Beyond pvmdr1 and pvcrt: search for relevant diversity in new Plasmodium vivax candidate genes associated with antimalarial drug resistance

• Grant number: 20/00433-8
• Support Opportunities: Regular Research Grants
• Start date: March 01, 2021
• End date: December 31, 2022
• Field of knowledge: Biological Sciences - Parasitology - Protozoology of Parasites
• Agreement: Swedish Research Council (VR)
• Mobility Program: SPRINT - Projetos de pesquisa - Mobilidade
• Principal Investigator: Marcelo Urbano Ferreira
• Grantee: Marcelo Urbano Ferreira
• Principal researcher abroad: José Pedro Blanco Panadés Gil
• Institution abroad: Karolinska Institutet, Sweden
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated researchers: Priscila Thihara Rodrigues
• Associated research grant: 16/18740-9 - Scientific bases for residual malaria elimination in the Brazilian Amazon, AP.TEM

Abstract

Drug resistance has been for more than a century the hallmark of Plasmodium falciparum. This capacity has driven its expansion worldwide, in particular during the long period of established chloroquine (CQ) resistance. P. vivax is the other species well established to be capable of evasion from antimalarial drug action. P. vivax drug resistance has been initially described against anti-folate antimalarials, through mutations in the pvdhfr and pvdhps genes, mirroring the mechanisms previously unveiled for P. falciparum. CQ resistance is also reported and a rising threat, including in South America. The involved mechanisms show some differences to P. falciparum. In P. vivax, the key gene seems to be pvmdr1, with pvcrt playing here a secondary role. Mixed P. falciparum/P.vivax infections are clinically managed with artemisinin combination therapy (ACT) worldwide. Hence, P. vivax is consequently frequently exposed to a range of ACT drugs beyond CQ and primaquine. Most importantly, proposals for the use of ACT as a mainstay for the management of CQ-R P. vivax infections are gaining momentum, in particular using dihydroartemisinin-piperaquine (DHA-PPQ). Unfortunately, at least P. falciparum seems highly efficient on fast developing resistance against this drug. From the first PPQ mass drug administration application in China in the early 1980s, this capacity has been lately showcased in the swift and spectacular collapse of DHA-PPQ upon large scale nation-wide implementation in Cambodia. The P. falciparum mechanism of piperaquine resistance has been robustly associated in Southeast Asia with increased copy number in the pfPM2 and pfPM3 genes, both coding for functionally overlapping plasmepsins. The question remains if P. vivax will follow a similar pattern. Here we characterize plasmepsine gene amplifications in Brazilian isolates of P. vivax and P. falciparum that have not been previously exposed to PPQ, providing an important clue as for the parasite capacity to develop PPQ resistance upon its local introduction. (AU)

Scientific publications

(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)

FERREIRA, MARCELO U.; DE SOUSA, TAIS NOBREGA; RANGEL, GABRIEL W.; JOHANSEN, IGOR C.; CORDER, RODRIGO M.; LADEIA-ANDRADE, SIMONE; GIL, JOSE PEDRO. Monitoring Plasmodium vivax resistance to antimalarials: Persisting challenges and future directions. INTERNATIONAL JOURNAL FOR PARASITOLOGY-DRUGS AND DRUG RESISTANCE, v. 15, p. 9-24, APR 2021. (20/00433-8)