Using Apicoplast-Deficient Parasites to Identify Anti-Malaria Compounds That Specifically Target This Organelle

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Investigator: Joseph L. Derisi, PhD
Sponsor: Bill & Melinda Gates Foundation

Location(s): United States

Description

Joseph DeRisi of the University of California, San Francisco in the U.S. will generate a strain of apicoplast-free P. falciparum parasites to identify anti-malarial compounds from the Malaria Box that specifically target this organelle, which is essential for malaria parasite survival.

Researchers at UCSF and Stanford have developed a straightforward chemical method for generating live, attenuated apicoplast-deficient blood-stage malaria parasites. The attenuated strains can be used as malaria vaccines to induce immune responses after administration of the live, attenuated Plasmodium parasite or erythrocytes infected with the live, attenuated Plasmodium parasite. The major advantage of this approach is that the attenuation is achieved chemically and does not require genetic manipulation, thus allowing development of immunogenic vaccines against clinically relevant, circulating field strains of Plasmodium. Furthermore, this approach leads to the irreversible loss of the apicoplast, thereby eliminating the risk of genetic reversion or resistance. The resulting attenuated malaria parasite lacks critical metabolites synthesized by the apicoplast and is dependent on exogenous factors. When these factors are missing, the parasite cannot complete their life cycle and die. Loss of the apicoplast genome is easily validated by quantitative PCR following chemical treatment and rescue. Apicoplast-deficient strains may be proliferated indefinitely and grown in large quantities in the presence of required factors in vitro. This chemical method can also be applied to Plasmodium parasites that infect other mammalian species for testing of vaccine candidates.

The attenuated blood-stage malaria parasites can also be used in pathway-specific drug discovery screens for the development of anti-malarials. Drug candidates can be specifically identified or validated to target pathways involved in the function, replication and maintenance of the apicoplast. 

Current and future work is focused on validating attenuated vaccine candidates using in vivo models for rodent and human malaria.