The National Institutes of Health has renewed a major grant that funds a 91̽»¨-led research center to understand malaria in India.

The initiative — , which was first funded in 2010 — is one of 10 NIH-supported International Centers of Excellence for Malaria Research, or ICEMRs. The National Institute of Allergy and Infectious Diseases that it would provide $9.3 million in funds to the South Asia ICEMR over the next seven years, beginning July 1, 2017.

South Asia sits in the middle of the malaria corridor that cuts from Southeast Asia to Africa.

“India is a country of critical importance for understanding the spread of virulent malaria globally,” said , a 91̽»¨professor of chemistry and the director of the Malaria Evolution in South Asia ICEMR. “While most deaths caused by drug-resistant strains of malaria have occurred in Africa, most drug-resistant parasites arise first in Asia.”

Malaria in India remains underappreciated. The country has 1.3 billion people and more than 90 percent of the population live in areas where there is risk of malaria transmission. India had an estimated 13 million cases of malaria in 2015, according to the World Health Organization. Beyond that, the picture of malaria in India is one of diversity.

“There is enormous variation in the prevalence of malaria around the country — variation in levels of immunity and variation in the species of mosquitoes that spread the disease,” said Laura Chery, the South Asia ICEMR’s associate director. “Most importantly, there is unexpectedly high genetic diversity in malaria parasites that are circulating in India.”

In addition to researchers from the UW, the South Asia ICEMR also includes U.S. scientists from Harvard University, the Fred Hutchinson Cancer Research Center, the Center for Infectious Disease Research and Stanford University. But by far the largest contingent of researchers that make up the center’s efforts are the dozens of scientists, clinicians and field workers at sites across India.

“We have formed wonderful, productive partnerships with hospitals, clinics, government agencies and community members,” said Chery. “Together, we have learned to do advanced science on the ground at clinically important sites.”

Through partnerships with local hospitals and research institutes, the center currently works out of six sites across India. The locations capture the diversity of this massive country: Four sites are in eastern and northeastern India, where malaria is endemic and cases can reach as high as 50 to 100 per 1,000 people. Two other sites are on the west coast, where the prevalence of malaria can be relatively low — fewer than 1 case per 1,000 people. But these sites include urban hospitals that attract and treat large numbers of malaria patients, including migrants from other parts of the country.

“We believe that movement of people within the country can partly explain the complexity of malaria in India,” said Rathod. “However, we do not fully understand the basis for such variations.”

At each site, staff enroll patients to obtain malaria parasite samples, as well as information on each patient’s health history. From on-site laboratories in India, center staff and partners pursue a number of research projects: analyzing parasite samples for signs of drug resistance, understanding the basis for variations in disease presentation, sequencing parasite genomes and determining their genetic relatedness to one another, and testing how well different mosquito species take up various malaria strains.

In addition to setting up complex research infrastructure, in its first seven years the center has made some surprising conclusions about malaria in India. Parasites in India show more genetic diversity than parasites in the rest of the world combined, according to Rathod. As a consequence, some standard laboratory tests for drug resistance, developed elsewhere in the world, do not accurately predict whether Indian parasites will show drug resistance.

Drug resistance is a major concern in malaria. Chloroquine was once an effective drug to fight malaria. But a generation ago, malaria parasites began to evolve resistance to it, rendering it largely ineffective. Today, the drug artemisinin is considered the best treatment against malaria. But artemisinin-resistant strains of malaria already have been identified in Southeast Asia. The Indian government and the South Asia ICEMR are on the lookout for artemisinin resistance among patients in northeastern and eastern India. Beyond that, the South Asia ICEMR is looking for parasites that mutate at extraordinary rates, as seen in Southeast Asia.

“By getting a clearer picture of malaria in India, we’re ‘closing the gap’ on how this complex parasite behaves globally,” Rathod said.

For the 2017-2024 cycle, other South Asia ICEMR project leaders are , director of the National Institute of Malaria Research in India, and at Harvard University. Additional U.S.-based senior contributors are at the Center for Infectious Disease Research, at Stanford University and and at the Fred Hutchinson Cancer Research Center. Additional India-based senior contributors are Anup Anvikar at National Institute of Malaria Research; Subrata Baidya at Agartala Government Medical College; D.R. Bhattacharrya and P.K. Mohapatra at Regional Medical Research Centre, NE Region; Edwin Gomes at Goa Medical College & Hospital; Sanjeeb Kakati at Assam Medical College; Ashwani Kumar at National Institute of Malaria Research, Goa Field Unit; Sanjib Mohanty and A.K. Singh at Ispat General Hospital; and Swati Patankar at Indian Institute of Technology Bombay.

###

For more information, contact Rathod at rathod@uw.edu or 206-384-9404 and Chery at lauraarn@uw.edu or 206-321-2409.

Grant number: U19AI089688

The 91̽»¨’s — along with partners at the (CIDR) and (GMC) of India — have discovered that specific types of parasite proteins, when combined with high parasite biomass, strongly predict severe malaria disease in adults. The discovery, published May 16 in the journal , is a significant advancement in understanding the causes of severe malaria. Quantitative characterization of disease presentations and biotechnology capabilities at the ICEMR lab at Goa Medical College combined with specialized assays for molecular host-parasite interactions and machine learning tools at the CIDR helped unlock the mysteries of what leads to the development of severe malaria disease.

