MARCIA DALASTRA LAURENTI
Projetos de Pesquisa
Unidades Organizacionais
Departamento de Patologia, Faculdade de Medicina - Docente
LIM/50 - Laboratório de Patologia das Moléstias Infecciosas, Hospital das Clínicas, Faculdade de Medicina - Líder
LIM/50 - Laboratório de Patologia das Moléstias Infecciosas, Hospital das Clínicas, Faculdade de Medicina - Líder
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- SUSCEPTIBILITY OF PERITONEAL MACROPHAGE FROM DIFFERENT SPECIES OF NEOTROPICAL PRIMATES TO EX VIVO Leishmania (L.) infantum chagasi-INFECTION(2012) CARNEIRO, Liliane Almeida; LAURENTI, Marcia Dalastra; CAMPOS, Marliane Batista; GOMES, Claudia Maria de Castro; CORBETT, Carlos Eduardo Pereira; SILVEIRA, Fernando TobiasThis study examined the susceptibility of peritoneal macrophage (PM) from the Neotropical primates: Callithrix jacchus, Callithrix penicillata, Saimiri sciureus, Aotus azarae infulatus and Callimico goeldii to ex vivo Leishmania (L.) infantum chagasi-infection, the etiological agent of American visceral leishmaniasis (AVL), as a screening assay for evaluating the potential of these non-human primates as experimental models for studying AVL. The PM-susceptibility to infection was accessed by the PM-infection index (PMI) at 24, 72 h and by the mean of these rates (FPMI), as well as by the TNF-alpha, IL-12 (Capture ELISA) and Nitric oxide (NO) responses (Griess method). At 24h, the PMI of A. azarae infulatus (128) was higher than those of C. penicillata (83), C. goeldii (78), S. sciureus (77) and C. jacchus (55). At 72h, there was a significant PMI decrease in four monkeys: A. azarae infulatus (128/37), C. penicillata (83/38), S. sciureus (77/38) and C. jacchus (55/12), with exception of C. goeldii (78/54). The FPMI of A. azarae infulatus (82.5) and C. goeldii (66) were higher than C. jacchus (33.5), but not higher than those of C. penicillata (60.5) and S. sciureus (57.5). The TNF-alpha response was more regular in those four primates which decreased their PMI at 24/72 h: C. jacchus (145/122 pg/mu L), C. penicillata (154/130 pg/mu L), S. sciureus (164/104 pg/mu L) and A. azarae infulatus (154/104 pg/mu L), with exception of C. goeldii (38/83 pg/mu L). The IL-12 response was mainly prominent in A. infulatus and C. goeldii which presented the highest FPMI and, the NO response was higher in C. goeldii, mainly at 72 h. These findings strongly suggest that these New World primates have developed a resistant innate immune response mechanism capable of controlling the macrophage intracellular growth of L. (L.) i. chagasi-infection, which do not encourage their use as animal model for studying AVL.
- The antifungal compound butenafine eliminates promastigote and amastigote forms of Leishmania (Leishmania) amazonensis and Leishmania (Viannia) braziliensis(2016) BEZERRA-SOUZA, Adriana; YAMAMOTO, Eduardo S.; LAURENTI, Marcia D.; RIBEIRO, Susan P.; PASSERO, Luiz Felipe D.The production of ergosterol lipid, important for the Leishmania membrane homeostasis, involves different enzymes. This pathway can be blocked to azoles and allylamines drugs, such as Butenafine. The aim of the present work was to evaluate the anti-leishmanicidal activity of this drug in 2 major species of Leishmania responsible for causing the American tegumentar leishmaniasis (L (L.) amazonensis and L (V.) braziliensis). Butenafine eliminated promastigote forms of L amazonensis and L braziliensis with efficacy similar to miltefosine, a standard anti-leishmania drug. In addition, butenafine induced alterations in promastigote forms of L amazonensis that resemble programmed cell death. Butenafine as well as miltefosine presented mild toxicity in peritoneal macrophages, however, butenafine was more effective to eliminate intracellular amastigotes of both L amazonensis and L braziliensis, and this effect was not associated with elevated levels of nitric oxide or hydrogen peroxide. Taken together, data presented herein suggests that butenafine can be considered as a prototype drug able to eliminate L amazonensis and L braziliensis, etiological agents of anergic diffuse and mucocutaneous leishmaniasis, respectively.
