The manipulation of the human immune response by the liver stages of the malaria parasite.
Final Report Abstract
I have achieved two major scientific breakthroughs during the project period. The first was being involved in showing that the eukaryotic initiation factor-2alpha (eIF2alpha) kinase (IK2) is responsible for the translational and developmental arrest of sporozoites. This arrest is alleviated by eIF2alpha phosphatase upon infection of a host liver cell. It had long been known that messenger RNA accumulates during various developmental stages of the malaria parasite without getting translated until the appropriate time. However, the cause and mechanism had remained elusive. Our results show that IK2 appears to be responsible for the translational arrest of these mRNAs in sporozoites until an eIF2alpha phosphatase facilitates developmental progression upon successful liver infection. My second scientific achievement was the successful high-throughput screen of a large library of 4422 commercially available compounds with previously demonstrated blood stage activity. I established a cell-based assay to detect chemical scaffolds with potent activity against both parasite developmental forms. I showed that a new imidazolopiperazine (IP) scaffold series is overrepresented in hepatic stage hits. Consistently, an orally available optimized IP lead with potent in vivo blood-stage therapeutic activity confers complete causal prophylactic protection in rodent models of malaria. The open source chemical tools resulting from my effort provide potential starting points for future drug discovery programs as well as opportunities for researchers to investigate the biology of parasite liver stages.
Publications
- The Plasmodium eukaryotic initiation factor-2alpha kinase IK2 controls the latency of sporozoites in the mosquito salivary glands.” The Journal of experimental medicine (2010) vol. 207 (7) pp. 1465-74
Zhang M, Fennell C, Ranford-Cartwright L, Sakthivel R, Gueirard P, Meister S, Caspi A, Doerig C, Nussenzweig RS, Tuteja R, Sullivan WJ, Roos DS, Fontoura BM, Ménard R, Winzeler EA, Nussenzweig V