In India, malaria kills 50,000 to 100,000 people each year, accounting for approximately 20 percent of malaria deaths globally. In south and southeast Asia, severe malaria primarily occurs in adults. The molecular basis for severe manifestations of the disease in adults is not well-understood. This study, led by Joseph Smith and colleagues at Seattle-based CIDR and the 91̽»¨, shows that in patients with severe malaria, red blood cells infected with the malaria parasite bind to a key regulatory protein on blood vessels, endothelial protein C receptor. Adhesion proteins from the malaria parasite facilitate this interaction. The researchers found that expression of these parasite proteins, accompanied by high parasite load, predicts severe manifestations in adults with malaria. These findings may help develop future treatments for severe malaria.

This multi-institutional collaboration is part of , the Malaria Evolution in South Asia (MESA) initiative based at the 91̽»¨International Center of Excellence for Malaria Research (ICEMR) and funded by the U.S. National Institute of Allergy and Infectious Diseases, part of the U.S. National Institutes of Health. With the approval and support of the Indian Council of Medical Research, this program has established new malaria research sites across India, including one at Goa Medical College.

“Such complex interactions between physicians, scientists, and patients are possible due to the local leadership of Dr. Edwin Gomes, the Head of the Department of Medicine at Goa Medical College,” said Laura Chery, associate director of the MESA-ICEMR.

The MESA-ICEMR has enrolled more than 1,000 malaria patients at GMC since April 2012.

“This study, involving CIDR, GMC and UW, is a model for how US-India partnerships can contribute to our understanding of a potentially lethal disease,” said co-author , 91̽»¨professor of chemistry and MESA-ICEMR Program Director.

###

For more information, contact Rathod at 206-384-9404 or rathod@chem.washington.edu.

Adapted from a release prepared by the Center for Infectious Disease Research.

If human trials underway are successful, the compound — known by its acronym DSM265 — could give doctors a new tool to prevent and treat infection by the microscopic parasites that cause malaria, a mosquito-borne disease that kills more than 500,000 people annually.

The team’s efforts stem from new, streamlined processes to identify and optimize chemical compounds that show promise against malaria parasites. The scientists in this international partnership — spanning 20 institutions on three continents — pooled their collective expertise to accelerate the pace of discovery and validation. This novel anti-malarial drug is their first major breakthrough for use in humans.

“This is the first of a new class of molecules that’s going into humans,” said 91̽»¨chemistry professor , and leaders of this endeavor. “Until now, everything else in humans has been variations of drugs that have been developed in the distant past.”

DSM265 targets a cellular protein made by the malaria parasite. Malaria parasites rely on this protein — known by its acronym DHODH — to express their genes and copy those genes when it’s time to divide. Since DHODH provides a critical function, this drug could impair the parasite at multiple stages of its life cycle, including one elusive stage when it hides in the human host’s liver.

Rathod’s partners include with the University of Texas Southwestern Medical Center at Dallas and at Monash University in Melbourne. The three research groups and their recent partners in Europe, Australia and the U.S. shared information and divided tasks openly, playing to the strengths of each group. Rathod’s lab at the 91̽»¨was involved from the start.

“All the enabling chemistry work was done here first, and all the tests on malaria parasite cells and human cells started and have continued here,” said Rathod.

Since DHODH performs such a critical role in malaria cells, scientists had long sought drugs that would inactivate it. The Texas researchers studied the malaria DHODH protein, working to identify a chemical compound that would cripple it. Once they found a chemical that showed promise, Rathod’s lab undertook validation, modification, and fine-tuning. With additional guidance and collaboration from advisors at the , Rathod’s group altered the chemical compound to increase its potency against DHODH.

They also had to ensure that the compound would not target the human version of the DHODH protein, which performs an important role in our cells. In all, Rathod’s group made more than 500 versions of the initial compound and tested how well it inhibited malaria parasites in the lab. The 265^th version — DSM265 — showed the most promise.

“‘DSM’ actually stands for ‘Dallas-Seattle-Melbourne,’ our three cities,” said Rathod. “We wanted to name it after our founding teams that are working really hard at each site.”

Rathod and his group passed DSM265 and related compounds to their collaborators at Monash University, who tested how our human cells might modify or metabolize the compound. These experiments ensured that a drug based on DSM265 would last for a long time in our bodies — an ideal feature for a single-dose anti-malarial treatment — and would not produce toxic byproducts. They also determined what doses of the compound might be the most effective in humans.

Rathod’s lab also developed and performed experiments to test how well the malaria parasite might evolve to become resistant against DSM265.

“We developed methods to watch the malaria parasites mutate and try to generate solutions against DSM265 in real time,” said Rathod. “And with whole genome sequencing, we can really look at the whole scene as it’s unfolding in front of us.”

If doctors know the conditions that permit the malaria parasite to develop resistance to DSM265, they can tailor the drug’s use in a clinical setting to lower that risk.

Rathod hopes that the development and discovery pipeline for DSM265 will pave the way for a faster and more collaborative drug development process in what he calls “the long war against malaria.” The project benefited from an open process, Rathod said. Researchers also transferred their patent rights for DSM265 to the , a Bill & Melinda Gates Foundation-supported nonprofit public-private partnership that is leading some of the clinical and field trials, in the hopes of accelerating the drug’s clinical development.

Other authors from the 91̽»¨include John White and Sreekanth Kokkonda, senior scientists with the 91̽»¨Department of Chemistry and researchers in Rathod’s lab.

The DHODH research projects in Rathod’s and Phillips’s labs were funded by the U.S. National Institutes of Health grants AI075594 and AI103947.

###

For more information, contact Rathod at 206-384-9404 or rathod@chem.washington.edu.