- Evaluation of Leishmania (Leishmania) infantum excreted-secreted antigens for detection of canine leishmaniasis(2016) PINEDO-CANCINO, Viviana; LAURENTI, Marcia Dalastra; KESPER, Norival; UMEZAWA, Eufrosina SetsuThe efficacy of tests with L (L.) infantum excreted-secreted antigens (ESA) to detect canine leishmaniasis (CanL) was evaluated using immunoblotting (ESA-blot), ELISA (ESA-ELISA) and ELISA with alkaline extract from promastigotes (PAE). Of one hundred fifty-five domestic dogs tested, 100 were suspected of CanL, 23 had other diseases and 32 were healthy. Sera from the dogs suspected of CanL were tested by immunohistochemistry (IHC), and 54% were confirmed to be infected by L (L.) infantum (38 symptomatic and 16 asymptomatic). Of these, 100% were positive by ESA-blot, ESA-ELISA and PAE-ELISA. In the ESA blot their sera recognized polypeptides in the 26.5-31.5 kDa region. Of the 46% of dogs with negative IHC, 44-53% tested positive in all three tests irrespective of clinical status. The twenty-three dogs with other diseases were negative by ESA-blot, but sera from 9% and 26% of them reacted with ESA-ELISA and PAE-ELISA, respectively. The 32 healthy dogs were negative in all the tests. ESA-blot showed good correlation with IHC in the detection of CanL and a high specificity index.
- Infectious Diseases in Free-Ranging Blonde Capuchins, Sapajus flavius, in Brazil(2017) BUENO, Marina Galvao; CATO-DIAS, Jose Luiz; LAROQUE, Plautino de Oliveira; VASCONCELLOS, Silvio Arruda; FERREIRA NETO, Jose Soares; GENNARI, Solange Maria; FERREIRA, Fernando; LAURENTI, Marcia Dalastra; UMEZAWA, Eufrosina Setsu; KESPER, Norival; KIRCHGATTER, Karin; GUIMARES, Lilian Oliveira; PAVANATO, Heloise Juliao; VALENCA-MONTENEGRO, Monica MafraThe main threats to primates worldwide are the degradation, fragmentation, and loss of their habitats; hunting (especially for bushmeat); and illegal trade. For many species, the most important threat is forest fragmentation, resulting in small populations that are restricted to isolated forest patches. In this situation, primates are particularly vulnerable to disease. The Endangered blonde capuchin (Sapajus flavius) is now restricted to a few forest patches in Northeast Brazil. We investigated the occurrence of parasites and bacterial diseases in one of three free-ranging groups of S. flavius in a small forest patch in Paraiba state, Northeast Brazil. We tested for antibodies against Leishmania spp., Trypanosoma cruzi, Toxoplasma gondii, Leptospira spp. (24 strains), and Brucella spp.. We used molecular analysis to detect Plasmodium spp., and evaluated blood smears for the presence of hemoparasites. All individuals tested negative for Leptospira spp. and B. abortus, but 8 of 48 (16%) presented antibodies for both Leishmania spp. and T. cruzi. We identified antibodies to T. gondii in 12% of the individuals tested. Plasmodium brasilianum infection was present in 4% of the individuals tested, and blood smears showed microfilariae parasites in 46% of the individuals tested. The occurrence of these infectious diseases in S. flavius may pose a significant threat in terms of reduced recruitment and poor survival rates, and an understanding of the influence of pathogens is crucial for the management of small populations of primates.
