UK:Brazil Joint Centre Partnership in Leishmaniasis (JCPiL). work plan 1 molecular pathology of leishmaniasis: towards host-directed therapy in leishmaniases

• Grant number: 19/25393-1
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: January 01, 2020
• End date: March 31, 2024
• Field of knowledge: Biological Sciences - Immunology - Applied Immunology
• Agreement: MRC, UKRI ; Newton Fund, with FAPESP as a partner institution in Brazil
• Principal Investigator: Hiro Goto
• Grantee: Luiza de Campos Reis
• Host Institution: Faculdade de Medicina (FM). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated research grant: 18/14398-0 - UK:Brazil Joint Centre Partnership in Leishmaniasis (JCPiL), AP.TEM

Abstract

Understanding the pathophysiology of the various clinical forms of leishmaniasis found in Brazil requires a deep phenotyping of patient responses that operate at the site of infection. Aiming the phenotyping, there is an ongoing molecular pathology project (with MRC funding) including data sharing through a digital pathology platform. In this project, new multiplex immunohistochemistry and RNA-FISH assays, Nanostring whole tissue transcriptomics and Nanostring Digital Spatial Profiling (DSP) were developed with identification of some new targets for therapy at the University of York, initially in cases of CL caused by L. donovani in Sri Lanka. Besides standard procedures and clinical forms to enable quantification and reliable comparison of parameters of lesions were developed. Building on these achievements, in this WP1, we aim to procceed the deep phenotyping in patients across the spectrum of leishmaniasis found in Brazil, comparing cutaneous and mucosal lesions of patients infected with L. braziliensis and L. guyanensis as well as in bone marrow aspirates of patients with VL infected with L. infantum. Cognisant of that host-directed therapies, in contrast to current parasite therapy, will play a role in the treatment of patients with leishmaniasis (alone or as adjunct to conventional chemotherapy) and the increasing evidence that at least for some forms of leishmaniasis we observe similarities in the immunological profile of that found in the tumor microenvironment, we will focus on defining regulatory pathways or checkpoints pathways (eg IGF-I, IDO-1, IL-10, CTLA-4, PD-L1 / PD -1). In addition, with the advent of new approaches using Nanostring Digital Spatial Profiling RNA phenotyping will provide the development of new tools to analyse the expression of genes in a spatially resolved form in biopsy samples, providing an unprecedent insight into the host-parasite interaction. We aim to reach relevant, spatially resolved data on the immune mechanisms that operate in the various forms of leishmaniasis and on the response of the parasite to these, and to identify the host pathways that may be the focus for the development of new therapies for use alone or as an adjunct to conventional chemotherapy. With the development of avatar mice using control and patient cells and with infection with Leishmania strains derived from patients, assayss aiming treatment are planned with the use of inhibitors or immunotherapeutics as antigomirs. (AU)

Scientific publications

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(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

REIS, LUIZA C.; RAMOS-SANCHEZ, EDUARDO MILTON; ARAUJO, FERNANDA N.; LEAL, ARIANE F.; OZAKI, CHRISTIANE Y.; SEVILLANO, ORLANDO R.; USCATA, BERNARDINA A.; GOTO, HIRO. Pleiotropic Effect of Hormone Insulin-Like Growth Factor-I in Immune Response and Pathogenesis in Leishmaniases. JOURNAL OF IMMUNOLOGY RESEARCH, v. 2021, MAY 5 2021. (14/08340-8, 19/25393-1, 18/14398-0, 17/02959-4)

SOUZA, MARINA DE ASSIS; RAMOS-SANCHEZ, EDUARDO MILTON; MUXEL, SANDRA MARCIA; LAGOS, DIMITRIS; REIS, LUIZA CAMPOS; PEREIRA, VALERIA REGO ALVES; BRITO, MARIA EDILEUZA FELINTO; ZAMPIERI, RICARDO ANDRADE; KAYE, PAUL MARTIN; FLOETER-WINTER, LUCILE MARIA; et al. miR-548d-3p Alters Parasite Growth and Inflammation in Leishmania (Viannia) braziliensis Infection. FRONTIERS IN CELLULAR AND INFECTION MICROBIOLOGY, v. 11, JUN 10 2021. (18/23512-0, 14/14756-2, 19/25393-1, 18/14398-0, 18/24693-9)

RAMOS-SANCHEZ, EDUARDO MILTON; REIS, LUIZA CAMPOS; SOUZA, MARINA DE ASSIS; MUXEL, SANDRA MARCIA; SANTOS, KAMILA REIS; LAGOS, DIMITRIS; PEREIRA, VALERIA REGO ALVES; DE BRITO, MARIA EDILEUZA FELINTO; KAYE, PAUL MARTIN; FLOETER-WINTER, LUCILE MARIA; et al. miR-548d-3p Is Up-Regulated in Human Visceral Leishmaniasis and Suppresses Parasite Growth in Macrophages. FRONTIERS IN CELLULAR AND INFECTION MICROBIOLOGY, v. 12, p. 14-pg., 2022-02-10. (19/25393-1, 14/14756-2, 18/14398-0, 18/24693-9, 18/23512-0)

LUIZA CAMPOS REIS; JOSÉ ANGELO LAULETTA LINDOSO; BEATRIZ JULIETA CELESTE; LUCIA MARIA ALMEIDA BRAZ; EDUARDO MILTON RAMOS-SANCHEZ; EDITE HATSUMI YAMASHIRO-KANASHIRO; HIRO GOTO; LUIZA KEIKO MATSUKA OYAFUSO. Unusual manifestation of genital cutaneous leishmaniasis in an immunocompetent patient from São Paulo, Brazil: A case report. Revista da Sociedade Brasileira de Medicina Tropical, v. 54, 2021-03-22. (19/25393-1)