HIRO GOTO

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Departamento de Medicina Preventiva, Faculdade de Medicina - Docente
LIM/38 - Laboratório de Epidemiologia e Imunobiologia, Hospital das Clínicas, Faculdade de Medicina - Líder

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  • article 2 Citação(ões) na Scopus
    Cell activation state influences the modulation of HLA-DR surface expression on human monocytes/macrophages by parenteral fish oil lipid emulsion
    (2011) TORRINHAS, R. S.; JACINTHO, T.; GOTO, H.; GIDLUND, M.; SALES, M. M.; OLIVEIRA, P. A.; WAITZBERG, D. L.
    Abnormal surface expression of HLA-DR by leukocytes is associated with a poor prognosis in critical care patients. Critical care patients often receive total parenteral nutrition with lipid emulsion (LE). In this study we evaluated the influence of fish oil LE (FO) on human monocyte/macrophage (M phi) expression of surface HLA-DR under distinct activation states. Mononuclear leukocytes from the peripheral blood of healthy volunteers (n=18) were cultured for 24 hours without LE (control) or with 3 different concentrations (0.1, 0.25, and 0.5%) of the follow LE: a) pure FO b) FO in association (1:1-v/v) with LE composed of 50% medium-chain trygliceride and 50% soybean oil (MCTSO), and c) pure MCTSO. The leukocytes were also submitted to different cell activation states, as determinate by INF-g addition time: no INF-gamma addition, 18 hours before, or at the time of LE addition. HLA-DR expression on MO surface was evaluated by flow cytometry using specific monoclonal antibodies. In relation to controls (for 0.1%, 0.25%, and 05%: 100) FO decreased the expression of HLA-DR when added alone in simultaneously-activated M., for 0.1%: 70 (59 +/- 73); for 0.25%: 51 (48 +/- 56); and for 05%: 52.5 (50 +/- 58)1 or in association with MCTSO [in simultaneously-activated MO, for 0.1%: 50.5 (47 +/- 61); for 25%: 49 (45 +/- 52); and for 0.5%: 51 (44 54) and in previously-activated Mf, for 1.0%: 63 (44 +/- 88); for 0.25%: 70 (41 +/- 88); and for 0.5%: 59.5 (39 +/- 79)1 in culture medium (Friedman p < 0.05). In relation to controls (for 0.1%, 0.25%, and 0.5%: 100), FO did not influence the expression of these molecules on non-activated M phi [for 0.1%: 87.5(75 +/- 93); for 0.25%: 111 (98 +/- 118); and for 0.5%: 101.5 (84 +/- 113)]. Results show that parenteral FO modulates the expression of HLA-DR on human MO surface accordingly to leukocyte activation state. Further clinical studies evaluating the ideal moment of fish oil LE infusion to modulate leukocyte functions may contribute to a better understanding of its immune modulatory properties.
  • article 25 Citação(ões) na Scopus
    Recombinant Leishmania infantum Heat Shock Protein 83 for the Serodiagnosis of Cutaneous, Mucosal, and Visceral Leishmaniases
    (2014) CELESTE, Beatriz Julieta; SANCHEZ, Maria Carmen Arroyo; RAMOS-SANCHEZ, Eduardo Milton; CASTRO, Luiz Guilherme M.; COSTA, Francisco Assis Lima; GOTO, Hiro
    Routine serological diagnoses for leishmaniases, except in visceral cases, are performed using whole-parasite antigens. We used enzyme-linked immunosorbent assay (ELISA) to evaluate the performance of Leishmania infantum rHsp83 compared with L. major-like total promastigote antigen in the diagnosis of cutaneous (CL), mucosal (ML), and visceral leishmaniases (VL). ELISA-rHsp83 was significantly more sensitive than ELISA-L. major-like when considering either CL/ML (P = 0.041) or all leishmaniasis patients (P = 0.013). When samples from other infectious disease patients were evaluated for cross-reactivity, ELISA-rHsp83 was more specific than ELISA-L. major-like, specifically for Chagas disease samples (P < 0.001). We also evaluated the anti-rHsp83 antibody titers months after treatment and observed no significant difference in ML (P = 0.607) or CL (P = 0.205). We recommend ELISA-L. infantum-rHsp83 as a routine confirmatory serological assay for the diagnosis of Leishmania infection because of the high sensitivity, the specificity, and the insignificant cross-reactivity with other infectious diseases.
