Sidnei Ferro Costa

Universidade Estadual Paulista (Unesp)

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Valéria Marçal Félix de Lima

Universidade Estadual Paulista (Unesp)

Gabriela Torres Rebech

Universidade Estadual Paulista (Unesp)

Jaqueline Poleto Bragato

Universidade Estadual Paulista (Unesp)

Jéssica Henrique de Freitas

Universidade Estadual Paulista (Unesp)

Matheus Fujimura Soares

Universidade Estadual Paulista (Unesp)

Paulo Sérgio Patto dos Santos

Universidade Estadual Paulista (Unesp)

Flávia de Rezende Eugênio

Universidade Estadual Paulista (Unesp)

Marilene Oliveira dos Santos Maciel

Universidade Estadual Paulista (Unesp)

Gabriela Lovizutto Venturin

Universidade Estadual Paulista (Unesp)

Larissa Martins Melo

Universidade Estadual Paulista (Unesp)

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Universidade Estadual Paulista (Unesp)

Universidade de São Paulo

Fundação Faculdade de Odontologia

Fundação Oswaldo Cruz

Universidade de Ribeirão Preto

Universidade Federal de Pelotas

Universidade Paulista

Centro Universitario Toledo

Fundação Faculdade de Medicina

Hospital São Rafael

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Eosinophilic inflammation in lymph nodes of dogs with visceral leishmaniasis

Parasite Immunology (2018)

Sidnei Ferro Costa Gabriel Franco Trivellato Gabriela Torres Rebech Marilene Oliveira dos Santos Maciel Larissa Martins Melo

Eosinophils are traditionally associated with the immune response against helminth parasites. However, several studies have demonstrated that these cells have a role regarding protective immunity in leishmaniasis. Here, we examined the relationship between the presence of eosinophils and parasite load in biopsy samples from dogs, obtained through fine needle puncture and aspiration of lymph nodes. Histological slides containing biopsy material from lymph nodes of dogs with canine visceral leishmaniasis and healthy dogs were used to obtain baseline eosinophil counts. Subsequently, scrapings were taken from slides for DNA extraction and determination of parasite load, using real-time PCR (qRT-PCR). Additionally, production of nitric oxide (NO) and reactive oxygen species (ROS) levels by eosinophils in the peripheral blood of dogs with canine visceral leishmaniasis and healthy dogs was measured. The eosinophil percentage were higher in lymph nodes of infected group, and the parasite load showed a significant negative correlation with the eosinophil count. The production of NO and ROS by eosinophils in the peripheral blood was higher in the dogs with canine visceral leishmaniasis. All the results together suggest that eosinophils may participate in antileishmanial immunity in canine visceral leishmaniasis.

Parasite load

10.1111/pim.12567

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Leishmania infantum infection modulates messenger RNA, microRNA and long non-coding RNA expression in human neutrophils in vitro

PLoS neglected tropical diseases (2024)

Natália Francisco Scaramele Jéssica Antonini Troiano Juliana de Souza Felix Sidnei Ferro Costa Mariana Cordeiro Almeida

In the Americas, L . infantum (syn. chagasi ) is the main cause of human visceral leishmaniasis. The role of neutrophils as part of the innate response to Leishmania spp. infection is dubious and varies according to the species causing the infection. Global expression of coding RNAs, microRNAs and long non-coding RNAs changes as part of the immune response against pathogens. Changes in mRNA and non-coding RNA expression resulting from infection by Leishmania spp. are widely studied in macrophages, but scarce in neutrophils, the first cell to encounter the trypanosomatid, especially following infection by L . infantum . Herein, we aimed to understand the expression patterns of coding and non-coding transcripts during acute in vitro infection of human neutrophils by L . infantum . We isolated neutrophils from whole blood of healthy male donors (n = 5) and split into groups: 1) infected with L . infantum (MOI = 5:1), and 2) uninfected controls. After 3 hours of exposure of infected group to promastigotes of L . infantum , followed by 17 hours of incubation, total RNA was extracted and total RNA-Seq and miRNA microarray were performed. A total of 212 genes were differentially expressed in neutrophils following RNA-Seq analysis (log 2 (FC)±0.58, FDR≤0.05). In vitro infection with L . infantum upregulated the expression of 197 and reduced the expression of 92 miRNAs in human neutrophils (FC±2, FDR≤0.01). Lastly, 5 downregulated genes were classified as lncRNA, and of the 10 upregulated genes, there was only 1 lncRNA. Further bioinformatic analysis indicated that changes in the transcriptome and microtranscriptome of neutrophils, following in vitro infection with L . infantum , may impair phagocytosis, apoptosis and decrease nitric oxide production. Our work sheds light on several mechanisms used by L . infantum to control neutrophil-mediated immune response and identifies several targets for future functional studies, aiming at the development of preventive or curative treatments for this prevalent zoonosis.

