Prolonged Immune Signaling and ADHD: Exploring Links to Development and Symptoms

Viruses have existed in humans for thousands of years. They evolve to use human cells for replication. Some viruses can enter cells without causing symptoms.

The hepatitis A virus is highly contagious and causes severe liver inflammation. It spreads through close contact or contaminated food and water. Despite the availability of an effective vaccine since the 1990s, there have been 45,000 confirmed cases in the U.S. since 2016, resulting in 424 deaths.

Researchers have studied the hepatitis A virus to understand how it works. Dr. Stanley M. Lemon, a professor at UNC School of Medicine, has focused on positive-strand RNA viruses since the 1980s.

“Hepatitis A virus knows how liver cells operate better than we do,” said Lemon. By studying this virus, scientists learn about cell responses, the immune system, and aspects of cancer.

A Newfound Infection Partner

Lemon’s recent research explored how hepatitis A virus enters liver cells and hijacks their machinery for replication.

Along with his team, Lemon discovered a protein called PDGFA-associated protein 1 (PDAP1) that hepatitis A virus uses to replicate and infect liver cells. Their findings were published in Science Advances.

The researchers identified PDAP1 through a CRISPR screen targeting over 19,000 human genes. They found PDAP1 played a significant role in the virus’s ability to replicate.

PDAP1 had no known function, but previous studies suggested links to gastrointestinal cancers and glioblastomas. One study indicated that PDAP1 helps immune cells manage stress, which piqued the researchers’ interest.

Exploiting the Liver’s Stress Response

The “integrated stress response” helps cells cope with stress by maintaining minimal function until recovery. Liver cells experience stress when their metabolism falters or when they become infected. They reduce protein production and focus on a few survival proteins.

Researchers found that hepatitis A virus exploits this protein production to make its own proteins after infecting liver cells.

To study PDAP1’s role, the team removed it from liver cells using CRISPR-Cas9 and also deleted it in a mouse model. Liver cells without PDAP1 could not support virus replication, and the mice were resistant to infection.

This revealed that without PDAP1, the virus could not use the stress response for its advantage.

PDAP1, Infectious Diseases, and Cancer

With new insights into PDAP1’s role, Lemon anticipates that cell biologists will explore it further, especially regarding protein production and cell survival during stress.

The integrated stress response regulates cellular fate, influencing cell survival and death. Cancer cells often manipulate this response to grow. Studying how viruses operate can provide insights into the cellular mechanisms involved in infectious diseases and cancer.

Reference: Shirasaki T, Lenarcic E, Misumi I, et al. Hepatovirus translation requires PDGFA-associated protein 1, an eIF4E-binding protein regulating endoplasmic reticulum stress responses. Sci Adv. 2024;10(47):eadq6342. doi: 10.1126/sciadv.adq6342