  • article 5 Citação(ões) na Scopus
    Validation of ELISA with recombinant antigens in serological diagnosis of canine Leishmania infantum infection
    (2021) FUJIMORI, Mahyumi; ALMEIDA, Arleana do Bom Parto Ferreira de; BARROUIN-MELO, Stella Maria; CORTEZ, Luiz Ricardo Paes de Barros; DUTHIE, Malcolm Scott; HIRAMOTO, Roberto Mitsuyoshi; PINHO, Flaviane Alves de; REED, Steven Gregory; SOUSA, Valeria Regia Franco; SOUZA, Nazare Fonseca; SOARES, Rodrigo Martins; TOLEZANO, Jose Eduardo; SANCHEZ, Maria Carmen Arroyo; GOTO, Hiro
    BACKGROUND Dogs are the main peridomiciliary reservoir of Leishmania infantum thus the correct diagnosis of infection is essential for the control of the transmission and treatment as well. However, the diagnosis is based on serological assays that are not fully effective. OBJECTIVE We aimed to establish an effective serological assay for the diagnosis of L. infantum infected dogs using Leishmania-derived recombinant antigens. METHODS Leishmania derived rK39-, rK28-, rKR95-based enzyme-linked immunosorbent assay (ELISA) was standardized using symptomatic and asymptomatic L. infantum-infected dogs. Then 2,530 samples from inquiry in endemic areas for VL were evaluated and the results compared with recommended assays by the Brazilian Ministry of Health (MH algorithm). Further samples from a cohort of 30 dogs were searched. FINDINGS For rK39-, rK28- and rKR95-ELISA the sensitivity was around 97% and specificity 100%. The positivity of these three ELISA in the inquiry samples was 27-28%, around 10% higher than the assays currently in use. When cohort samples were searched, we observed likely false-negative results (> 65%) with supposedly negative samples that turned positive six months later with the assays in use (MH algorithm). MAIN CONCLUSIONS For the diagnosis of L. infantum-infected dogs, rK39-based ELISA showed better diagnostic performance than other assays in use in Brazil and worldwide.
  • article 18 Citação(ões) na Scopus
    ATP6V(0)d2 controls Leishmania parasitophorous vacuole biogenesis via cholesterol homeostasis
    (2019) PESSOA, Carina Carraro; REIS, Luiza Campos; RAMOS-SANCHEZ, Eduardo Milton; ORIKAZA, Cristina Mary; CORTEZ, Cristian; LEVATTI, Erica Valadares de Castro; BADARO, Ana Carolina Benites; YAMAMOTO, Joyce Umbelino da Silva; D'ALMEIDA, Vania; GOTO, Hiro; MORTARA, Renato Arruda; REAL, Fernando
    V-ATPases are part of the membrane components of pathogen-containing vacuoles, although their function in intracellular infection remains elusive. In addition to organelle acidification, V-ATPases are alternatively implicated in membrane fusion and anti-inflammatory functions controlled by ATP6V(0)d2, the d subunit variant of the V-ATPase complex. Therefore, we evaluated the role of ATP6V(0)d2 in the biogenesis of pathogen-containing vacuoles using ATP6V(0)d2 knock-down macrophages infected with the protozoan parasite Leishmania amazonensis. These parasites survive within IFN gamma/LPS-activated inflammatory macrophages, multiplying in large/fusogenic parasitophorous vacuoles (PVs) and inducing ATP6V(0)d2 upregulation. ATP6V(0)d2 knock-down decreased macrophage cholesterol levels and inhibited PV enlargement without interfering with parasite multiplication. However, parasites required ATP6V(0)d2 to resist the influx of oxidized low-density lipoprotein (ox-LDL)-derived cholesterol, which restored PV enlargement in ATP6V(0)d2 knock-down macrophages by replenishing macrophage cholesterol pools. Thus, we reveal parasite-mediated subversion of host V-ATPase function toward cholesterol retention, which is required for establishing an inflammation-resistant intracellular parasite niche. Author summary V-ATPases control acidification and other processes at intracellular vesicles that bacteria and parasites exploit as compartments for replication and immune evasion. We report that the protozoan intracellular parasite Leishmania amazonensis resists inflammatory macrophage immune responses and upregulates an alternative isoform of subunit d of V-ATPase (ATP6V(0)d2). Leishmania are still sequestered within acidified parasitophorous vacuoles (PVs) in cells lacking ATP6V(0)d2, but these PVs do not enlarge in volume, a distinguishing feature of intracellular infection by these parasites. Cholesterol levels in ATP6V(0)d2-deficient cells are reduced and exogenous cholesterol repletion can restore vacuole size, leading to enhanced parasite killing. This study demonstrates the ATP6V(0)d2-mediated interplay of macrophage cholesterol retention and control of the biogenesis of large pathogen-containing vacuoles. The study provides grounds for the development of new therapeutic strategies for diseases caused by intracellular pathogens sheltered in host cell compartments.
