Lead Institution: New York University
ICEMR website: http://malariacenterindia.org/
Malaria remains a significant public health burden in India. Plasmodium falciparum, P. vivax and P. malariae are common malaria parasite species, transmitted by at least six vectors including Anopheles stephensi, An. fluviatilis, An. culicifacies, An. baimaii and An. minimus. Such complex malaria in India impacts its epidemiology, transmission, and clinical manifestation. The overall goal of the Center for the Study of Complex Malaria (CSCMi) is to help develop the knowledge, tools, and evidence-based strategies needed to support Indian malaria intervention and control programs, and to build malaria research capacity in India, in partnership with local researchers, clinicians, and public health workers at several institutes.
CSCMi research has included projects on the epidemiology, genomics, drug resistance, transmission, and pathogenesis of malaria. For example:
- Magnetic resonance imaging (MRI) to study cerebral malaria (CM) pathogenesis at a tertiary hospital in Rourkela, Odisha. This includes applying advanced machine-learning models of CM disease causation, informed by clinical (neuroimaging, fundus examination, EEG) and laboratory (var gene transcript analysis, coagulation factors, plasma biomarkers) investigations.
- Cross-sectional, longitudinal, and clinic-based epidemiology studies to describe the burden of symptomatic and asymptomatic malaria and use genome sequencing devices to identify P. falciparum drug resistance alleles and P. vivax recurrences.
- Vector studies including adult surveys to discern biting behavior, insecticide resistance assays, and Anopheles population genomics.
- A socio-behavioral study to determine beliefs on what types of interventions reduce malaria and to identify demand and supply side barriers to malaria control measures in the northeastern state of Meghalaya.
- An implementation study to assess the effectiveness of establishing temporary mobile malaria camps in remote inaccessible villages to screen and treat malaria infections in tribal populations. The project, named "Durgama Anchalare Malaria Nirakaran," is being used by the state of Odisha to assist with its malaria elimination drive.
Cerebral malaria: unravelling pathogenic mechanisms to inform new adjunct therapies
Researchers are conducting a multidisciplinary project at the Ispat General Hospital (IGH) in Rourkela, Odisha, to investigate the origin of brain swelling and to characterize brain lesions associated with cerebral malaria (CM) in children and adults. CM is a multi-factorial syndrome with a mortality rate of approximately 15-25 percent even when appropriate treatment and intensive care are provided. The pathogenesis of fatal CM is still not well understood, although several hypotheses have been put forward, including mechanical obstruction of micro vessels by P. falciparum-parasitized red blood cells, hyper-activation of host immune cells leading to the excessive release of potentially harmful pro-inflammatory cytokines, and critical hematologic dysfunctions.
To date, approximately 140 CM patients and more than 50 control patients have been enrolled and had MRI brain scans at and after admission. ICEMR investigators were able to attribute the cause of increased brain volume in CM to a fully reversible focal or diffuse vasogenic edema. Findings indicated for the first time a link between severe falciparum malaria and the occurrence of posterior reversible encephalopathy syndrome (PRES) across both age groups, providing a key piece of the puzzle of fatal CM.
Researchers have also expanded the range of magnetic resonance (MR) investigative techniques to include approaches never before used in malaria-endemic areas, such as time-of-flight MR angiography and MR spectroscopy. These provide a better understanding of whether the sequestration of P. falciparum-parasitized erythrocytes occurs preferentially in specific areas of the brain, and how the cerebral vasculature reacts to flow disruption. In addition, researchers are working on a better characterization of the clinical features associated with CM in Indian patients, using funduscopy to detect and record retinopathies, and micro-EEG to investigate the occurrence and frequency of subclinical seizures.
These clinical approaches are combined with extensive serological and biomarker analyses using screening platforms such as Luminex technology at IGH, as well as in-house bead assays, to evaluate markers associated with disease severity and outcome. Using molecular biology and machine learning, CSCMi researchers are also characterizing P. falciparum virulence factors. The team has also successfully implemented the first minimally invasive autopsy series of malaria patients in India, leading to the collection and ongoing analyses of tissue samples from fatal adult CM cases. This approach will help decipher the pathogenic mechanisms underlying the development of fatal CM, and the associated kidney, liver and lung involvement often seen in adult patients.
