In vitro study of cellular immune response against synthetic drugs with antileishmanial activities

• Grant number: 13/07275-5
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: July 01, 2013
• End date: October 31, 2016
• Field of knowledge: Biological Sciences - Parasitology - Protozoology of Parasites
• Principal Investigator: André Gustavo Tempone Cardoso
• Grantee: Thaís Alves da Costa Silva
• Host Institution: Instituto Adolfo Lutz (IAL). Coordenadoria de Controle de Doenças (CCD). Secretaria da Saúde (São Paulo - Estado). São Paulo , SP, Brazil

Abstract

Neglected diseases cause more than 534,000 deaths annually and is prevalent mostly in poor/developing countries. Leishmaniasis fit this frame and cause approximately 2.1 million DALYs (disability-adjusted life year), expressed as the number of years lost due to ill health, disability or early death. Among the various clinical forms that the disease presents, this it is being dependent on the parasite species, strain and host immune status. Visceral leishmaniasis (VL) is the most severe form of the disease, if untreated it´s fatal. The limited therapeutic tools available in the market for the VL treatment has several limitations, such as hepato, nephro and cardiotoxic effect. Often, the toxicity may be related to immune response induced by the drug, for example, high TNF-± production generated by the amphotericin B action, which despite their antiparasitic activity may lead to an exacerbated inflammation. In this context immunomodulatory drugs may be the key of treatment outcome. Thus, looking for new therapies, the study of drugs activity that are already on the market for other diseases, drug repositioning, has been promising for neglected diseases. Within this scenario, the objective of this project is to evaluate in vitro, the cellular immune response against synthetic drugs with anti-Leishmania (Leishmania) infantum activities (preliminary data), such as cyclobenzaprine (muscle relaxant), sertraline and amitriptyline (anti- depression). Thus, in addition to studies of anti-Leishmania activity and toxicity in mammalian cells, assays are conducted in macrophages previously infected with L. (L.) infantum and co-cultured with splenic lymphocytes. These cells will be treated with the drugs under study to investigate Th1, Th2 and Th17 interactions in treatment outcome in vitro by flow cytometry. The study of the cellular immune response elicited by anti-Leishmania drugs could contribute to the choice and design of more selective drugs, targeted for an effective control and modulation of Leishmania spp infection.

Scientific publications

(6)

(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)

DA COSTA-SILVA, THAIS ALVES; GRECCO, SIMONE S.; DE SOUSA, FERNANDA S.; LAGO, JOAO HENRIQUE G.; MARTINS, EUDER G. A.; TERRAZAS, CESAR A.; VARIKUTI, SANJAY; OWENS, KATHERINE L.; BEVERLEY, STEPHEN M.; SATOSKAR, ABHAY R.; et al. Immunomodulatory and Antileishmanial Activity of Phenylpropanoid Dimers Isolated from Nectandra leucantha. Journal of Natural Products, v. 78, n. 4, p. 653-657, APR 2015. (13/50318-7, 12/18756-1, 13/07275-5)

GRECCO, SIMONE S.; COSTA-SILVA, THAIS A.; JERZ, GEROLD; DE SOUSA, FERNANDA S.; ALVES CONSERVA, GEANNE A.; MESQUITA, JULIANA T.; GALUPPO, MARIANA K.; TEMPONE, ANDRE G.; NEVES, BRUNO J.; ANDRADE, CAROLINA H.; et al. Antitrypanosomal activity and evaluation of the mechanism of action of dehydrodieugenol isolated from Nectandra leucantha (Lauraceae) and its methylated derivative against Trypanosoma cruzi. Phytomedicine, v. 24, p. 62-67, JAN 15 2017. (15/11936-2, 13/07275-5)

DA COSTA-SILVA, THAIS ALVES; GALISTEO, JR., ANDRES JIMENEZ; LAULETTA LINDOSO, JOSE ANGELO; BARBOSA, LEANDRO R. S.; TEMPONE, ANDRE GUSTAVO. Nanoliposomal Buparvaquone Immunomodulates Leishmania infantum-Infected Macrophages and Is Highly Effective in a Murine Model. Antimicrobial Agents and Chemotherapy, v. 61, n. 4, APR 2017. (15/15822-1, 15/23403-9, 13/07275-5, 13/50228-8)

ROMANELLI, MAIARA MARIA; DA COSTA-SILVA, THAIS ALVES; CUNHA-JUNIOR, EDEZIO; DIAS FERREIRA, DAIANE; GUERRA, JULIANA M.; GALISTEO, JR., ANDRES JIMENEZ; PINTO, ERIKA GRACIELLE; BARBOSA, LEANDRO R. S.; TORRES-SANTOS, EDUARDO CAIO; TEMPONE, ANDRE GUSTAVO. Sertraline Delivered in Phosphatidylserine Liposomes Is Effective in an Experimental Model of Visceral Leishmaniasis. FRONTIERS IN CELLULAR AND INFECTION MICROBIOLOGY, v. 9, OCT 29 2019. (18/10279-6, 15/15822-1, 13/07275-5, 15/23403-9)

MARTINS, LIGIA F.; MESQUITA, JULIANA T.; PINTO, ERIKA G.; COSTA-SILVA, THAIS A.; BORBOREMA, SAMANTA E. T.; GALISTEO JUNIOR, ANDRES J.; NEVES, BRUNO J.; ANDRADE, CAROLINA H.; AL SHUHAIB, ZAINAB; BENNETT, ELLIOT L.; et al. Analogues of Marine Guanidine Alkaloids Are in Vitro Effective against Trypanosoma cruzi and Selectively Eliminate Leishmania (L.) infantum Intracellular Amastigotes. Journal of Natural Products, v. 79, n. 9, p. 2202-2210, SEP 2016. (12/18756-1, 11/23703-1, 13/07275-5, 13/50228-8)

TEMPONE, ANDRE GUSTAVO; FERREIRA, DAIANE DIAS; LIMA, MARTA LOPES; COSTA SILVA, THAIS ALVES; BORBOREMA, SAMANTA E. T.; REIMAO, JULIANA QUERO; GALUPPO, MARIANA K.; GUERRA, JULIANA MARIOTTI; RUSSELL, ANGELIE J.; WYNNE, GRAHAM M.; et al. Efficacy of a series of alpha-pyrone derivatives against Leishmania (L.) infantum and Trypanosoma cruzi. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, v. 139, p. 947-960, OCT 20 2017. (15/50075-2, 15/23403-9, 13/07275-5)