Researchers at Emory University, UGA and the Georgia Institute of Technology, along with national and international collaborators, will investigate the mechanisms behind “resilience” following malaria infection.
The investigators believe learning why malaria causes acute, potentially lethal disease in some humans and animals, while others are much more resilient or tolerant, could lead them to better intervention strategies, including new and better drugs, for malaria and other diseases.
The Defense Advanced Research Projects Agency and the Army Research Laboratory are supporting the research through a $6.4 million contract. The research partnership is part of DARPA’s THoR (Technologies for Host Resilience) program and is termed the HAMMER (Host Acute Models of Malaria to study Experimental Resilience) project.
Malaria, which is transmitted through mosquito bites, is the most widespread human parasitic disease and is endemic in approximately 100 countries. It causes fever, pain and other acute responses, and in severe cases it can become deadly within days of the onset of symptoms.
Resilience in some people and non-human primates allows them to control the disease and avoid adverse outcomes, so that the disease is not incapacitating, said Mary R. Galinski, principal investigator for the project and a professor of medicine and infectious diseases at Emory University School of Medicine, Emory Vaccine Center and Yerkes National Primate Research Center.
The researchers hope they may identify features associated with resilience and develop interventions that could enhance that resilience, she said.
“Some infectious diseases are particularly difficult to eradicate because of genetic mechanisms that allow them to successfully evade the immune system,” said Juan B. Gutierrez, an associate professor of mathematics and bioinformatics at UGA and co-leader of the project. “With the HAMMER project we want to come up with mechanisms that strengthen the host instead of curing a host by targeting the parasite.”
Galinski and Gutierrez are partnering with Rabindra Tirouvanziam, another key leader for the project and an assistant professor of pediatrics at the Emory University School of Medicine. They are joined by more than 40 established investigators from across the country.
THoR’s HAMMER project focuses on the malaria parasite Plasmodium knowlesi, which can infect both humans and non-human primates. P. knowlesi causes mild chronic infections in some monkeys, such as long-tailed and pig-tailed macaques, which are its natural hosts. However, it causes severe, virulent infections in other monkeys, such as rhesus macaques.
Using systems biology approaches, the THoR’s HAMMER team will generate large datasets on characteristics of P. knowlesi infection in the two types of non-human primates and in humans. They will then develop and apply mathematical models to compare and contrast the different scenarios of infection to identify particular host features associated with resilience. This may yield insights that could lead to novel interventions for malaria, including new drugs.
The researchers will use surgically implanted devices to gather real-time physiological data, including temperature, heart rate, blood pressure and mobility, from the two types of monkeys. Then, by combining this information with the monkeys’ clinical and molecular data, they will look for signs of severe disease.
The researchers’ ultimate goal is to test candidate therapies in highly susceptible hosts with the aim of reducing disease severity and death in the absence of effective antimalarial chemotherapy, or in conjunction with antimalarial chemotherapy.
The THoR’s HAMMER project builds upon the scientific infrastructure of the Malaria Host-Pathogen Interaction Center (MaHPIC), a malaria systems biology partnership between Emory, UGA, Georgia Tech and the CDC Foundation, established in 2012 with federal funds from the National Institute of Allergy and Infectious Diseases.
“Our systems biology team, which has become well-established through our MaHPIC consortium, plans to positively impact the work of all THoR projects by continuing to promote cross-fertilization of ideas both within our team and among all THoR project participants nationally,” said Tirouvanziam.