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Researchers Make Surprising Hepatitis A Discovery

SEP 21, 2016 | KRISTI ROSA
Researchers at the University of North Carolina at Chapel Hill have made an interesting discovery regarding hepatitis A (HAV). They found that contrary to previous hypotheses, the cause of liver inflammation from infection comes from an intrinsic response triggered within cells that are infected with the virus that essentially provokes them to self-terminate, according to a press release

Previous to this discovery, researchers attributed liver inflammation to be the result of immune system cells attacking infected cells within the liver.
Study author Stanley Lemon, MD, professor of medicine at UNC’s School of Medicine and UNC’s Institute for Global Health & Infectious Diseases, explained, “The virus evokes a response in the infected cell that activates a pre-programmed cell death pathway. In effect, the cell commits suicide, sacrificing itself along with the virus in an effort to save the host. This results in inflammation within the liver that we recognize as hepatitis.”
When speaking with Contagion on how they reached their discovery, Jason Whitmire, PhD, associate professor at the Carolina Vaccine Institute and Department of Genetics and study author explained, “We developed a new mouse model that supports HAV infection and recapitulates the clinical symptoms of HAV in humans, including acute liver damage. We found that type-1 interferons are highly restrictive for HAV. HAV has evolved mechanisms to inactivate the interferon induction pathway in humans but not in mice. We learned that we could infect mice when the interferon pathway was genetically inactivated.”
He continued, “Once we established this model, we were then able to ask how HAV results in acute liver damage. Previously, it was thought that acute hepatitis was caused by adaptive immune cells, such as virus-specific T cells and B cells. However, our new model revealed that hepatocytes respond to infection through a pathway involving proteins called MAVS and IRF3 that result in hepatocyte apoptosis. Thus, hepatocytes respond to infection by committing suicide in an effort to diminish overall virus burdens. If enough hepatocytes are infected and undergo cell-death, then liver functions could be compromised.”
Through findings such as these, researchers are able to acquire a better understanding of how the virus works. In addition to learning the cause of liver inflammation, UNC researchers teamed up with researchers at North Carolina State University to create an alternative animal model that mirrors how the virus functions in humans. For the first time, researchers found that HAV does not just occur in humans and primates, but can also occur in mice and guinea pigs, which suggests a “broader host range,” according to the study.
When speaking of the implications of this finding with Contagion, Dr. Whitmire commented, “We learned that interferons are a major barrier for HAV infection. The virus must avoid cellular sensors that initiate the interferon response. In human cells, HAV proteases efficiently inactivate key cellular proteins that induce interferons. However, HAV cannot cleave these cellular proteins in other species because of differences in their amino acid sequences. To jump species, the virus would have to evolve to recognize the divergent protein sequences and cleave them. This could happen naturally but is a high hurdle and probably happens very infrequently.”  
In future study, the researchers at UNC aim to take a closer look at both “innate” and “adaptive” immune system responses to gain a better understanding of the immune system’s role in fighting HAV, processes that currently remain unclear to hepatitis researchers for any of the hepatitis viruses, according to the press release.
Dr. Whitmore told Contagion, “We plan to continue to use this mouse model to explore how other molecular pathways contribute to liver injury and we will use this model to explore how adaptive immune responses lead to eventual HAV control. We anticipate that lessons learned in this model will inform about how other viruses of the liver cause disease.”
Hepatitis A is a highly contagious disease that can be transmitted by ingesting food or water that has been contaminated with the feces of an infected person or by coming into contact with an infected individual. The long incubation process of the infection paired with the fact that sometimes infected individuals might not even exhibit any of the common symptoms, can allow it to go untreated for a while, which can result in the virus being transmitted to a number of individuals. The best way to avoid this is to receive a HAV vaccine.
The fact that HAV can spread fairly quickly can result in outbreaks that can cost a substantial amount of money to quell. Such outbreaks of infection have been occurring throughout the United States in recent months, due to contaminated strawberries and scallops.
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