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SDSU researchers to examine how influenza D infects cells

Chithra Sreenivasan examining guinea pig tracheal and lung tissue
Postdoctoral research associate Chithra Sreenivasan successfully isolated antigens in tracheal and lung tissues to prove that the guinea pig could be used as an animal model to study the virus as part of her doctoral work. She is part of a South Dakota State University research team, led by Professor Feng Li, that will investigate how influenza D infects cells to evaluate the likelihood of the virus becoming a risk to humans through a five-year, $2.6 million National Institutes of Health Research Project grant.

The SDState research team that discovered the influenza D virus will continue its work through a five-year, $2.6 million National Institutes of Health Research Project grant. The work will focus on how influenza D infects cells to evaluate the likelihood of the virus becoming a risk to humans.

“This helps us maintain our momentum,” said Professor Feng Li, a virologist in the Department of Biology and Microbiology in the College of Natural Sciences. He leads a research team that includes Professor and Assistant Department Head Radhey Kaushik and Assistant Research Professor Dan Wang. Two postdoctoral research associates and three graduate students also work on the project.

Li and his group will also collaborate with Emory University Professor of Pediatrics and Infectious Diseases Gregory Melikian, who will investigate the path of the virus after it enters the cell using real-time single virus tracking imagery.

Hieshi Yu prepares to do plasmid extraction
Jieshi Yu prepares to do a plasmid extraction to examine how the influenza D binds to receptors on the cell membrane.

“Humans do not have pre-existing immunity to influenza D. That is why we need to know how the virus replicates—it will give us a target for the development of a vaccine as well as antivirals,” Li explained.

“It is the foundational work that Dr. Li and his group have done that led to them receiving this NIH RO1 grant,” Kaushik said. “This grant signifies the importance of the virus and gives the SDSU team national and international recognition.” The RO1 grant allows researchers to apply for a continuation award during the final year of the project.

Li acknowledged the contributions of doctoral students Jieshi Yu and Runxia Liu, now a postdoctoral researcher at Yale, and Chithra Sreenivasan, now a postdoctoral research associate at SDSU, for generating the data for the grant application.

Assessing exposure to virus

The SDSU researchers originally isolated the influenza D virus from a diseased pig in 2011, but later found that cattle were the primary reservoir. “Influenza had never been found in cattle before,” said Li, who also does research through the South Dakota Biosystems Networks and Translational Research and Center for Biologics Research and Commercialization.

SDSU alumnus Ben Hause,now vice president of research, development and diagnostics at Cambridge Technologies in Minnesota, identified and characterized those two lineages of the virus as part of his doctoral research under Li’s tutelage. One lineage lives only in cattle, while the other spreads to both cattle and pigs.

Through a previous National Institutes of Health grant, the research group identified influenza D antibodies in goats, sheep and horses in the Midwest and proved that the guinea pig can serve as an animal model to study the virus. The group published 10 papers based on these discoveries.

“Finding antibodies [in the blood] does not mean the virus is causing disease, but that the animals are being exposed to the virus,” Kaushik said. “Influenza D itself does not seem to produce severe clinical symptoms, but in association with other bacterial and viral agents, it can be part of a respiratory disease complex.”

In 2016, the International Committee of Taxonomy of Viruses officially announced a new genus, Orthomyxovirdae, with a single species, Influenza D virus, because of its distinctness from other influenza types—A, B and C.

Determining how virus enters cells

“Influenza D has not been shown to be pathogenic in humans, so no one should be afraid. However, we need to know more about the virus, so we can be ahead of it should it become a threat to humans,” Kaushik explained. Several small studies have found influenza D antibodies in blood samples from humans, many of whom work closely with animals.

“This award will allow us to answer questions regarding chemical and molecular details about the virus, including its interaction with the host,” Li said. “When a virus adapts itself to pigs, it is a wake-up call that this virus may have some features that may allow it to cross species and affect humans.” The 2009 influenza pandemic, for instance, involved a strain that originated from pigs.  

To get into a cell, the virus must first attach to a receptor on the cell membrane. “Each virus attaches to specific types of glycoproteins—sugar molecules attached to a protein backbone—on the cell surface,” Kaushik said. The glycoprotein is the bait that fools the cell into engulfing the virus.

Influenza viruses bind to specific receptors on the glycoproteins. These receptors are different in humans and animals. However, preliminary investigations show influenza D can bind to the receptor that human influenza C uses as well as to nonhuman receptors, Wang explained. The researchers will compare the two influenza D lineages to ascertain “what is the virus determinant that might enable the virus to jump from pig or cattle to humans.”

Furthermore, a previous study showed that influenza D can withstand high temperatures and acidic environments. “It is the most stable of the four influenza viruses,” Wang said. “If influenza D would one day jump from animals to humans, influenza could potentially become a year-round health problem.”

The work performed through this grant will help the researchers understand the molecular basis of influenza D transmission, its pathogenesis in different species and its clinical importance, if any, Kaushik explained. “It will pave the path to devising strategies to control virus transmission in different animal species and in humans.”