Lead Institution: University of Washington
ICEMR website: http://rathodlab.org/icemr/
The MESA ICEMR studies how genetic plasticity, or adaptability of malaria parasites, effects parasite drug resistance, virulence, host immunity, and successful transmission in diverse environments.
Previously unreported geographic variations found in parasite genomes, disease severity markers, drug sensitivity and mosquito vectors
The MESA-ICEMR has study sites in southwest, central and northeast India. These sites are located in urban and peri-urban areas as well as deep rural pockets and forest communities. The diverse set of locations facilitates detailed analyses of parasite isolates and vectors collected across vastly different topographic, demographic and geographic contexts across the country.
Phenotypic and genotypic analyses of Indian isolates from the MESA-ICEMR sites point to geographic variations in parasite genomes and drug sensitivity. Genomic analysis and stratification reveal that the Indian isolates collected from the study sites segregate in a cluster different from the isolates of Africa, South America, Southeast Asia, and even adjoining regions of Bangladesh and Myanmar. Interestingly, a meta-analysis reveals that despite var transcript profiles showing extensive within-host and between-site differences, the var profile signatures associated with severe malaria in African children are highly predictive of severe malaria in Indian adults and vice-versa.
This region-specific trend is also observed in artemisinin sensitivity of clinical isolates collected from the southwestern and northeastern sites. Phenotype-based assays show that a higher proportion of northeastern parasites have reduced artemisinin sensitivity compared to southwestern isolates. This is significant considering the proximity of northeast India to southeast Asia where artemisinin resistance is entrenched. Artemisinin resistance in India is detectable but is not as high as in Southeast Asia. Such drug sensitivity data are essential for monitoring the efficacy and effectiveness of artemisinin-based combination therapy (ACT) in these regions.
Researchers are also engaged in transmission studies examining mosquitoes in the field and in the lab to observe host-parasite-vector interactions that contribute to malaria transmission and possible dissemination of drug resistance traits. In the rainy season, Anopheles stephensi is the dominant vector in most of India. However, during the dry season, transmission and parasite reservoirs appear to be sustained in new ways: a previously underappreciated marsh mosquito, Anopheles subpictus, facilitates dry season malaria transmission cycle of both P. vivax and P. falciparum in Goa.
Novel mechanisms of drug resistance and pathogenesis in Indian P. falciparum and P. vivax
The ability to adapt patient samples in laboratory culture conditions facilitates studies associating clinical phenotype with laboratory-characterized genotype. Ongoing work is pursuing complex mechanisms of antifolate resistance.
Additional studies are leading to a deeper understanding of pathogenesis and disease severity. Clinical presentation, genotypic analysis and machine learning reveal that DC6- and DC8-encoding var transcripts in combination with high parasite biomass are the strongest indicators of patient hospitalization and disease severity at the Goa study site. The study findings demonstrate an interplay between parasite biomass and specific Plasmodium falciparum var gene/PfEMP1 (P. falciparum erythrocyte membrane protein 1) adhesion types in the development of adult severe malaria and indicate that low impairment of endothelial protein C receptor (EPCR) function may contribute to parasite virulence.
Ongoing work also points to new molecular mechanisms of immune protection and of multi-organ involvement in Indian hosts, many of which have not been described previously.
The regional impact of the ICEMR includes:
- Identifying early markers of severe disease from malaria infections
- Mapping the movement of parasites, based on genomic characterization of isolates
- Improving predictive tools for antimalarial effectiveness in South Asia
- Improving mosquito infection studies to better define transmission
- Training and deploying the next generation of malaria scientists across India
View Associated sites for the South Asia ICEMR in a larger map
Map description: Associated sites in India (Panaji, Goa; Mumbai, Maharashtra; Agartala, Tripura; Dibrugarh, Assam; Rourkela, Orissa; New Delhi)
Principal Investigator: Pradipsinh Rathod, Ph.D.
- Pradipsinh K. Rathod, University of Washington (Epidemiology of Drug Resistance)
- Neena Valecha, National Institute of Malaria Research (Transmission: Vector-Parasite Interactions)
- Anupkumar Anvikar, National Institute of Malaria Research (Pathogenesis and Infection)
- ACIST Consulting (Thane, Maharashtra)
- Goa Medical College (Bambolim, Goa)
- Indian Institute of Technology Bombay (Mumbai, Maharashtra)
- King Edward Memorial Hospital (Mumbai, Maharashtra)
- Krishi Gram Vikas Kendra (Ranchi, Jharkhand)
- National Institute of Malaria Research Goa Field Unit (Panaji, Goa)
- National Institute of Malaria Research Headquarters (New Delhi)
- Regional Medical Research Centre, Northeast Region (Dibrugarh, Assam)
- Fred Hutchinson Cancer Research Center (Seattle, WA)
- Harvard T. H. Chan School of Public Health (Boston, MA)
- Seattle Children’s Research Institute (Seattle, WA)
- Stanford University (Stanford, CA)