In the heart of devastating outbreak, research team unlocks secrets of Ebola

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a vial is labeled and prepared to hold blood from an Ebola patient in Sierra Leone. Researchers from the UW-Madison, the University of Tokyo and the University of Sierra Leone will compare blood from those who died of the virus to those who survived and those who never got sick to try and develop treatment. (Photo courtesy of Kawaoka Lab.)

This story appeared first at news.wisc.edu.

In a comprehensive and complex molecular study of blood samples from Ebola patients in Sierra Leone, published today (Nov. 16, 2017) in Cell Host & Microbe, a scientific team led by the University of Wisconsin–Madison has identified signatures of Ebola virus disease that may aid in future treatment efforts.

Conducting a sweeping analysis of everything from enzymes to lipids to immune-system-associated molecules, the team — which includes researchers from Pacific Northwest National Laboratory (PNNL), Icahn School of Medicine at Mount Sinai, the University of Tokyo and the University of Sierra Leone — found 11 biomarkers that distinguish fatal infections from nonfatal ones and two that, when screened for early symptom onset, accurately predict which patients are likely to die.

With these results, says senior author Yoshihiro Kawaoka, a virology professor at the UW–Madison School of Veterinary Medicine, clinicians can prioritize the scarce treatment resources available and provide care to the sickest patients. Kawaoka is also a member of the GHI Advisory Committee and received a 2017 GHI Seed Grant to catalog viruses circulating among West Africans with an eye to improving diagnoses, identifying new viruses and, potentially, preventing the next epidemic.

Studying Ebola in animal models is difficult; in humans, next to impossible. Yet, in Sierra Leone in 2014, a natural and devastating experiment played out. In September of that year, an Ebola outbreak like no other was beginning to surge in the West African nation. By December, as many as 400 Ebola cases would be reported there each week.

That fall, Kawaoka sought access to patient samples. He has spent a career trying to understand infectious diseases like Ebola — how do they make people sick, how do bodies respond to infection, how can public health officials stay at least a step ahead?

“Here, there is a major outbreak of Ebola. It is very rare for us to encounter that situation,” says Kawaoka, who is also a professor of virology at the University of Tokyo.

Yet blood samples were proving difficult to obtain and people continued to die.

Then, just weeks before Christmas, Kawaoka learned about a colleague in his very own department at UW–Madison, a research fellow from Sierra Leone named Alhaji N’jai, who was producing radio stories for people back home to help them protect themselves from Ebola. The pair forged a fortuitous partnership.

“He knows many people high up in the Sierra Leone government,” says Kawaoka. “He is very smart and very good at explaining things in lay terms.”

By Christmas, Kawaoka, N’jai and Peter Halfmann, a senior member of Kawaoka’s team, were in Sierra Leone.

“On the first trip, Alhaji took me to Parliament and we talked to a special advisor to the president, then the vice chancellor of the University of Sierra Leone,” says Kawaoka. “We got the support of the university, which helped us identify military hospitals and provided space. We went to the Ministry of Health and Sanitation and the chief medical officer and we explained what we hoped to do.”

Yoshihiro Kawaoka, professor of pathobiological sciences at the UW-Madison School of Veterinary Medicine, meets with Ekundayo Thompson, vice chancellor of the University of Sierra Leone, while in the African nation to establish a partnership to study and fight Ebola while improving the research capacity and infrastructure of the University of Sierra Leone. (Photo courtesy of the Kawaoka Lab.)

By February of 2015, Kawaoka and other select senior researchers on his team, including Amie Eisfeld, set up a lab in a military hospital responding to the outbreak in the capital city of Freetown (the researchers never entered patient wards). With the approval of patients and the government of Sierra Leone, health workers collected blood samples from patients after they were diagnosed with Ebola and at multiple points thereafter.

They obtained 29 blood samples from 11 patients who ultimately survived and nine blood samples from nine patients who died from the virus. The samples were transported to the lab where Kawaoka’s experienced and expertly trained team inactivated the virus according to approved protocols. Blood samples were subsequently shipped to UW–Madison and partner institutions for analysis.

