Malaria Math

Emory scientists are pursuing a novel approach that could lead to host-directed therapies for the disease—that is, interventions to help people already infected with malaria to function as normally as possible by strengthening their physiological response rather than targeting the parasite.

We want to come up with ways to make the host feel better, to relieve the disease symptoms at least temporarily,” says Mary Galinski, principal investigator and professor of medicine and infectious diseases at Emory’s School of Medicine, the Emory Vaccine Center, and Yerkes National Primate Research Center.

Malaria, the most widespread human parasitic disease, is caused by a parasite delivered via the bite of a female Anopheles mosquito. But not everyone hosting the parasite gets sick—and it is that phenomenon that’s attracting interest at Emory.

Supported by a three-year Defense Advanced Research Projects Agency (DARPA) contract, the Emory research team is collaborating with scientists from the Georgia Institute of Technology, the University of Georgia, and several national and international institutions. The researchers are focusing not solely on the immune system, but also on other physiological mechanisms that produce malarial resilience.

“We know individuals can build up an immunity to fight the disease,” says Galinski. “But if they travel to another environment and don’t have a sustained immune response, they can still get very sick. DARPA wanted us to go beyond the immune system to examine what other kinds of physiological responses are going on.”

Host-directed therapies aimed at nonimmune processes would be valuable in the many areas of the world where symptomatic individuals are unable to quickly receive parasite-killing drugs or when there are no alternatives. In addition, an increasing variety of parasite strains are becoming drug resistant.

One potential benefit of the project is that it could lead to more effective drugs as well as improved malaria intervention strategies. Another is that host-directed therapies may be applicable beyond malaria, since loss of host resilience in the face of various infectious agents often relates to the same core set of physiological pathways escaping normal control.

“Examples of host-directed therapies include modulation of host danger molecules, fever signaling, and undue destruction of uninfected red blood cells—all of which play a role in triggering acute host symptoms in response to malaria infection,” says coprincipal investigator Rabindra Tirouvanziam, assistant professor in Emory’s Department of Pediatrics.

Researchers begin by identifying the complex physiological, biochemical, and pathogenic factors associated with resilience.

Drawing on his expertise in physiology and immunology, Tirouvanziam defines core pathways most likely to impact host resilience. These pathways are then matched with existing assay methods, leading to the introduction of novel platforms, such as real-time physiological assessments by telemetry, to provide a unique window into how acute symptoms develop in malaria-infected hosts.

The telemetric assessments are accomplished by compiling biometric data from two species of nonhuman primates, which share with humans a susceptibility to a particular malaria parasite used for the study. The telemetry continues after the primates are infected with malaria parasites, and researchers look for changes in the baseline parameters, Galinski says. The telemetry data is then correlated with clinical and other information drawn from systems biology work performed at Emory with human and nonhuman primates.

The huge datasets generated by the research will be used to build mathematical models to compare and contrast different infection scenarios that will identify particular host features associated with resilience. The end result will be a comprehensive picture of physiological responses in infected tissues, which researchers expect will point the way toward development of new antimalarial therapies and drugs.

“Malaria is a very complicated disease,” Galinski says, “and while you might get glimpses of promise and hope in certain metrics like the number of cases declining somewhere, the reality is that if you don’t have a sustained program to fight it, it can bounce back, potentially worse than it was before.”—Gary Goettling