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.”
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.
“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.
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.”
“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.
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.
By Ann Grauvogl/ November 9, 2017
If there is anything scientists are certain of when it comes to bats and their supposed role in causing human disease, it is that they still have a lot to learn.
Aside from well-established things like rabies virus, SARS coronavirus (the virus that causes severe acute respiratory syndrome) and Marburg virus (an extremely dangerous but rare hemorrhagic fever pathogen), bats appear to carry a plethora of other germs with unclear effects, if any, on human health.
And even some commonly believed bat paradigms may be incorrect. For example, some speculate that bats play a role in the transmission of Ebola simply because Ebola and Marburg are related pathogens. But scientific evidence to support such speculation is scant, at best.
A lack of evidence that bats are key reservoirs of human disease has not prevented their vilification or efforts to exterminate bat colonies where threats are presumed to lurk.
“The fact is that they provide important ecosystem services – insect control, pollination and seed dispersal, to name a few – and we want them around,” says Tony Goldberg, a University of Wisconsin-Madison epidemiologist and virus hunter. “But bats are also increasingly acknowledged as hosts of medically significant viruses. I have mixed feelings about that.”
To better understand the dynamics of bats and potential threats to human health, Goldberg and his colleagues explored the relationship of an African forest bat, a novel virus and a parasite. Their work, described in a report published July 13 in Nature Scientific Reports, identifies all three players as potentially new species, at least at the molecular level as determined by their genetic sequences.
Many viral pathogens often have more than one or two hosts or intermediate hosts needed to complete their life cycles. The role of bat parasites in maintaining chains of viral infection is little studied, and the new Wisconsin study serves up some intriguing insights into how viruses co-opt parasites to help do the dirty work of disease transmission.
The parasite in the current study is an eyeless, wingless fly, technically an ectoparasite. It depends on the bat to be both its eyes and wings. And it plays host to a virus, as the current study shows. For the virus, the fly plays the role of chauffeur. “From a virus’s perspective, an ectoparasite is like Uber. It’s a great way to get around – from animal to animal – at minimal expense and effort,” Goldberg explains.
The bat in the study belongs to the megabat suborder. It is a fruit bat and was trapped, tested and released by Goldberg’s colleague and study co-author Robert Kityo of Uganda’s Makerere University in Kampala.
The bat fly, according to the new study, was infected with a newly discovered rhabdovirus dubbed Kanyawara virus, a distant relative of the rabies virus. “These things were chock-full of the virus,” says Goldberg, a professor of pathobiological sciences at UW-Madison’s School of Veterinary Medicine. That said, he adds that “we don’t know if this virus is transmitted beyond the ectoparasite. We couldn’t find it in the bat. Maybe it is an insect virus.”
However, it is well known that ectoparasites transmit disease, says the Wisconsin epidemiologist, noting that things like ticks and fleas harbor important pathogens like typhus, bubonic plague, Lyme disease and Rocky Mountain spotted fever.
“Bat flies bite people if given the chance,” Goldberg says of the parasite, which he described as “shockingly large, leggy and fast – a parasite from hell.”
The report published this week notes that rare cases of human infection with bat-associated viruses remain enigmatic. The study cites the 1969 case of a British dockworker bitten by an unknown insect while unloading peanuts from Nigeria, and who was subsequently infected by Le Dantec virus, a relative of the virus Goldberg and his colleagues found in abundance in the bat flies they sampled. “Was the dockworker bitten by a bat fly? We’ll never know.”
The subtext of the research, according to Goldberg, is Ebola and the ecology of disease. Scientists are beginning to understand that serious pathogens like Ebola and SARS don’t come out of nowhere. They are already lurking in the environment, and the leap from an animal to a human can be just a matter of time and an organism’s ability to shift from one host to another.
“The big picture relevance of the research is that if we’re going to understand the diversity of viruses in the world, we need to look in unusual places,” Goldberg says. “We have a lot to learn about the basic distribution of species on the planet.”
By Terry Devitt, UW-Madison/ July 13, 2017
May 22, 2017 By Emily Hamer
A group of 75 University of Wisconsin–Madison students will be in the field May 21-26 to learn firsthand about the diversity of the state’s health care system.
As a part of the Wisconsin Express program, which is organized by the Wisconsin Area Health Education Centers, the students will travel to 11 communities across Wisconsin, learning about public health dilemmas in the state, Wisconsin Express statewide program coordinator Keri Robbins said. Students visit clinics, shadow health care professionals and participate in activities that help them learn about diverse Wisconsin communities such as, Native American tribes, Somali refugees, Amish populations, and more.