December 23, 2015–(BRONX, NY)–Ebola virus and bats have been waging a molecular battle for survival that may have started at least 25 million years ago, according to a study led by researchers at Albert Einstein College of Medicine, the University of Colorado-Boulder (CU-Boulder) and the U.S. Army Medical Research Institute of Infectious Diseases (USAMRIID) that published online today in the journal eLife. The findings shed light on the biological factors that determine which bat species may harbor the virus between outbreaks in humans and how bats may transmit the virus to people.
"We knew from our previous research that Ebola virus infects host cells by attaching its surface glycoprotein to a host cell receptor called NPC1," said study co-leader Kartik Chandran, Ph.D., associate professor of microbiology & immunology and the Harold and Muriel Block Faculty Scholar in Virology at Einstein. "Here, we show how bats have evolved to resist Ebola infection and how, in turn, the virus could have evolved to overcome that resistance." The other study co-leaders are Sara Sawyer, Ph.D., an associate professor of molecular, cellular, and developmental biology at CU-Boulder, and John Dye, Ph.D., Viral Immunology Branch Chief at USAMRIID.
Outbreaks of Ebola virus disease among humans are thought to begin when a person comes into contact with a wild animal carrying Ebola virus (a member of the family of filoviruses). "Unlike HIV or influenza virus, Ebola virus stays hidden in an unknown natural reservoir between outbreaks," said Dr. Dye. Prior research points to some types of bats as possible viral reservoirs, but little is known about how Ebola virus interacts with its presumed reservoir hosts.
To learn more, Dr. Chandran and his colleagues exposed cells from four types of African bats (two of them previously linked to Ebola) to several filoviruses, including Ebola virus. Cells from only one type of bat proved resistant to Ebola virus infection: the African straw-colored fruit bat, which is commonly hunted for bushmeat in West Africa and migrates long distances.
"We mapped this resistance to a single amino acid change in the NPC1 gene of this bat," said Dr. Chandran. "This tiny change prevents Ebola from binding to the NPC1 receptor." So the African straw-colored fruit bat–suspected as an Ebola virus reservoir in the recent Western African epidemic–was probably not guilty.
But that's only half the story. The researchers showed that a single amino acid change in Ebola's surface glycoprotein could overcome the resistance of African straw-colored fruit bat cells to infection. These findings hint at one way that a filovirus could evolve to better infect a host with receptors that are less than optimal. "There seems to be a low barrier for Ebola virus to multiply in cells of this type of bat," said Dr. Sawyer. "One has to wonder why that has not happened."
Interestingly, some non-Ebola filoviruses were able to infect cells from all of the types of bats tested, including the African straw-colored fruit bat. "Those viruses already had the amino acid change that allowed the mutated Ebola virus to infect straw-colored fruit bat cells, so they didn't have any problem binding to the different NPC1 receptors," said Dr. Chandran. The authors propose that this genetic change in the glycoprotein sequences of some filoviruses may have evolved to counteract changes in the NPC1 sequences of their bat hosts.
The research team then genetically analyzed NPC1 in 13 bat species. They found that the part of the NPC1 receptor where Ebola virus attaches has evolved rapidly in bats–more quickly than in humans and other primates. This rapid evolution, the researchers concluded, was likely driven by a long-term co-evolutionary 'arms race' between bats and filoviruses. How long? "We discovered that a gene segment derived from a filovirus found its way into some bat genomes at least 25 million years ago," said Dr. Chandran. This is almost twice the timespan that bats were thought to have been exposed to filoviruses.
"Identifying potential animal reservoir hosts for Ebola virus will provide a crucial guide for public health prevention and response programs going forward," said Dr. Dye.