  • article 6 Citação(ões) na Scopus
    Insulin-like growth factor-I serum levels and their biological effects on Leishmania isolates from different clinical forms of American tegumentary leishmaniasis
    (2016) SOUZA, Luana Dias de; VENDRAME, Celia Maria Vieira; JESUS, Amelia Ribeiro de; CARVALHO, Marcia Dias Teixeira; MAGALHAES, Andrea Santos; SCHRIEFER, Albert; GUIMARAES, Luiz Henrique; CARVALHO, Edgar Marcelino de; GOTO, Hiro
    Background: American tegumentary leishmaniasis (ATL) in Brazil is mostly caused by Leishmania (Viannia) braziliensis, with known forms of the disease being cutaneous (CL), mucosal (ML) and disseminated (DL) leishmaniasis. The development of the lesion in ATL is related both to the persistence of the Leishmania in the skin and to the parasite-triggered immune and inflammatory responses that ensue lesions. In this context one factor with expected role in the pathogenesis is insulin-like growth factor (IGF)-I with known effects on parasite growth and healing and inflammatory processes. In the present study, we addressed the effect of IGF-I on intracellular amastigote isolates from CL, ML and DL patients within human macrophage and we evaluated the IGF-I and IGF-binding protein-3 (IGFBP3) serum levels in patients presenting different clinical forms and controls from the endemic area. Methods: We evaluated biological variability in the responses of intracellular amastigotes of Leishmania isolates derived from CL, ML, and DL patients from an area for ATL in response to IGF-I. Intracellular amastigote growth was evaluated using the human macrophage cell line THP-1. Arginase activity in infected cells was evaluated quantifying the generated urea concentration. Serum samples from patients and controls were assayed using chemiluminescent immunometric assay to determine IGF-I and IGFBP3 levels. Results: We observed an increase in intracellular parasitism upon IGF-I stimulus in 62.5 % of isolates from CL, in 85.7 % from ML and only 42.8 % from DL cases. In DL, the basal arginase activity was lower than that of CL. We then evaluated the IGF-I and IGFBP3 serum levels in patients, and we observed significantly lower levels in ML and DL than in CL and control samples. Conclusions: The data suggest that IGF-I is modulated distinctly in different clinical forms of tegumentary leishmaniasis. IGF-I seemingly exerts effect on parasite growth likely contributing to its persistence in the skin in earlier phase. In addition the decreased IGF-I serum levels may affect the modulation of inflammation and lesion healing in chronic phase. In view of potential role of IGF-I in the pathogenesis of ATL we can speculate on therapeutic procedures taking into account the local IGF-I level.
  • article 10 Citação(ões) na Scopus
    Macrophages From Subjects With Isolated GH/IGF-I Deficiency Due to a GHRH Receptor Gene Mutation Are Less Prone to Infection by Leishmania amazonensis
    (2019) BARRIOS, Monica R.; CAMPOS, Viviane C.; PERES, Nalu T. A.; OLIVEIRA, Lais L. de; CAZZANIGA, Rodrigo A.; SANTOS, Marcio B.; AIRES, Murilo B.; SILVA, Ricardo L. L.; BARRETO, Aline; GOTO, Hiro; ALMEIDA, Roque P.; SALVATORI, Roberto; AGUIAR-OLIVEIRA, Manuel H.; JESUS, Amelia M. R.
    Isolated growth hormone (GH) deficiency (IGHD) affects approximately 1 in 4,000 to 1 in 10,000 individuals worldwide. We have previously described a large cohort of subjects with IGHD due to a homozygous mutation in the GH releasing hormone (GHRH) receptor gene. These subjects exhibit throughout the life very low levels of GH and its principal mediator, the Insulin Growth Factor-I (IGF-I). The facilitating role of IGF-I in the infection of mouse macrophages by different Leishmania strains is well-known. Nevertheless, the role of IGF-I in Leishmania infection of human macrophages has not been studied. This study aimed to evaluate the behavior of Leishmania infection in vitro in macrophages from untreated IGHD subjects. To this end, blood samples were collected from 14 IGHD individuals and 14 age and sex-matched healthy controls. Monocytes were isolated and derived into macrophages and infected with a strain of Leishmania amazonensis. In addition, IGF-I was added to culture medium to evaluate its effect on the infection. Cytokines were measured in the culture supernatants. We found that macrophages from IGHD subjects were less prone to Leishmania infection compared to GH sufficient controls. Both inflammatory and anti-inflammatory cytokines increase only in the supernatants of the control macrophages. Addition of IGF-I to the culture medium increased infection rates. In conclusion, we demonstrated that IGF-I is crucial for Leishmania infection of human macrophages.
