Integrated Network of Quiescence & Clearance mechanisms involved in Malaria Artemisinin Resistance – INMAR

In 15 years, the treatment of malaria patients by artemisinin derivatives (ARTs) associated with conventional antimalarial (Artemisinin-based Combination Therapy, ACT), lowered half of mortality in the endemic countries. However this historical progress is threatened by the recent decline in the effectiveness of ARTs characterized by delayed parasite clearance and high recrudescence rate in patients. The emergence of parasites resistant to both ARTs and antimalarial drug partners and the lack of short-term alternatives worsen this major threat. Resistant parasites have developed a quiescence mechanism, allowing them to escape most of the available antimalarial drugs, posing a new therapeutic problem which cannot be solved by conventional approaches. Despite the recent identification of a molecular marker, resistance to ARTs remains poorly understood that obstructs effective monitoring of its expansion and the identification of therapeutic solutions.
We wish to simultaneously explore the biochemical, metabolic and phenotypic grey areas of resistance to ARTs.

The survival of exposed Plasmodium falciparum to ARTs is based on the increased ability of resistant strains to enter in a quiescence state during the treatment, conferred by mutations in the Pfk13 gene. A fraction of parasites so supports oxidative damages related to malaria treatment, changes its cell cycle, and resumes growth once the drug eliminated.

This complex resistance mechanism would involve the UPR (Unfolded Protein Response) and the PI3K / PI3P / PfAKT pathways, the PfPK4 / eIF2alpha cascade and likely one or more transcription factor (s) yet unidentified. Furthermore, the survival of quiescent parasites is ensured by maintaining the activity of the respiratory chain in the mitochondrion and activation of the fatty acid metabolism by the FASII pathway in the apicoplast.

Moreover, clinical resistance of P. falciparum to ARTs is defined by slow parasite clearance in patients. Correlations are made between this delayed clearance, parasite recrudescence after treatment, PfK13 gene polymorphism and the increased risk of relapse. However, the relationship between the slow clearance and the parasite population concerned is not yet well-characterized.

The detailed study of these mechanisms with a new approach integrating all aspects of this resistance (induction of quiescence, specific metabolism and parasite clearance) offers, in addition to the overall understanding of the phenomenon, the possibility to identify relevant and original therapeutic targets.

This study will be done through the use of key tools such as: i) the P. falciparum strains F32-ART / F32-TEM, starting point of several major discoveries on ARTs resistance, ii) 'microsphiltration' and 'microfluidics' devices mimicking retention, red blood cells sorting and the phenomenon of 'pitting' in the spleen after treatment by ARTs, iii) new dosage methods of fatty acids and phosphoinositides of the parasite in a quiescence state or not.

This project brings a new and fully integrated vision of the different biochemical, cellular, molecular and pathophysiological parameters involved in the quiescence phenomenon associated with the parasite resistance to ARTs-based treatments.

The 3 partners have strong and recognized international skills in parasitology, molecular and cell biology, biochemistry, lipidomics, hematology and clinical.
This original and innovative work will lead to the identification of new therapeutic targets allowing the discovery of new antimalarial drugs or through the control of the quiescence to safeguard the effectiveness of ACTs currently used.