Turning Bat Genes Into Future Vaccines

Courtesy Photo | Heatmaps representing the members of the top set of genes in I interferon (IFN) induction (left), IFN response (middle) and antioxidative response (right) signalling pathways in A549 cells 96 h.p.i. with hRSV NS1 WT or mutant proteins. (Image from Ekaterina Esaulova, Maxim N. Artyomov and Daisy W. Leung)  

FORT BELVOIR, VA, UNITED STATES

10.10.2017

Courtesy Story

Defense Threat Reduction Agency's Chemical and Biological Technologies Department

Bats are the only mammal that can naturally sustain flight. In addition to this interesting ability, their immune response can thwart viruses that infect humans, making them an asset in vaccine development for the Department of Defense. Funded by the Defense Threat Reduction Agency’s Chemical and Biological Technologies Department, researchers are using differential gene expression (DGE) to identify differences in human and bat immune response, which will have future uses for public health and warfighter protection.

Suspected of being the reservoir of Ebola and Marburg filoviruses in the wild, bats seem to be asymptomatic or subclinical carriers of these viruses. Gaya Amarasinghe, Ph.D., from Washington University in St. Louis, and Christopher Basler, Ph.D., from Georgia State University, are using DGE to explore what property in the bat’s immune system protects them from virulence and the difference in human response.

To do so, Amarasinghe and Basler used the DGE method to discover how the respiratory syncytial virus (RSV) modulates gene expression in infected cells and evades the immune system. RSV usually causes cold-like symptoms in healthy adults; however, those with a weakened immune system, such as children and the elderly, may suffer serious complications or even death. While RSV is not an immediate threat to our warfighters, it is a public health concern and provides a model to mimic filovirus evolution.

People with weakened immune systems have difficulty fighting RSV because the virus “fights back.” Scientists have long known that a non-structural protein, NS1, present in the virus particle is key to the virus’s ability to evade the host immune response, but were unclear how it physically interacted with the hosts’ immune system.

“One of the surprising things we found [by using DGE] was that this protein does not target just one set of genes related to the immune response, but it globally modulates the immune response,” said Amarasinghe.

DGE can be used to identify immune response genes that are expressed after cells are infected with a virus mutated at a known site. Higher and lower expression of the immune response genes are depicted in a heat map, where dark red indicates enhanced expression and dark blue indicates suppressed expression when compared to infection by a virus.

Basler utilized these heat maps to demonstrate that filovirus proteins can successfully suppress activation of human immune response. Alternatively, in bat cells there is a robust innate immune response to the infection, which results in lower virulence without completely blocking virus replication.

The researchers used X-ray crystallography to solve the three-dimensional structure of the NS1 protein. An analysis of the resulting structure suggested that a region known as the alpha 3 helix might be critical for immune response suppression.

One hypothesis involved replacing the NS1 protein in the virus with mutant versions and then using DGE to test the mutated virus’ ability to modulate the immune response genes. The resulting heat maps of RSVs carrying mutations in the alpha 3 helix differed from those of the wild type.

This suggests the mutant RSVs may no longer be capable of suppressing the body’s immune response in order to give the virus a better chance of surviving and replicating. The researchers concluded that future RSV vaccines or treatments that target the alpha 3 helix to prevent immune suppression may help those with weakened immune systems.

Understanding how the RSV modulates gene expression in infected cells to evade the human immune response will assist in future vaccine development for warfighter safety. In addition, this effort demonstrates how DTRA-funded methods developed for biodefense can be applied to public health.

For additional information, visit the Nature Microbiology article, “Structural Basis for Human Respiratory Syncytial Virus NS1-Mediated Modulation of Host Responses.”

POC: Ashley Triplett, Ph.D.; [e-mail]

• Date Taken: 10.10.2017
• Date Posted: 10.10.2017 15:17
• Story ID: 251116
• Location: FORT BELVOIR, VA, US