  • article 16 Citação(ões) na Scopus
    CD4(+) T Cells Alter the Stromal Microenvironment and Repress Medullary Erythropoiesis in Murine Visceral Leishmaniasis
    (2018) PREHAM, Olivier; PINHO, Flaviane A.; PINTO, Ana Isabel; RANI, Gulab Fatima; BROWN, Najmeeyah; HITCHCOCK, Ian S.; GOTO, Hiro; KAYE, Paul M.
    Human visceral leishmaniasis, a parasitic disease of major public health importance in developing countries, is characterized by variable degrees of severity of anemia, but the mechanisms underlying this change in peripheral blood have not been thoroughly explored. Here, we used an experimental model of visceral leishmaniasis in C57BL/6 mice to explore the basis of anemia following infection with Leishmania donovani. 28 days post-infection, mice showed bone marrow dyserythropoiesis by myelogram, with a reduction of TER119(+) CD71(-/+) erythroblasts. Reduction of medullary erythropoiesis coincided with loss of CD169(high) bone marrow stromal macrophages and a reduction of CXCL12-expressing stromal cells. Although the spleen is a site of extramedullary erythropoiesis and erythrophagocytosis, splenectomy did not impact the extent of anemia or affect the repression of medullary hematopoiesis that was observed in infected mice. In contrast, these changes in bone marrow erythropoiesis were not evident in B6.Rag2(-/-) mice, but could be fully reconstituted by adoptive transfer of IFN gamma-producing but not IFN gamma-deficient CD4(+) T cells, mimicking the expansion of IFN gamma-producing CD4(+) T cells that occurs during infection in wild type mice. Collectively, these data indicate that anemia during experimental murine visceral leishmaniasis can be driven by defects associated with the bone marrow erythropoietic niche, and that this represents a further example of CD4(+) T cell-mediated immunopathology affecting hematopoietic competence.
  • article 3 Citação(ões) na Scopus
    Staphylococcus aureus Protection-Related Type 3 Cell-Mediated Immune Response Elicited by Recombinant Proteins and GM-CSF DNA Vaccine
    (2021) SANTOS, Kamila R.; SOUZA, Fernando N.; RAMOS-SANCHEZ, Eduardo M.; BATISTA, Camila F.; REIS, Luiza C.; FOTORAN, Wesley F.; HEINEMANN, Marcos B.; GOTO, Hiro; GIDLUND, Magnus; CUNHA, Adriano F.; FARIA, Angelica Rosa; ANDRADE, Helida M.; LAGE, Andrey P.; CERQUEIRA, Monica M. O. P.; LIBERA, Alice M. M. P. Della
    Staphylococcus aureus mastitis remains a major challenge for dairy farming. Here, 24 mice were immunized and divided into four groups: G1: control; G2: Granulocyte Macrophage Colony-Stimulating Factor (GM-CSF) DNA vaccine; G3: F0F1 ATP synthase subunit alpha (SAS), succinyldiaminopimelate (SDD), and cysteinyl-tRNA synthetase (CTS) recombinant proteins; and G4: SAS+SDD+CTS plus GM-CSF DNA vaccine. The lymphocyte subpopulations, and the intracellular interleukin-17A (IL-17A) and interferon-gamma production in the draining lymph node cells were immunophenotyped by flow cytometry. The immunophenotyping and lymphocyte proliferation was determined in spleen cells cultured with and without S. aureus stimulus. Immunization with S. aureus recombinant proteins generated memory cells in draining lymph nodes. Immunization with the three recombinant proteins plus GM-CSF DNA led to an increase in the percentage of IL-17A(+) cells among overall CD44(+) (memory), T CD4(+), CD4(+) T CD44(+) CD27(-), gamma delta TCR, gamma delta TCR+ CD44(+) CD27(+), and TCRV gamma 4(+) cells. Vaccination with S. aureus recombinant proteins associated with GM-CSF DNA vaccine downregulated T(H)2 immunity. Immunization with the three recombinant proteins plus the GM-CSF DNA led to a proliferation of overall memory T, CD4(+), and CD4(+) TEM cells upon S. aureus stimulus. This approach fostered type 3 immunity, suggesting the development of a protective immune response against S. aureus.