10.1371/journal.pntd.0012318

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GradO - o66 Avaliação dos efeitos da nicotina associada à obesidade no fêmur e tíbia de ratos: análise da densidade óssea radiográfica e da espessura óssea total e cortical

ARCHIVES OF HEALTH INVESTIGATION (2016)

Sidnei Ferro Costa Karoliny Canhet Paterno Mariza Akemi Matsumoto Leda Maria Pescinini Salzedas Roberta Okamoto

Este estudo teve como objetivo avaliar os efeitos da nicotina associada a obesidade no femur e tibia de ratos pela analise da densidade ossea radiografica e da espessura ossea total e cortical. Foram utilizados 28 ratos Wistar machos, de 28 semanas, sendo 14 nao obesos e 14 com obesidade induzida por dieta. Metade dos animais de cada grupo foram tratados com soro fisiologico 0,9% por via subcultânea e a outra metade com 6 mg/kg/dia de hemisulfato de nicotina por via subcutânea, em doses fracionadas a cada 12 horas, durante 60 dias. Apos a eutanasia, imagens digitais dos femures e tibias direitos foram obtidas utilizando o sistema Digora (Soredex, Orion Corporation, Helsinki, Finland). A densidade radiografica ossea foi mensurada no terco medio e na cabeca do femur, e no terco medio da tibia. Foram, tambem, mensuradas as espessura ossea total e cortical do terco medio de ambos os ossos. Os dados foram submetidos a analise estatistica pelo teste ANOVA de variância, pos-teste Tukey, com nivel de significância de 95%. Os resultados mostraram menor densidade no femur e na tibia bem como menor espessura total e cortical nos animais que receberam nicotina, comparados aos tratados com soro, embora diferenca estatistica (p<0,05) tenha sido encontrada apenas entre os animais obesos e em relacao a densidade radiografica do terco medio femural (2,22 ± 1,46 x 1,88 ± 0,07) e da cabeca (2,77 ± 0,27 x 2,30 ± 0,19), densidade radiografica do terco medio da tibia (1,62 ± 0,13 x 1,29 ± 0,17) e area cortical do terco medio femural (1,68 ± 0,06 x 1,49 ± 0.13). Conclui-se que a nicotina teve um efeito negativo sobre o tecido osseo do femur e da tibia, que se mostra ainda mais acentuado quando associada a obesidade. Descritores: Obesidade, Nicotina, Densidade Ossea. Agradecimentos/Apoio Financeiro: PIBIC/CNPq (Processo 129642/2015-0)

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MicroRNA-21 and microRNA-148a affects PTEN, NO and ROS in canine leishmaniasis

Frontiers in Genetics (2023)

Jéssica Henrique de Freitas Jaqueline Poleto Bragato Gabriela Torres Rebech Sidnei Ferro Costa Marilene Oliveira dos Santos

Canine Visceral leishmaniasis (CanL) poses a severe public health threat in several countries. Disease progression depends on the degree of immune response suppression. MicroRNAs (miRs) modulate mRNA translation into proteins and regulate various cellular functions and pathways associated with immune responses. MiR-21 and miR-148a can alter the parasite load and M1 macrophages are the principal cells in dogs' leishmanicidal activity. A previous study found increased miR-21 and miR-148a in splenic leukocytes (SL) of dogs with CanL using microarray analysis and in silico analysis identified PTEN pathway targets. PTEN is involved in the immune regulation of macrophages. We measured PTEN and the production of reactive oxygen species (ROS) and nitric oxide (NO) before and after transfection SLs of dogs with CanL with mimic and inhibition of miR-21 and miR-148a. PTEN levels increased, NO and ROS decreased in SLs from dogs with CanL. Inhibition of miRNA-21 resulted in PTEN increase; in contrast, PTEN decreased after miR-148a inhibition. Nitrite (NO2) levels increased after transfection with miR-21 inhibitor but were decreased with miR-148a inhibitor. The increase in miR-21 promoted a reduction in ROS and NO levels, but miR-148a inhibition increased NO and reduced ROS. These findings suggest that miR-21 and miR-148a can participate in immune response in CanL, affecting PTEN, NO, and ROS levels.