- Gene Signatures of Symptomatic and Asymptomatic Clinical-Immunological Profiles of Human Infection by Leishmania (L.) chagasi in Amazonian Brazil(2023) MATTA, Vania Lucia R. da; GONCALVES, Andre N.; GOMES, Claudia Maria C.; CHOUMAN, Islam H.; FERREIRA, Frederico M.; CAMPOS, Marliane B.; LIMA, Luciana V.; SANTOS, Thiago Vasconcelos dos; RAMOS, Patricia Karla; FURTADO, Rodrigo R.; LAURENTI, Marcia D.; CORBETT, Carlos Eduardo P.; NAKAYA, Helder I.; SILVEIRA, Fernando T.Individuals infected with Leishmania (L.) chagasi may present different asymptomatic and symptomatic stages of infection, which vary in the clinical-immunological profiles that can be classified as asymptomatic infection (AI), subclinical resistant infection (SRI), indeterminate initial infection (III), subclinical oligosymptomatic infection (SOI), and symptomatic infection (SI) (=American visceral leishmaniasis, AVL). However, little is known about the molecular differences between individuals having each profile. Here, we performed whole-blood transcriptomic analyses of 56 infected individuals from Para State (Brazilian Amazon), covering all five profiles. We then identified the gene signatures of each profile by comparing their transcriptome with those of 11 healthy individuals from the same area. Symptomatic individuals with SI (=AVL) and SOI profiles showed higher transcriptome perturbation when compared to those asymptomatic III, AI and SRI profiles, suggesting that disease severity may be associated with greater transcriptomic changes. Although the expression of many genes was altered on each profile, very few genes were shared among the profiles. This indicated that each profile has a unique gene signature. The innate immune system pathway was strongly activated only in asymptomatic AI and SRI profiles, suggesting the control of infection. In turn, pathways such as MHC Class II antigen presentation and NF-kB activation in B cells seemed to be specifically induced in symptomatic SI (=AVL) and SOI profiles. Moreover, cellular response to starvation was down-regulated in those symptomatic profiles. Overall, this study revealed five distinct transcriptional patterns associated to the clinical-immunological (symptomatic and asymptomatic) profiles of human L. (L.) chagasi-infection in the Brazilian Amazon.
- Th17 lymphocytes in atypical cutaneous leishmaniasis caused byLeishmania (L.) infantum chagasiin Central America(2020) FLORES, Gabriela Venicia Araujo; PACHECO, Carmen Maria Sandoval; OCHOA, Wilfredo Humberto Sosa; GOMES, Claudia Maria Castro; ZUNIGA, Concepcion; CORBETT, Carlos P.; LAURENTI, Marcia DalastraSkin lesions in nonulcerated cutaneous leishmaniasis (NUCL) caused byLeishmania (L.) infantum chagasiare characterized by a mononuclear inflammatory infiltrate in the dermis, which is composed mainly of lymphocytes, followed by macrophages, few plasma cells and epithelioid granulomas with mild tissue parasitism. Previous studies have shown that the main population of lymphocytes present in the dermal infiltrate is CD8(+)T cells, followed by CD4(+)T cells, which are correlated with IFN-gamma(+)cells. To improve the knowledge of cellular immune responses in NUCL, skin biopsies were submitted to immunohistochemistry using anti-ROR-gamma t, anti-IL-17, anti-IL-6, anti-TGF-beta, and anti-IL-23 antibodies to characterize the involvement of Th17 cells in the skin lesions of patients affected by NUCL. ROR-gamma t(+), IL-17(+), IL-6(+), TGF-beta(+)and IL-23(+)cells were observed in the dermal inflammatory infiltrate of NUCL skin lesions. A positive correlation between CD4(+)T-lymphocytes and ROR-gamma t(+)and IL-17(+)cells suggests that some of the CD4(+)T-lymphocytes in NUCL could be Th17 lymphocytes. Moreover, a positive correlation between ROR-gamma t(+)cells and TGF-beta(+), IL-6(+), IL-17(+)and IL-23(+)cells could indicate the role of these cytokines in the differentiation and maintenance of Th17 lymphocytes. Our findings improve knowledge of the pathogenesis of this rare and atypical clinical form of leishmaniasis.