  • article 7 Citação(ões) na Scopus
    Spatial distribution of canine Leishmania infantum infection in a municipality with endemic human leishmaniasis in Eastern Bahia, Brazil
    (2021) VARJAO, Bruno Milen; PINHO, Flaviane Alves de; SOLCA, Manuela da Silva; SILVESTRE, Ricardo; FUJIMORI, Mahyumi; GOTO, Hiro; VARJAO, Natasha Milen; DIAS, Roberta Costa; BARROUIN-MELO, Stella Maria
    Efforts to control a zoonotic disease such as visceral leishmaniasis (VL) caused by Leishmania infantum can be successful if they rely on comprehensive data on animal infection. In Bahia state, Brazil, human VL is endemic, yet some areas have no epidemiological data on canine L. infantum infection and canine leishmaniasis (CanL) to date. We aimed to perform an epidemiological study describing the spatial distribution and characterizing canine L. infantum infection in two districts of the municipality of Muritiba, where human cases have occurred. Brazilian official serodiagnostic protocol (ELISA and immunochromatographic tests), PCR and clinical examination were performed in 351 owned dogs. A seroprevalence of 15.7% (55/351) was found, and L. infantum identified in 88.8% (32/36) of PCR tested samples. Spatial distribution of positive dogs indicated infection in both urban and rural districts. There was no association between seropositivity and sex or breed, but dogs older than 2 years were 3.8 times more likely to be seropositive (95% CI 1.57 - 9.18) than younger dogs. Among seropositive dogs, 80% (44/55) had clinical manifestations of CanL: 75% (33/44) presented dermatopathy, 50% (22/44) emaciation, and 29.5% (13/44) ophthalmopathy. This is the first report on canine seroprevalence and natural L. infantum infection in Muritiba, Bahia.
  • article 8 Citação(ões) na Scopus
    Leptospirosis Infection in Sheep and Characterization of the Renal Inflammatory Response.
    (2011) CARVALHO, Sonia Maria de; GONCALVES, Larissa Maria Feitosa; MACEDO, Nicodemos Alves de; GOTO, Hiro; SILVA, Silvana Maria Medeiros de Sousa; MINEIRO, Ana Lys Bezerra Barradas; KANASHIRO, Edite Hatsumi Yamashiro; COSTA, Francisco Assis Lima
    Carvalho S.M., Gon alves L.M.F., Macedo N.A., Goto H., Silva S.M.M.S., Mineiro A.L.B.B., Kanashiro E.H.Y. & Costa F.A.L. 2011. [Leptospirosis Infection in Sheep and Characterization of the Renal Inflammatory Response.] Infeccao por leptospiras em ovinos e caracterizacao da resposta inflamatoria renal. Pesquisa Veterinaria Brasileira 31(8):637-642. Departamento de Clinica e Cirurgia Veterinaria, Centro de Ciencias Agrarias, Universidade Federal do Piaui, Campus Socopo, Teresina, PI 64046-550, Brazil. E-mail: fassisle@gmail.com Lepitospirosis is a serious worldwide distribution disease which affects man and other animals. The infection is generally asymptomatic in animals. In cases whose symptoms are present, symptoms are similar to other infections. In the present study serum samples from 119 sheep and their kidneys were collected during their slaughter in outdoor markets in the city of Teresina, Piaui, Brazil. The Microscopic Agglutination Test (MAT) obtained 34 positive serological samples for one or more Leptospira spp. serovar with occurrence rate of 28.6% of leptospiral antibodies. There were 23 cases of infection for a single serovar, and 11 cases with coagglutination for two or more serovars. Autumnalis had the highest occurrence (29.4%) among the pathogenic serovars. The histopathological analysis of 36 kidney fragments revealed tubulo-interstitial alterations in 33 (91.7%) positive animals. Tubular lesions were observed in 20 (55.5%) positive animals. The Warthin Starry staning revealed the presence of Leptospira in 8 (22.20%) of the 36 positive samples. The immunoperoxidase staining revealed the presence of Leptospira in 12 (60%) of 20 positive samples. The inflammatory infiltrate in the positive animals was significantly more evident in the cortical-medullar and cortical regions than in the medullar region (p=0.000), however, there was no difference between positive and negative animals. The presence of hyaline casts in the proximal tubules was significantly higher in positive animals compared to the negative ones (p=0.0001). Discrete lesion was observed in glomeruli. In conclusion, the results from this study showed that sheep which are positive for Leptospira present tubulo-intersticial renal lesions with the presence of Leptospira in the tubules, conferring to these animals the condition of asymptomatic carriers.