Study examines how dangerous respiratory viruses circumvent body’s defenses

May 20, 2014
 
Researchers at the University of North Carolina at Chapel Hill are studying how some of the most dangerous viruses on the planet tailor their defenses to get around the body’s immune system.

The study, published online May 20 in mBio, the journal of the American Society for Microbiology, could contribute to a better understanding of how viruses such as H5N1 bird flu, the H1N1 flu, SARS and MERS viruses work to fool the body’s disease defenses. The study garnered immediate worldwide attention.

Dr. Ralph Baric

Ralph S. Baric, PhD, professor of epidemiology at the UNC Gillings School of Global Public Health and of microbiology and immunology in the School of Medicine, and his fellow researchers, several from UNC’s epidemiology department, compared host responses to such infections as severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV).

Using comparative systems biology analysis combined with experimental validation, the study identified strategies employed by the viruses to mislead interferon-stimulated genes (ISGs), the body’s first line of defense against viruses, into altering their responses to infections or delaying reactions to the diseases.

The study keyed on ISGs because they produce an antiviral response that regulates and fights pathogens, stimulates adaptive immune responses and wound repair. When these viruses interfere with the ISG response, they have a better chance of gaining a foothold in the body by establishing themselves before the body can react.

“Our data suggest an entirely new mechanism by which highly virulent respiratory viruses garner control of critical host defense programs to increase virus replication during infection” Baric said.

The data also spotlighted the ability of both SARS-CoV and MERS-CoV to inhibit recognition, delay interferon induction and sequester ISG production to try to neutralize the innate immune response.

Researchers used computers and empirical studies at UNC and the University of Wisconsin to gain insights into the viral mechanisms for manipulating and controlling ISG responses. For example, in cases where H1N1 virus provoked an immediate response by the body’s ISG, SARS was able to delay reaction by ISG and thereby establish itself more firmly in the host, making itself much more difficult to eradicate. Both MERS and H5N1 modify ISGs in a similar manner, illustrating similarities between these two highly lethal viruses, which cause mortality rates between 40 and 50 percent. MERS-CoV infections recently have increased dramatically in the Middle East, and three cases have appeared in the U.S.

The findings highlight strategies that highly pathogenic viruses use to control the host antiviral state. In each case, the strategy contributes to successful infection and may explain differences in virulence seen between viral families and strains.

“Understanding these strategies and how the viruses manipulate the body’s defenses can be another weapon in the fight against these deadly diseases,” said lead author Vineet D. Menachery, PhD, postdoctoral fellow in epidemiology at the Gillings School. “By systemically comparing these highly pathogenic viruses and how they manipulate the immune response, we can identify common pathways they utilize and design therapeutics with broad impact.”

UNC co-authors, in addition to Baric and Menachery, include Alexandra Schafer, PhD, Amy C. Sims, PhD, Lisa E. Gralinski, PhD, and Casey Long, BS.