- Expression of Foxp3, TGF-beta and IL-10 in American cutaneous leishmaniasis lesions(2014) RODRIGUES, F. M. D.; COELHO NETO, G. T.; MENEZES, J. G. P. B.; GAMA, M. E. A.; GONCALVES, E. G.; SILVA, A. R.; LAURENTI, M. D.; CORBETT, C. E. P.; SILVEIRA, F. T.; GOMES, C. M. C.Regulatory T cells (Tregs) are a unique population of CD25+CD4+ T cells that regulate innate and adaptive immune responses and have the ability to control the excessive or misdirected effects of the immune system. This modulation involves different mechanisms, such as the suppression of T cell proliferation and cytokine production, the secretion of suppressive cytokines (IL-10 and TGF-beta) and the induction of effector T cell apoptosis in humans with infectious diseases such as Leishmania infections. The aim of this study was to evaluate the expression of Foxp3, IL-10 and TGF-beta through immunohistochemistry in 22 skin biopsies of patients with localized cutaneous leishmaniasis (LCL) caused by Leishmania (Viannia) spp. from an endemic area in pre-Amazonian area of Maranho State, Brazil. The density of these markers was also analyzed according to the species of parasite and the progression of the disease. The cellular density was 234 cells/mmA(2) for Foxp3+ cells, 357 cells/mmA(2) for TGF-beta+ cells and 648 cells/mmA(2) for IL-10+ cells in the studied skin lesions. The analysis of the cellular density of these immunological markers in relation to the species of Leishmania demonstrated that lesions caused by L. (V.) braziliensis had a lower density of Foxp3+ cells than lesions caused by L. (Viannia) spp. The expression of IL-10 was also lower in lesions caused by L. (V.) braziliensis. There were no significant differences in TGF-beta expression between the two groups. The evaluation of these markers according to the progression of the disease did not reveal any significant differences. These findings suggest that Treg Foxp3+ cells, IL-10, and TGF-beta play important roles in the immunopathogenesis of LCL and that these roles differ depending on the causal Leishmania species.
- Detection of Pintomyia fischeri (Diptera: Psychodidae) With Leishmania infantum (Trypanosomatida: Trypanosomatidae) Promastigotes in a Focus of Visceral Leishmaniasis in Brazil(2021) GALVIS-OVALLOS, Fredy; UETA, Adriele Eiko; MARQUES, Gabriella de Oliveira; SARMENTO, Ana Maria Casagrande; ARAUJO, Gabriela; SANDOVAL, Carmen; TOMOKANE, Thaise Yumie; MATTA, Vania Lucia Ribeiro da; LAURENTI, Marcia Dalastra; GALATI, Eunice Aparecida BianchiVisceral leishmaniasis is spreading in Brazil where the main vector of its agent, Leishmania infantum Nicolle, 1908, is the Lutzomyia longipalpis (Lutz & Neiva, 1912) species complex (Diptera: Psychodidae: Phlebotominae), on which many of the activities of the visceral leishmaniasis surveillance program are based. However, there are areas where canine, and/or human cases have been occurring without the presence of this species complex as in the western part of the Greater Sao Paulo Metropolitan region, where Embu das Artes municipality is situated. In this area, Pintomyia fischeri (Pinto, 1926) has been implicated as potential vector of Le. infantum but so far its natural infection with this parasite has not yet been ascertained. Therefore, the present study sought to investigate the natural infection in sand flies of a CVL focus in Embu das Artes. The sand fly collections were undertaken with Shannon and CDC traps, monthly, between 1800 and 2100 hours from November 2018 to October 2019, inclusive. A total of 951 sand flies (457 males and 494 females), belonging to 10 species, were captured. Pintomyia fischeri was the predominant species (89.5%); of which 426 females were dissected and one of them (0.23%) was found to be harboring flagellates in its midgut. A sample of these flagellates was isolated in culture and characterized by a 234 base pair fragment of Leishmania heat-shock protein 70 gene (hsp70) and restriction fragment length polymorphism with Hae III restriction enzyme as Le. infantum. This finding reinforces previous evidence of Pi. fischeri as a vector of Le. infantum in foci of visceral leishmaniasis and highlights the importance of vector surveillance in areas where this species occurs.