10.3389/fgene.2023.1106496

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Vitamins A and D and Zinc Affect the Leshmanicidal Activity of Canine Spleen Leukocytes

Animals (2021)

Fabiana M. de O. Hernandez Marilene Oliveira dos Santos Gabriela Lovizutto Venturin Jaqueline Poleto Bragato Gabriela Torres Rebech

Canine leishmaniasis (CanL) is a chronic disease caused by

Affect

10.3390/ani11092556

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Influence of weight gain on the modulation of wound healing following tooth extraction

Bone (2018)

Cristiane Furuse Aline Ferreira de Almeida Sidnei Ferro Costa Ana Cláudia Ervolino da Silva Roberta Okamoto

10.1016/j.bone.2018.06.017

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Induction of miR 21 impairs the anti-Leishmania response through inhibition of IL-12 in canine splenic leukocytes

PLoS ONE (2019)

Larissa Martins Melo Jaqueline Poleto Bragato Gabriela Lovizutto Venturin Gabriela Torres Rebech Sidnei Ferro Costa

Visceral Leishmaniasis is a chronic zoonosis and, if left untreated, can be fatal. Infected dogs have decreased cellular immunity (Th1) and develop a potent humoral response (Th2), which is not effective for elimination of the protozoan. Immune response can be modulated by microRNAs (miRNAs), however, characterization of miRNAs and their possible regulatory role in the spleen of infected dogs have not been done. We evaluated miRNA expression in splenic leukocytes (SL) from dogs naturally infected with Leishmania infantum and developing leishmaniasis (CanL; n = 8) compared to healthy dogs (n = 4). Microarray analysis showed increased expression of miR 21, miR 148a, miR 7 and miR 615, and downregulation of miR 150, miR 125a and miR 125b. Real-time PCR validated the differential expression of miR 21, miR 148a and miR 615. Further, decrease of miR 21 in SL, by means of transfection with a miR 21 inhibitor, increased the IL-12 cytokine and the T-bet/GATA-3 ratio, and decreased parasite load on SL of dogs with CanL. Taken together, these findings suggest that L. infantum infection alters splenic expression of miRNAs and that miR 21 interferes in the cellular immune response of L. infantum-infected dogs, placing this miRNA as a possible therapeutic target in CanL.

10.1371/journal.pone.0226192

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Regulatory effect of PGE₂ on microbicidal activity and inflammatory cytokines in canine leishmaniasis

Parasite Immunology (2020)

Gabriela Lovizutto Venturin Jaqueline Poleto Bragato Larissa Martins Melo Gabriela Torres Rebech Sidnei Ferro Costa

Canine leishmaniasis (CanL) is caused by the intracellular parasite Leishmania infantum. Prostaglandin E2 (PGE2 ) exerts potent regulatory effects on the immune system in experimental model Leishmania infection, but this influence has not yet been studied in CanL. In this study, PGE2 and PGE2 receptor levels and the regulatory effect of PGE2 on arginase activity, NO2 , IL-10, IL-17, IFN-γ, TNF-α and parasite load were evaluated in cultures of splenic leucocytes obtained from dogs with CanL in the presence of agonists and inhibitors. Our results showed that splenic leucocytes from dogs with CanL had lower EP2 receptor levels than those of splenic leucocytes from healthy animals. We observed that NO2 levels decreased when the cells were treated with a PGE2 receptor agonist (EP1/EP2/EP3) or COX-2 inhibitor (NS-398) and that TNF-α, IL-17 and IFN-γ cytokine levels decreased when the cells were treated with a PGE2 receptor agonist (EP2) or PGE2 itself. The parasite load in splenic leucocyte cell cultures from dogs with CanL decreased after stimulation of the cells with PGE2 . We conclude that Leishmania infection of dogs modulates PGE2 receptors and speculate that the binding of PGE2 to its receptors may activate the microbicidal capacity of cells.

