Researchers Unearth Gatekeepers To Hepatitis A Virus Infection Of Human Cells

There has been no clue about how hepatitis A virus manages to enter a person’s liver cells and cause an infection. The researchers at the University of North Carolina School of Medicine have now solved this mystery.

The research team designed experiments using gene-editing tools and revealed that the molecules called gangliosides to act as gatekeepers to permit the entry of the virus into the liver cells of the host.

Their findings demonstrated that gangliosides are key players in the hepatitis A virus (HAV). They also revealed how the viral RNA transitions between different compartments in the liver cells of human beings replicate and cause an infection.

Gangliosides are molecules that are found ubiquitously in bodily fluids and tissues.

“Discovering that gangliosides are essential receptors for HAV infection adds an interesting plot twist to the hepatitis A story. Gangliosides are structurally similar across mammalian species, unlike proteins, which help explain the cross-species transmission of ancient hepatoviruses. Understanding what helps a virus jump from one animal species to another is incredibly important, as evidenced so plainly by the current COVID-19 pandemic,” senior author Stanley Lemon, MD, professor of medicine and microbiology at the UNC School of Medicine and member of the UNC Institute for Global Health and Infectious Diseases told EurekAlert.

The hepatitis A virus was discovered nearly five decades ago. Though there is a vaccine, there isn’t any way to treat it. The virus infects over 1.4 million individuals throughout the world every year and in the last few years, an increasing number of HAV cases are reported in the U.S. and some of them have been fatal.

HAV infects individuals via mechanisms similar to that of other viruses. It interacts with the receptor molecules on the surface of the host cells and enters it.

Determining the receptor for a virus not only helps researchers understand how it enters the host, but also paves the way towards developing antivirals and drug molecules that can block the interaction to prevent or treat the disease.

Among the five different hepatitis viruses discovered so far, researchers have identified the receptors for hepatitis C virus and hepatitis B virus only. The receptor for HAV remained elusive until now since it uniquely existed in two different modes namely the nonenveloped viruses (nHAV) and the quasi-enveloped viruses (eHAV). While the former type comprised of a protein shell surrounding an RNA genome, the latter had capsids containing the viral genome that were cloaked withing the host cell membranes.

Once the HAV enters the liver, eHAV gets released from infected liver cells to circulate in the blood. But the nHAV particles get shed in the feces. Both of these are equally infectious.

The researchers found that the gene ‘UGCG’ which coded for gangliosides was the lead culprit. When they knocked out this gene, they could prevent HAV infection. They could also treat liver-derived cells with a chemical inhibitor that prevented HAV infection.

"This means gangliosides are essential for a late-step entry of HAV into cells. They function as true receptors,” Anshuman Das, Ph.D., a postdoc in the Lemon lab at the time of this research and now at Duke University told EurekAlert.