By David Baker
Research of the Malaria Centre in the areas of Malaria Parasite Biology and Drug Discovery involves a number of disciplines ranging from population genetics and genomics, to cell biology and immunology, through to design of small molecule inhibitors.
The ability to obtain whole genome sequences of malaria parasite isolates in large numbers represents a breakthrough that has allowed us to address key questions about malaria which were just not possible, until recently. Large-scale genome sequencing of malaria parasites of all species ongoing at LSHTM is illuminating all aspects of parasite biology, including parasite genome and population structure and dynamics, surveillance of drug resistance and species-specific mechanisms of immune evasion.
Most of the over 400,000 annual deaths from malaria are caused by infection with P. falciparum, but we now know that severe disease and death can also be caused by P. knowlesi. This is largely a parasite of primates, but since 2004 evidence has accumulated that humans living in proximity to monkeys in Malaysia, Indonesia and neighbouring countries can become infected with P. knowlesi. Development of a highly efficient reverse genetics technology for P. knowlesi in vitro at LSHTM has transformed our ability to study this important pathogen and gives hope that new control measures will follow.
The increasing incidence of both prolonged treatment time and treatment failure with artemisinin-based drug combinations in parts of Southeast Asia over the last 12 years is linked to the presence of mutant forms of the Kelch 13 protein. So far, these mutants have not been detected in Africa, where alternative mechanisms may be in play. Exciting findings at LSHTM, deploying new gene editing techniques for P. falciparum, have identified the AP-2μ adaptor protein as a strong candidate resistance marker linked to artemisinin susceptibility.
These newly recognised threats, together with previous experience, indicate that the emergence of drug resistant parasites is possible whenever a new drug is rolled out, and emphasise the need for ongoing drug development. Novel compounds that can kill malaria parasites need to be identified, either by screening large chemical libraries, or through a rational approach in which inhibitors are designed to block the activity of functions essential for parasite development.
With this rational design objective, conditional reverse genetics is being deployed at LSHTM to target P. falciparum merozoite egress and invasion at the molecular level, with a view to developing new antimalarial drugs. In our new malaria labs, we are attempting to block a key signalling molecule (the cGMP-dependent protein kinase, PKG) with small molecule inhibitors, some of which are identified by high throughput screening in partnership with the Tres Cantos Open lab Foundation.
Serology is a powerful approach when coupled with recent advances in recombinant protein technology, and LSHTM researchers are deploying both to study malaria epidemiology and the human immune response to infection. Recombinant protein microarrays covering an ever-increasing repertoire of parasite proteins is generating new epidemiological understanding in a number of settings worldwide, for multiple parasite species, by interrogating antibody responses in a large sample of malaria exposed people to more than a hundred recombinant Plasmodium proteins. This approach has also led to development of serological tools for measurement of P. vivax and P. knowlesi exposure in the field