Canine leishmaniasis

Prostaglandin E2 receptor

10.1111/pim.12713

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MicroRNA-194 regulates parasitic load and IL-1β-dependent nitric oxide production in the peripheral blood mononuclear cells of dogs with leishmaniasis

PLoS neglected tropical diseases (2024)

Sidnei Ferro Costa Matheus Fujimura Soares Jaqueline Poleto Bragato Marilene Oliveira dos Santos Maciel Gabriela Torres Rebech

Domestic dogs are the primary urban reservoirs of Leishmania infantum , the causative agent of visceral leishmaniasis. In Canine Leishmaniasis (CanL), modulation of the host’s immune response may be associated with the expression of small non-coding RNAs called microRNA (miR). miR-194 expression increases in peripheral blood mononuclear cells (PBMCs) of dogs with leishmaniasis with a positive correlation with the parasite load and in silico analysis demonstrated that the TRAF6 gene is the target of miR-194 in PBMCs from diseased dogs. Here, we isolated PBMCs from 5 healthy dogs and 28 dogs with leishmaniasis, naturally infected with L . infantum . To confirm changes in miR-194 and TRAF6 expression, basal expression of miR-194 and gene expression of TRAF6 was measured using qPCR. PBMCs from healthy dogs and dogs with leishmaniasis were transfected with miR-194 scramble, mimic, and inhibitor and cultured at 37° C, 5% CO 2 for 48 hours. The expression of possible targets was measured: iNOS, NO, T-bet, GATA3, and FoxP3 were measured using flow cytometry; the production of cytokines IL-1β, IL-4, IL-6, IL-10, TNF-α, IFN-γ, and TGF-β in cell culture supernatants was measured using capture enzyme-linked immunosorbent assays (ELISA). Parasite load was measured using cytometry and qPCR. Functional assays followed by miR-194 inhibitor and IL-1β blockade and assessment of NO production were also performed. Basal miR-194 expression was increased in PBMC from dogs with Leishmaniasis and was negatively correlated with TRAF6 expression. The mimic of miR-194 promoted an increase in parasite load. There were no significant changes in T-bet, GATA3, or FoxP3 expression with miR-194 enhancement or inhibition. Inhibition of miR-194 increased IL-1β and NO in PBMCs from diseased dogs, and blockade of IL-1β following miR-194 inhibition decreased NO levels. These findings suggest that miR-194 is upregulated in PBMCs from dogs with leishmaniasis and increases parasite load, possibly decreasing NO production via IL-1β. These results increase our understanding of the mechanisms of evasion of the immune response by the parasite and the identification of possible therapeutic targets.

Parasite load

Canine leishmaniasis

10.1371/journal.pntd.0011789

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miR-148a regulation interferes in inflammatory cytokine and parasitic load in canine leishmaniasis

PLoS neglected tropical diseases (2023)

Gabriela Torres Rebech Jaqueline Poleto Bragato Sidnei Ferro Costa Jéssica Henrique de Freitas Marilene Oliveira dos Santos

Canine leishmaniasis (CanL) is a severe public health threat. Infected animals mediate transmission of the Leishmania protozoan to humans via the sandfly’s bite during a blood meal. CanL progression depends on the degree of suppression of the immune response, possibly associated with microRNAs (miR), which can modulate mRNA translation into proteins and (consequently) regulate cell function. Increased miR-148a in splenic leukocytes (SL) of dogs with CanL was observed in previous studies, and in silico analysis, identified possible pathways involved in immune response regulation that are affected by this miR. Therefore, we evaluated the involvement of miR-148a in the regulation of TNF-α, IL-6, IL-12, IL-1β, iNOS, MHCII, CD80, CD3, T-bet, and GATA-3 transcription factors and their relationship with parasite load in SL of dogs with CanL. Splenic leukocytes obtained from healthy and diseased dogs were transfected with miR-148a mimic and inhibitor oligonucleotides. After 48 hours, expression levels of MHCII, CD80, iNOS, CD3, T-bet, and GATA-3 were evaluated by flow cytometry, and concentrations of TNF-α, IL-12, IL-6, and IL-1β were measured in culture supernatants by capture enzyme-linked immunosorbent assays. Transfection of SL with miR-148a mimics decreased iNOS levels in cells and TNF-α, IL-6, and IL-12 in the supernatants of cultured SL from CanL dogs. Interestingly, transfection with miR-148a inhibitor decreased parasite load in SL cells. These results suggest a direct or not regulatory role of this miR in the immune response to Leishmania infantum infection. We conclude that miR-148a can modulate immune responses by regulating inflammatory cytokines during CanL. Our results contribute to understanding the complex host/parasite interaction in CanL and could assist the development of treatments.

Parasite load

10.1371/journal.pntd.0011039

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Citations (2)