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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- In situ expression of Th17 immunologic mediators in American cutaneous leishmaniasis caused by Leishmania (V.) braziliensis and Leishmania (L.) amazonensis in the Brazilian Amazon(2023) RODRIGUES, G. F.; ALCâNTARA, L. S.; BARROS, J. P. B.; LIMA, A. C. S. de; CAMPOS, M. B.; MORAES, C.; FERREIRA, A. F.; MATTA, V. L. R.; LAURENTI, M. D.; CORBETT, C. E. P.; SILVEIRA, F. T.; GOMES, C. M. C.American cutaneous leishmaniasis (ACL) presents a wide spectrum of clinical and immunopathological manifestations. In Brazil, Leishmania (L.) amazonensis[La] and Leishmania(V.)braziliensis[Lb] show the highest pathogenic potential for humans causing different clinical forms: localized cutaneous leishmaniasis (LCL : Lb/La), anergic diffuse cutaneous leishmaniasis (ADCL : La) and mucocutaneous leishmaniasis (MCL : Lb). ADCL and MCL are the most severe forms and infection leads to a cellular immune response at the hyposensitivity and hypersensitivity poles. Th17-cells are involved in the ACL pathogenesis, are derived from naïve TCD4+ cells regulated by RORγt, differentiate in presence of IL-6, TGF-β, IL- 1β, IL-23 and express IL-17. Aim of this study was to characterize the cellular immune response mediated by Th17-profile cells through in situ determination of the expression of RORγt, IL-17, IL-6, TGF-β, IL-1β, and IL-23 in the ACL clinical-immunopathological spectrum caused by L.(L.)amazonensis and L.(V.)braziliensis. Biopsies of skin and mucosal lesions from forty patients including ADCL(n=8), LCL[La](n=17), LCL[Lb](n=9) and MCL(n=6), were examined by immunohistochemistry. The immunostained cells density (cells/mm2) was determined in image analysis system using AxionVision 4.8 software (Zeiss). As the disease evolution time (DET) was different among ACL patients, the effect of DET on the expression of immunological markers was evaluated in different clinical forms and histopathological changes, using ANCOVA. Our results showed significantly increased expression of RORγt, IL-17, IL-6, IL-1β and IL-23 in patients with ACL polar forms (ADCL and MCL); higher TGF-β expression was found in ADCL. DET influenced the expression of RORγt and IL-6 in: clinical forms of ACL and in categories of parasitism. DET also affected the production of RORγt, IL-17, IL-6, TGF-β and IL-1β in types of inflammatory infiltrate, evidencing that DET had effect on the expression of Th17 profile cytokines in ACL. Together, the expression of immunological mediators of Th17 profile in the ACL spectrum, as well as the DET effect, demonstrate the participation of this cell lineage in the immunopathogenesis of ACL, mainly in the polar and more severe forms of ACL spectrum. The dubious role played by Th17-cells may favors immune response suppression and parasitic persistence in ADCL, while in MCL it contributes to an exacerbated immune response and parasite scarcity.
- 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.
- Comparative Genomic Analyses of New and Old World Viscerotropic Leishmanine Parasites: Further Insights into the Origins of Visceral Leishmaniasis Agents(2023) SILVEIRA, Fernando Tobias; SOUSA, Edivaldo Costa; SILVESTRE, Rodrigo Vellasco Duarte; SANTOS, Thiago Vasconcelos dos; SOSA-OCHOA, Wilfredo; VALERIANO, Concepcion Zuniga; RAMOS, Patricia Karla Santos; CASSEB, Samir Mansour Moraes; LIMA, Luciana Vieira do Rego; CAMPOS, Marliane Batista; MATTA, Vania Lucia da; GOMES, Claudia Maria; FLORES, Gabriela V. Araujo; PACHECO, Carmen M. Sandoval M.; CORBETT, Carlos Eduardo; LAURENTI, Marcia DalastraVisceral leishmaniasis (VL), also known as kala-azar, is an anthropozoonotic disease affecting human populations on five continents. Aetiologic agents belong to the Leishmania (L.) donovani complex. Until the 1990s, three leishmanine parasites comprised this complex: L. (L.) donovani Laveran & Mesnil 1903, L. (L.) infantum Nicolle 1908, and L. (L.) chagasi Lainson & Shaw 1987 (=L. chagasi Cunha & Chagas 1937). The VL causal agent in the New World (NW) was previously identified as L. (L.) chagasi. After the development of molecular characterization, however, comparisons between L. (L.) chagasi and L. (L.) infantum showed high similarity, and L. (L.) chagasi was then regarded as synonymous with L. (L.) infantum. It was, therefore, suggested that L. (L.) chagasi was not native to the NW but had been introduced from the Old World by Iberian colonizers. However, in light of ecological evidence from the NW parasite's enzootic cycle involving a wild phlebotomine vector (Lutzomyia longipalpis) and a wild mammal reservoir (the fox, Cerdocyon thous), we have recently analyzed by molecular clock comparisons of the DNA polymerase alpha subunit gene the whole-genome sequence of L. (L.) infantum chagasi of the most prevalent clinical form, atypical dermal leishmaniasis (ADL), from Honduras (Central America) with that of the same parasite from Brazil (South America), as well as those of L. (L.) donovani (India) and L. (L.) infantum (Europe), which revealed that the Honduran parasite is older ancestry (382,800 ya) than the parasite from Brazil (143,300 ya), L. (L.) donovani (33,776 ya), or L. (L.) infantum (13,000 ya). In the present work, we have now amplified the genomic comparisons among these leishmanine parasites, exploring mainly the variations in the genome for each chromosome, and the number of genomic SNPs for each chromosome. Although the results of this new analysis have confirmed a high genomic similarity (similar to 99%) among these parasites [except L. (L.) donovani], the Honduran parasite revealed a single structural variation on chromosome 17, and the highest frequency of genomic SNPs (more than twice the number seen in the Brazilian one), which together to its extraordinary ancestry (382,800 ya) represent strong evidence that L. (L.) chagasi/L. (L.) infantum chagasi is, in fact, native to the NW, and therefore with valid taxonomic status. Furthermore, the Honduran parasite, the most ancestral viscerotropic leishmanine parasite, showed genomic and clinical taxonomic characteristics compatible with a new Leishmania species causing ADL in Central America.