For comparison, the research team also obtained blood samples from 10 healthy volunteers with no exposure to Ebola virus.

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“Our team studied thousands of molecular clues in each of these samples, sifting through extensive data on the activity of genes, proteins and other molecules to identify those of most interest,” says Katrina Waters, a biologist at PNNL and a corresponding author of the study. “This may be the most thorough analysis yet of blood samples of patients infected with the Ebola virus.”

The team found that survivors had higher levels of some immune-related molecules, and lower levels of others compared to those who died. Plasma cytokines, which are involved in immunity and stress response, were higher in the blood of people who perished. Fatal cases had unique metabolic responses compared to survivors, higher levels of virus, changes to plasma lipids involved in processes like blood coagulation, and more pronounced activation of some types of immune cells.

UW-Madison’s Yoshihiro Kawaoka, Peter Halfmann and Alhaji Njai stand outside of a military hospital with Foday Sahr, a Sierra Leone military official and chair of microbiology at the University of Sierra Leone. Ebola patients are treated at many of the country’s military hospitals like the Joint Medical Unit.
(Photo courtesy of the Kawaoka Lab.)

Pancreatic enzymes also leaked into the blood of patients who died, suggesting that damage from these enzymes contributes to the tissue damage characteristic of fatal Ebola virus disease.

And, critically, the study showed that levels of two biomarkers, known as L-threonine (an amino acid) and vitamin D binding protein, may accurately predict which patients live and which die. Both were present at lower levels at the time of admission in the patients who ultimately perished.

“We want to understand why those two compounds are discriminating factors,” says Kawaoka. “We might be able to develop drugs.”

When Ebola virus leads to death, experts believe it is because of overwhelming viral replication. Symptoms of infection include severe hemorrhaging, vomiting and diarrhea, fever and more.

Kawaoka and his collaborators hope to better understand why there are differences in how patients’ bodies respond to infection, and why some people die while others live. The current study is part of a larger, multicenter effort funded by the National Institutes of Health.

“This may be the most thorough analysis yet of blood samples of patients infected with the Ebola virus.”

Katrina Waters

“The whole purpose is to study the responses of human and animal bodies to infection from influenza, Ebola, SARS and MERS, and to understand how they occur,” Kawaoka explains. “Among the various pathways, is there anything in common?”

In the current Ebola study, the team found that many of the molecular signals present in the blood of sick, infected patients overlap with sepsis, a condition in which the body — in response to infection by bacteria or other pathogens — mounts a damaging inflammatory reaction.

And the results contribute a wealth of information for other scientists aimed at studying Ebola, the study authors say.

Kawaoka says he is grateful to UW–Madison, University Health Services and Public Health Madison and Dane County for assistance, particularly with respect to his research team’s travel between Madison and Sierra Leone. Each provided protocols, monitoring, approval and other needed support during the course of the study.

“I hope another outbreak like this never occurs,” says Kawaoka. “But hopefully this rare opportunity to study Ebola virus in humans leads to fewer lives lost in the future.”

By Kelly April Tyrell, UW communications/ November 16, 2017

THE STUDY WAS FUNDED BY A JAPANESE HEALTH AND LABOR SCIENCES RESEARCH GRANT; BY GRANTS FOR SCIENTIFIC RESEARCH ON INNOVATIVE AREAS FROM THE MINISTRY OF EDUCATION, CULTURE, SPORTS, SCIENCE AND TECHNOLOGY OF JAPAN; BY EMERGING/RE-EMERGING INFECTIOUS DISEASES PROJECT OF JAPAN; AND BY AN ADMINISTRATIVE SUPPLEMENT TO GRANT U19AI106772, PROVIDED BY THE U.S. NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES, PART OF THE NATIONAL INSTITUTES OF HEALTH. SUPPORT WAS ALSO PROVIDED BY THE DEPARTMENT OF SCIENTIFIC COMPUTING AT THE ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI AND BY A GRANT FROM THE NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES (P41 BM013493). SOME ANALYSES WERE PERFORMED AT THE ENVIRONMENTAL MOLECULAR SCIENCES LABORATORY, A NATIONAL SCIENTIFIC USER FACILITY SPONSORED BY THE U.S. DEPARTMENT OF ENERGY OFFICE OF BIOLOGICAL AND ENVIRONMENTAL RESEARCH.