CSCMi studies are providing new insight into the pathophysiology of CM, and corroborate hypotheses suggesting that an impaired blood-brain barrier and vascular engorgement are contributors to the increased brain volume seen in CM patients. Ultimately, researchers aim to decipher pathogenic mechanisms underlying the development of CM to inform new adjunct treatments and decrease the fatality rate of this neurological syndrome.
Epidemiology of malaria in India: asymptomatic, submicroscopic, and heterogeneous
Researchers have undertaken cross-sectional, longitudinal, and clinic-based epidemiology studies to describe the burden of malaria at several different field sites in India over time. Initial studies with colleagues at the Indian Council of Medical Research, National Institute for Malaria Research have shown that malaria has 'gone underground,' with a high proportion of asymptomatic and submicroscopic infections. CSCMi researchers piloted reactive case detection (RCD) strategies at two field sites, where household members and neighbors of patients identified with a Plasmodium infection at the clinic were tested for malaria. This strategy had limited success of detecting additional cases of malaria in the neighborhood of the index case identified at the clinic, concluding that RCD in areas of low malaria transmission is labor-intensive and not a useful strategy in those settings. The team undertook census studies at three field sites, finding common use of repellents (mats, coils, vaporizers, or creams) for mosquito control, but with inconsistent association with reduction in malaria cases, indicating that further clinical trial testing of repellents is required to consolidate their role in vector-borne disease control.
In approximately 350 subjects from three field sites, high-throughput analyses of antibody responses to P. vivax and P. falciparum antigens using genome-scale protein microarrays found significant seropositivity, indicating past exposure to malaria. Higher reactivity in asymptomatic versus symptomatic samples was observed for both species, indicating that antibodies are correlated with protection.
Genomics of Indian malaria parasites: whole genomes, population genetics, and drug resistance
ICEMR investigators conducted genomic epidemiology studies of malaria in India and at several global sites and showed that P. vivax exhibits greater genetic diversity than P. falciparum. Expanding this effort, they undertook a large-scale cross-ICEMR population genomics study sequencing hundreds of P. vivax clinical isolates from several endemic countries including India, identifying signatures of global dispersal and drug resistance.
The team also developed a next generation sequencing core in New Delhi and implemented the use of handheld sequencing devices at remote field sites. These were used to develop methods for amplicon deep sequencing of six P. falciparum drug resistance genes from clinical isolates, identifying novel Pfkelch13 mutations and prevailing Pfcrt resistance mutations at two field sites.
The CSCMi is a collaborative research institute comprising Indian, US, UK, and European malaria experts and dedicated staff. Studies occur at several sites in India, forming a regional network of field stations across the country undertaking research, training, capacity building, and transfer of novel technologies.
View Associated sites for the India ICEMR in a larger map.
Map Description: Associated sites for the India ICEMR: Rourkela, Sundargarh, Kedujhar, West Khasi Hills, West Jaintia Hills, South Garo Hills, Jabalpur.
Principal Investigator: Jane M. Carlton, PhD.
- Sandra Albert, Indian Institute of Public Health/National Lutheran Health & Medical Board
- Sanjib Mohanty, Ispat General Hospital, Rourkela, Odisha, India
- Praveen Sahu, Community Welfare Society Hospital
- Community Welfare Society Hospital, Rourkela, Odisha, India
- Indian Council of Medical Research/National Institute for Research in Tribal Health, Jabalpur, MP, India
- Indian Institute of Public Health/National Lutheran Health & Medical Board, Shillong, Meghalaya, India
- Ispat General Hospital, Rourkela, Odisha, India
- London School of Hygiene and Tropical Medicine, London, UK
- Seattle Children’s Research Institute, Seattle, USA
- Umeå University, Umeå, Sweden
- University of Heidelberg, Heidelberg, Germany
- University of Manchester, Manchester, UK