- Role of antigen-presenting cells in non-ulcerated skin lesions caused by Leishmania (Leishmania) infantum chagasi(2023) PACHECO, Carmen M. Sandoval M.; FLORES, Gabriela V. Araujo V.; FERREIRA, Aurea F. F.; MATTA, Vania L. R. da; GOMES, Claudia M. de Castro M.; SOSA-OCHOA, Wilfredo H. H.; ZUNIGA, Concepcion; SILVEIRA, Fernando T. T.; CORBETT, Carlos E. P.; LAURENTI, Marcia D.In Central America, infection by Leishmania (Leishmania) infantum chagasi causes visceral leishmaniasis and non-ulcerated cutaneous leishmaniasis (NUCL). This work aimed to evaluate the participation of subpopulations of antigen-presenting cells in skin lesions of patients affected by NUCL through double-staining immunohistochemistry using cellular and intracellular markers. Twenty-three skin biopsies from patients affected by NUCL were used. Histological sections stained by HE were used for histopathological study. Immunohistochemical studies were performed using primary antibodies against Langerhans cells, dermal dendritic cells, T lymphocytes, and the cytokines IL-12, IFN-gamma, TNF-alpha, iNOS, and IL-10. The histopathological lesions were characterized by an inflammatory infiltrate, predominantly lymphohistiocytic, of variable intensity, with a diffuse arrangement associated with epithelioid granulomas and discreet parasitism. Double-staining immunohistochemistry showed higher participation of dendritic cells producing the proinflammatory cytokine IL-12 in relation to the other evaluated cytokines. Activation of the cellular immune response was marked by a higher density of CD8 Tc1-lymphocytes followed by CD4 Th1-lymphocytes producing mainly IFN-gamma. The data obtained in the present study suggest that antigen-presenting cells play an important role in the in situ immune response through the production of proinflammatory cytokines, directing the cellular immune response preferentially to the Th1 and Tc1 types in NUCL caused by L. (L.) infantum chagasi.
- Leishmania (L.) infantum chagasi isolated from skin lesions of patients affected by non-ulcerated cutaneous leishmaniasis lead to visceral lesion in hamsters(2023) FLORES, Gabriela V. Araujo; PACHECO, Carmen M. Sandoval; FERREIRA, Aurea F.; TOMOKANE, Thaise Yumie; NUNES, Juliana B.; COLOMBO, Fabio A.; SOSA-OCHOA, Wilfredo H.; ZUNIGA, Concepcion; SILVEIRA, Fernando T.; CORBETT, Carlos E. P.; LAURENTI, Marcia D.In Central America, Leishmania (L.) infantum chagasi infection causes visceral leishmaniasis (VL) and non -ulcerated cutaneous leishmaniasis (NUCL). The aim of the present study was to evaluate the course of an experimental infection in hamsters caused by L. (L.) infantum chagasi isolated from patients affected by NUCL compared with a strain isolated from a patient with VL. Stationary phase parasites in culture were inoculated through subcutaneous and intraperitoneal routes in hamsters. Following the post-infection times, a histopath-ological study, parasite load and cytokine determination in skin from the cutaneous inoculation site and viscera were performed. Animals subcutaneously infected with the different strains did not develop macroscopic lesions at the inoculation site, and the histopathological changes in the dermis were very slight. Regarding the histo-pathological study of the viscera, we observed the portal mononuclear inflammatory infiltrate, the presence of nodules in the hepatic parenchyma and the proliferation of macrophages in the spleen, which increased over the infection course. Overall, the parasite load in the liver and spleen and in the total IgG titres in the sera of infected hamster showed an increase with the time of infection, regardless of the route of inoculation. Regarding cellular immunity, we did not observe an increase or decrease in pro-and anti-inflammatory cytokines compared to the healthy control, except for IL-10, which was evident in the infected animals. The data showed that strains iso-lated from NUCL cause visceral lesions in the hamsters regardless of the route of inoculation, and they were similar to parasites isolated from VL humans.