Morehouse School of Medicine Microbiologist Awarded National Institutes of Health Grant to Develop New Intervention Against Cerebral Malaria
$2.7 million grant to fund international team to research potential treatment for severe malaria which kills approximately 500,000 children annually.
ATLANTA – FEBRUARY 4, 2022 – Morehouse School of Medicine (MSM) Professor of Microbiology Biochemistry Immunology Jonathan Stiles has been awarded a grant from the National Institutes of Health’s (NIH) National Institute of Neurological Disorders and Stroke (NINDS) to develop new adjunctive therapy against cerebral malaria. The $2.7 million R01 grant will support researchers at Morehouse School of Medicine; University of California, Riverside; Michigan State University; University of Ghana; and Kwame Nkrumah University of Science and Technology.
Human cerebral malaria (HCM) is a severe form of Plasmodium falciparum (P.f.) malaria associated with approximately 500,000 deaths in children annually, mostly in Africa, and impaired brain function in some survivors. Children with HCM have parasitized red blood cells (pRBCs) which block cerebral micro-circulation and cause brain inflammation, swelling, and impaired consciousness with unarousable coma. Most adjunctive treatments developed to date against HCM have not reduced fatal outcomes mainly because treatments have focused on clearance of circulating parasites but neglected the involvement of damaging parasite and host factors appearing early in infection or remaining after treatment.
The proposed study, entitled “Protective role of Neuregulin-1 against cerebral malaria-induced neuronal injury and behavioral sequelae,” uses a novel 3D in vitro brain organoid model and animal models developed at MSM as well as human studies in West Africa to clarify the role of Neuregulin-1 (NRG1), a potent anti-inflammatory neuropeptide that improves survival rates in children with HCM. The project will clarify the role of NRG1 in attenuation of the disease and mechanisms mediating its function.
The outstanding international team of investigators involved in the project is led by Principal Investigators Morehouse School of Medicine’s Drs. Jonathan Stiles and Byron Ford at University of California, Riverside. They are joined by co-investigators Alexander Quarshie and Roger Simon at MSM; Michael Boivin (Michigan State University); Andrew Adjei and Michael Wilson (University of Ghana); and Stephen Sarfo (Kwame Nkrumah University of Science and Technology, located in Kumasi, Ghana).
With previous NIH funding, the team determined that circulating free heme and parasite histidine rich protein 2 (HRP2), by-products of parasitized erythrocyte lysis, were responsible for the brain inflammation, blood-brain barrier (BBB) dysfunction, and brain injury associated with HCM. However, defining the mechanism(s) mediating these effects was challenging in the absence of suitable models. Using their in vitro 2D cell culture, 3D brain organoid, and animal models (ECM; Plasmodium berghei ANKA in C57BL/6), the researchers determined that heme and HRP2 were responsible for cellular apoptosis, inflammation, and tissue disorganization. Following a screen of therapeutic agents against ECM, they identified NRG1, an 8 kDa neuropeptide currently undergoing clinical trials against heart failure which attenuates ECM when delivered intravenously at 5μg/kg to augment depleted NRG1 in severe disease.
This round of NIH funding will enable the team to use a human stem cell-derived neurovascular unit (NVU; brain chip), ECM, and clinical studies to determine the mechanism by which NRG1 attenuates cerebral malaria.
“We hypothesize that therapeutic administration of NRG1 will attenuate heme and HRP2-induced NVU damage and ECM mortality,” said Dr. Stiles. “Understanding the role of NRG1 in cerebral malaria pathogenesis and sequelae in survivors will enable us determine the feasibility of targeting NRG1 in future clinical trials while building biomedical research capacity in Ghana with the ultimate goal of improving the survival of children with HCM.”
This groundbreaking research will provide research training and mentoring opportunities for MSM graduate students and postdoctoral scientists and aligns with MSM’s vision of leading the creation and advancement of health equity.
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Founded in 1975, Morehouse School of Medicine (MSM) is among the nation’s leading educators of primary care physicians, biomedical scientists, and public health professionals. An independent and private historically-Black medical school, MSM was recognized by the Annals of Internal Medicine as the nation’s number one medical school in fulfilling a social mission—the creation and advancement of health equity. MSM faculty and alumni are noted for excellence in teaching, research, and public policy, as well as exceptional patient care. MSM is accredited by the Commission on Colleges of the Southern Association of Colleges and Schools to award doctoral and master’s degrees. To learn more about programs and donate today, please visit www.msm.edu or call 404-752-1500.
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