 

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2018 Global Health Symposium

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The Global Health Institute at the University of Wisconsin-Madison is pleased to welcome Professor Susan Paskewitz as the keynote speaker for the 14th annual Global Health Symposium: Advancing Health in Uncertain Times. The symposium begins at 4:30 p.m., Tuesday, April 10, 2018.

Paskewitz is professor and chair of the Department of Entomology in the College of Agricultural and Life Sciences. She also is co-director of the Upper Midwestern Center of Excellence for Vector-Borne Disease funded by the Centers for Disease Control and Prevention and a member of the GHI Advisory Committee. Her research focuses on medically important arthropods, including ticks and mosquitoes, and the human pathogens they transmit. She also teaches classes in global health and medical entomology.

The annual symposium provides a forum for the UW-Madison global health community to showcase recent work and connect with each other. The evening includes oral and poster presentations and a closing panel on a global health hot topic.

Watch this page for more details and registration information.

Call for abstracts

Deadline: February 12, 2018

The call is open to members and partners of the UW-Madison community who are addressing global health and disease. From basic research to education to applied projects in the field, the symposium hopes to showcase the full spectrum of UW-Madison global health activity. We encourage and welcome presentations from all disciplines—from arts, agriculture, and business, to education, engineering, and humanities, to all of the health sciences and more. 

Following the keynote address, selected oral presenters will deliver their work in 15-minute (including time for questions), concurrent sessions. Posters will be available for viewing all evening, and a poster session follows the presentations. Hors d’oeuvres will be served during the networking reception that closes the evening.

Abstract Submission Form

 

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Apply now for 2018 global health grants

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The University of Wisconsin-Madison Global Health Institute (GHI) is pleased to announce the application period is open for its 2018 grants and awards. This competitive grant program is designed to support global health efforts of faculty, staff and graduate students across campus, fostering the Wisconsin Idea locally and globally.

This year, the Institute will offer a new grant, the Henry Anderson III Graduate Student Award in Environmental, Occupational and Public Health, in addition to Graduate Student Research Awards, Visiting Scholar Awards and Faculty and Staff Travel Awards. There will be no Seed Grant awards in 2018.

An expert on environmental and occupational disease, public health, epidemiology, disease and exposure surveillance, Henry Anderson III, M.D., is an adjunct professor in the Department of Population Health and former chief medical officer for the Wisconsin Division of Public Health. With the graduate student award, he hopes to support students pursuing research in the area of environment, occupation and global health.

The deadline for GHI grant applications is 11:59 p.m. January 29, 2018.

  • Henry Anderson III Graduate Student Award in Environmental, Occupational and Public Health supports graduate students interested in pursuing research in those topic areas. Application information is available here.
  • Graduate Student Research Awards supports doctoral students pursuing work in any relevant discipline whose graduate work will enhance global health activities on the UW-Madison campus and beyond. Grants of up to $5,000 each will be awarded. Application information is available here.
  • Visiting Scholar Awards brings visitors to UW-Madison who substantially enhance global health activities on campus in collaboration with a sponsoring UW-Madison faculty member or faculty team. Grants of up to $8,000 each will be awarded. Application information is available here.
  • Faculty and Staff Travel Awards are available for UW-Madison faculty and staff who are GHI affiliates. They can be used for international travel related to educational and research activities. Grants of up to $2,500 each will be awarded. Application information is available here.

