New mechanisms of drug resistance in malaria parasites: a molecular, epidemiological and social study — the Research Portal of the Institute of Tropical Medicine
Mira Martinez, Sofia, (PhD Student)
As already described, drug resistance of malaria parasites can be defined as a complex problem and it should be dealt with from different perspectives. Thus, I intend to carry out my research in a multidisciplinary way, involving different disciplines, such as epidemiology, molecular research and anthropology. But, at the same time, it will be approached in a transdisciplinary way, involving different sectors of society: industry, non-profit organizations (NPO), patients, physicians and other health workers, citizens of endemic areas and researchers from different fields.
The main objective of our project is to fill the gap between our findings in the lab about a recently discovered drug resistance mechanism and the field. For that we will study the relevance of this new mechanism in natural infections, investigate which drugs are susceptible to development of parasite resistance by this mechanism, and study the importance of the role of citizens, such as patients and health workers, in avoiding development of drug resistance.
Objective 1. To determine the expression dynamics of clag3 genes in P. falciparum infections. As a starting point to assess the relevance of the novel mechanism of drug resistance controlled at the epigenetic level, we will characterize in natural infections the transcriptional dynamics of the genes responsible for this mechanism: clag3 genes. Expression of these genes in natural infections has never been studied before. For this purpose we will work with blood samples from travelers returning from malaria endemic countries that present P. falciparum infection.
Objective 2. Preliminary exploration of clag3 genes association with particular malaria phenotypes and patient characteristics. We will investigate associations between clag3 expression patterns and specific malaria outcomes, disease and patient characteristics. For this purpose, we will initially work with the samples used in our first objective. In a second phase, we will include in our research additional samples from endemic areas, collected as part of ongoing extensive epidemiological studies on drug resistance. Through the study of clag3 expression in samples from patients that have presented treatment failure, we would assess the relevance of this mechanism in clinical cases of drug resistance.
Objective 3. To identify the specific polymorphic regions of clag3 genes that determine transport specificity. The results of our previous studies imply that CLAG3.1 or CLAG3.2 confer different transport efficiency to PSAC. clag3.1 and clag3.2 share 95% of nucleotide sequence. Thus, we hypothesize that the polymorphic regions of the genes confer the transport specificity to each clag3 gene. From the analysis of clag3 sequences in samples used for the previous objectives or, if time permits, using transfection experiments in cultured parasites, I intend to identify the specific polymorphic regions of clag3 that determine transport specificity.
Objective 4. To identify drugs susceptible to failure by parasite resistance through epigenetic switches in clag3 genes. Knowing that blasticidin transport depends on clag3 gene expression and that PSAC is a general transporter for essentially all compounds that enter infected RBCs via NPPs46, it is reasonable to expect the same mechanism in other drugs with similar properties. We intend to screen antimalarial drugs and drug leads with parasite lines with known clag3 expression pattern, to assess their susceptibility to this novel resistance mechanism.
Objective 5. To analyze the role of communication between health workers and patients in the development of drug resistance. As already described, citizens play a key role in preventing the development of drug resistance. I will focus my research on communication between health workers and patients as an important tool to achieve a good treatment adherence, essential for avoiding development of drug resistance. I plan to assess the information given to symptomatic malaria patients in routine health encounters regarding the importance of treatment adherence and how this information is understood and interpreted by the patients themselves.