The study is titled "Filovirus receptor NPC1 contributes to species-specific patterns of ebolavirus susceptibility in bats." In addition to Dr. Chandran, Dr. Sawyer and Dr. Dye, other authors were: Melinda Ng, Esther Ndungo, Rohit Jangra, Ph.D. B.V.Sc & A.H., and Rohan Biswas, all at Einstein; Maryska Kaczmarek, John Hawkins, and Ann Demogines, Ph.D., all at University of Texas at Austin; Andrew Herbert, Ph.D., Ana Kuehne, and Rebekah James, all at USAMRIID; Tabea Binger and Marcel Müller, Ph.D., at University of Bonn Medical Center, Robert Gifford, Ph.D. at University of Glasgow, Meng Yu, Ph.D. and Lin-Fa Wang, Ph.D. at Duke-NUS Graduate Medical School; Thijn Brummelkamp, Ph.D., at Netherlands Cancer Institute, Christian Drosten, Ph.D. at German Centre for Infectious Diseases Research; and Jens Kuhn, Ph.D. at NIH's Integrated Research Facility at Fort Detrick.
This research was supported by grants from National Institutes of Health (AI101436, GM093086), the Defense Threat Reduction Agency (HDTRA1-11-C-0061, CB3948), EU FP-7 Antigone, EBOKON Project, and National Research Foundation Singapore. The authors report no conflicts of interest.
About Ebola Virus:
Ebola virus is notorious for killing up to 50 percent of the people it infects. Ebola virus disease–the severe, usually fatal disease that Ebola virus causes in humans and in nonhuman primates–was first documented in 1976 in villages along the Ebola River in the Democratic Republic of the Congo, Africa. The recent Ebola epidemic is the largest in recorded history, affecting multiple countries in Western Africa. Through December of this year, there have been over 28,000 total cases of the disease (including suspected, probable, and confirmed) and more than 11,000 deaths, according to the Centers for Disease Control and Prevention. There are no FDA-approved treatments or vaccines for Ebola virus disease.
About Albert Einstein College of Medicine
Albert Einstein College of Medicine is one of the nation's premier centers for research, medical education and clinical investigation. During the 2015-2016 academic year, Einstein is home to 731 M.D. students, 193 Ph.D. students, 106 students in the combined M.D./Ph.D. program, and 278 postdoctoral research fellows. The College of Medicine has more than 1,900 full-time faculty members located on the main campus and at its clinical affiliates. In 2015, Einstein received $148 million in awards from the National Institutes of Health (NIH). This includes the funding of major research centers at Einstein in aging, intellectual development disorders, diabetes, cancer, clinical and translational research, liver disease, and AIDS. Other areas where the College of Medicine is concentrating its efforts include developmental brain research, neuroscience, cardiac disease, and initiatives to reduce and eliminate ethnic and racial health disparities. Its partnership with Montefiore Medical Center, the University Hospital and academic medical center for Einstein, advances clinical and translational research to accelerate the pace at which new discoveries become the treatments and therapies that benefit patients. Through its extensive affiliation network involving Montefiore, Jacobi Medical Center — Einstein's founding hospital, and three other hospital systems in the Bronx, Brooklyn and on Long Island, Einstein runs one of the largest residency and fellowship training programs in the medical and dental professions in the United States. For more information, please visit http://www.einstein.yu.edu, read our blog, follow us on Twitter, like us on Facebook, and view us on YouTube.
About United States Army Medical Research Institute of Infectious Diseases
USAMRIID's mission is to provide leading edge medical capabilities to deter and defend against current and emerging biological threat agents. Research conducted at USAMRIID leads to medical solutions–vaccines, drugs, diagnostics, and information–that benefit both military personnel and civilians. The Institute plays a key role as the lead military medical research laboratory for the Defense Threat Reduction Agency's Joint Science and Technology Office for Chemical and Biological Defense. USAMRIID is a subordinate laboratory of the U.S. Army Medical Research and Materiel Command. For more information, visit http://www.usamriid.army.mil.
About University of Colorado-Boulder
Set in one of the world's most inspiring and entrepreneurial learning environments, the University of Colorado Boulder enables each member of our community to reach their potential and to Be Boulder through an extraordinary range of challenging academic, research and service opportunities. As Colorado's flagship university, we are proud to educate its future workforce, to contribute to its quality of life and to advance the economy, culture and health of Colorado, the nation and world. For more information, please visit http://www.colorado.edu.