- Chromosomal segments may explain the antibody response cooperation for canine leishmaniasis pathogenesis(2020) BATISTA, Luis F. S.; TORRECILHA, Rafaela B. P.; SILVA, Rafaela B.; UTSUNOMIYA, Yuri T.; SILVA, Thais B. F.; TOMOKANE, Thaise Y.; PACHECO, Acacio D.; BOSCO, Anelise M.; PAULAN, Silvana C.; ROSSI, Claudio N.; COSTA, Gustavo N. O.; MARCONDES, Mary; CIARLINI, Paulo C.; NUNES, Caris M.; MATTA, Vania L. R.; LAURENTI, Marcia D.Visceral leishmaniasis (VL) is marked by hyperactivation of a humoral response secreting high quantity of immunoglobulins (Igs) that are inaccessible to intracellular parasites. Here we investigated the contributions of the antibody response to the canine leishmaniasis pathogenesis. Using correlation and genome-wide association analysis, we investigated the relationship of anti-Leishmania infantum immunoglobulin classes levels with parasite burden, clinical response, renal/hepatic biochemical, and oxidative stress markers in dogs from endemic areas of VL. Immunoglobulin G (IgG) and IgA were positively correlated with parasite burden on lymph node and blood. Increased IgG, IgA and IgE levels were associated with severe canine leishmaniasis (CanL) whereas IgM was elevated in uninfected exposed dogs. Correlations of IgM, IgG and IgA with creatinine, urea, AST and ALT levels in the serum were suggested an involvement of those Igs with renal and hepatic changes. The correlogram of oxidative radicals and antioxidants revealed a likely relationship of IgM, IgG and IgA with oxidative stress and lipid pemxidation in the blood, suggested as mechanisms mediating tissue damage and CanL worsening. The gene mapping on chromosomal segments associated with the quantitative variation of immunoglobulin classes identified genetic signatures involved with reactive oxygen species generation, phagolysosome maturation and rupture, free iron availability, Thl/Th2 differenciation and, immunoglobulin clearance. The findings demonstrated the roles of the antibody response as resistance or susceptibility markers and mediators of CanL pathogenesis. In addition we pinpointed candidate genes as potential targets for the therapy against the damage caused by exacerbated antibody response and parasitism in VL.
- Antileishmanial activity of meroditerpenoids from the macroalgae Cystoseira baccata(2017) SOUSA, Carolina Bruno de; GANGADHAR, Katkam N.; MORAIS, Thiago R.; CONSERVA, Geanne A. A.; VIZETTO-DUARTE, Catarina; PEREIRA, Hugo; LAURENTI, Marcia D.; CAMPINO, Lenea; LEVY, Debora; UEMI, Miriam; BARREIRA, Luisa; CUSTODIO, Luisa; PASSERO, Luiz Felipe D.; LAGO, Joao Henrique G.; VARELA, JoaoThe development of novel drugs for the treatment of leishmaniases continues to be crucial to overcome the severe impacts of these diseases on human and animal health. Several bioactivities have been described in extracts from macroalgae belonging to the Cystoseira genus. However, none of the studies has reported the chemical compounds responsible for the antileishmanial activity observed upon incubation of the parasite with the aforementioned extracts. Thus, this work aimed to isolate and characterize the molecules present in a hexane extract of Cystoseira baccata that was found to be bioactive against Leishmania infantum in a previous screening effort. A bioactivity-guided fractionation of the C. baccata extract was carried out and the inhibitory potential of the isolated compounds was evaluated via the MIT assay against promastigotes and murine macrophages as well as direct counting against intracellular amastigotes. Moreover, the promastigote ultrastructure, DNA fragmentation and changes in the mitochondrial potential were assessed to unravel their mechanism of action. In this process, two antileishmanial meroditerpenoids, (3R)- and (3S)-tetraprenyltoluquinol (1a/1b) and (3R)- and (3S)-tetraprenyltoluquinone (2a/2b), were isolated. Compounds 1 and 2 inhibited the growth of the L. infantum promastigotes (IC50 = 44.9 +/- 4.3 and 94.4 +/- 10.1 mu M, respectively), inducing cytoplasmic vacuolization and the presence of coiled multilamellar structures in mitochondria as well as an intense disruption of the mitochondrial membrane potential. Compound 1 decreased the intracellular infection index (IC50 = 25.0 +/- 4.1 mu M), while compound 2 eliminated 50% of the intracellular amastigotes at a concentration > 88.0 mu M. This work identified compound 2 as a novel metabolite and compound 1 as a biochemical isolated from Cystoseira algae displaying antileishmanial activity. Compound 1 can thus be an interesting scaffold for the development of novel chemotherapeutic molecules for canine and human visceral leishmaniases studies. This work reinforces the evidence of the marine environment as source of novel molecules.