex contributes to down-modulation of immune responses, especially T cell suppression, enabling parasite survival and persistence. In this study, we tested the therapeutic potential of anti-PD-1 and anti-PD-L1 monoclonal antibodies (MoAbs) against a non-healing L. amazonensis infection in BALB/c mice. We observed that L. amazonensis induced PD-1 expression on both CD4+ and CD8+ T cells, and that anti-PD-1 and anti-PD-L1 treatment significantly increased IFN-{gamma}-producing CD4+ and CD8+ T cells, respectively. Compared with infection controls, mice that received treatment with anti-PD-1 and anti-PD-L1, but not anti-PD-L2, displayed bigger lesions with significantly lower parasite loads. Treatment did not affect anti-Leishmania antibody or IL-10 production, but anti-PD-1 treatment reduced both IL-4 and TGF-{beta} production. Together, our results highlight the therapeutic potential of an anti-PD-1-based treatment in promoting the reinvigoration of T cells for the control of parasite burden.

immunology↗