To learn more about previous grant recipients, visit the global health research pages. For more information about the grants and grant process, contact the Global Health Institute, 265-9299.

By Ann Grauvogl/ November 9, 2017

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With deer season on horizon, lab ramps up for CWD testing

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This article was first published by the University of Wisconsin-Madison.

More than half a million hunters will take to Wisconsin’s woods and fields this fall in pursuit of white-tailed deer, the state’s iconic big game animal. If trends continue, nearly 100,000 of those hunters will be successful.

To date, there is no evidence showing that CWD can be or has been transmitted from animals to humans, but preliminary results from a Canadian study reported that cynomolgus macaques given infected meat in their diet contracted CWD. PHOTO: USDA AGRICULTURAL RESEARCH SERVICE

But against the backdrop of another productive bow and gun season in Wisconsin, several state agencies, including the Wisconsin Veterinary Diagnostic Laboratory (WVDL) on the University of Wisconsin–Madison campus, are gearing up to make the 2017 deer harvest a safe one for hunters and their families.

Last year, some 6,600 Wisconsin hunters submitted tissue samples from harvested deer to WVDL for testing for chronic wasting diesease (CWD), the infectious neurological disease that has been found in both wild and captive deer in at least 24 Wisconsin counties, mostly in the southern half of the state.

This year, there may be a new urgency to test deer taken in the hunt as preliminary results from a Canadian study released in April reported that cynomolgus macaques given infected meat in their diet over a three-year period contracted CWD.

Hunters should strongly consider testing their deer, especially if the animals were taken in any of the Wisconsin counties affected by CWD, says veterinarian Keith Poulsen. WVDL PHOTO

The study, conducted by the Canadian Food Inspection Agency, has only been published in abstract form and has yet to complete the peer review process. The findings, however, are a signal that more research on the risk of CWD to human health is necessary and that hunters should strongly consider testing their deer, especially if the animals were taken in any of the Wisconsin counties affected by CWD, says veterinarian Keith Poulsen, diagnostic and case outreach coordinator for WVDL and member of the Global Health Institute advisory committee.

“This is the first controlled study of contaminated meat causing clinical disease,” says Poulsen of the research, where over a three-year period five monkeys were fed a diet that included the equivalent of a single seven-ounce venison steak per month. Three of the monkeys became infected, with two showing clinical signs of the disease. “The results show we need to continue this work.”

To date, there is no evidence showing that CWD — which has been found in deer, elk, moose and reindeer — can be or has been transmitted from animals to humans. CWD is one in a family of diseases caused by a prion, a nearly indestructable infectious agent whose epidemiology and mechanisms of action and transmission are not fully understood.

“The chance of someone getting prion disease is remote, but not zero,” Poulsen explains. “It would be a mistake to ignore it.”

Bones of animals from necropsies sent through the tissue digester after testing at Wisconsin Veterinary Diagnostic Laboratory. PHOTO: HYUNSOO LÉO KIM

CWD first definitively emerged in Wisconsin’s deer herd in 2001. Since that time, WVDL, in cooperation with the Wisconsin Department of Natural Resources (DNR), has provided free testing of harvested deer for hunters.

CWD has so far been found in both wild or captive cervids — deer, elk or moose — in more than 20 states and Canada.

WVDL is one of only 19 labs in the United States capable of testing for CWD and other prion diseases. The lab works closely with both the DNR and the Wisconsin Department of Health Services to help manage the disease, conduct surveillance, and ensure human health.

The only way to diagnose CWD in an animal is to test the brain, tonsils or lymph nodes after death. There is no viable test for live animals. For hunters submitting tissue samples for testing, the average turnaround time from when a deer is brought to a sampling station is about 10 days. WVDL can process as many as a thousand samples a day. Samples are bar coded to ensure a match between a hunter and the sample submitted for testing, and results can be tracked online.

WVDL also tests for CWD in samples sent from more than half a dozen other states.

Written by Terry Devitt, September 11, 2017.

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