By David Kelly
Featured Image Credit: Nexu Science Communication
The highly infectious and sometimes deadly Hepatitis C is transmitted via infected blood or blood products. Replicating well in the liver, it is the leading cause of liver disease worldwide. Despite killing 399,000 people annually, Hepatitis C is rarely accompanied by any obvious clinical symptoms.
Diagnoses often occur only six to twelve months after the infection. This triggers a low-level inflammatory response. These responses eventually cause fibrotic scarring of the liver. This non-functioning liver tissue results in a build up of toxins, often referred to as jaundice.
Jaundice, and other side-effects of liver fibrosis, are usually the first noticeable symptoms of Hepatitis C virus infections. However, by then there is often significant damage to the liver. While HCV is treatable with new medicines, early detection could prevent unnecessary damage.
The Normal Immune Response
A group of scientists, led by Nigel Stevenson, Assistant Professor in Immunology at Trinity, set out to understand how the virus avoids being discovered for months after infection.
Normally, our cells intercommunicate using molecules called cytokines. These molecules work by activating specific cascades of other molecules within our cells called signalling pathways. These signalling pathways trigger hundreds of molecules within our cells to increase inflammation and anti-viral activity.
This immune response kills and clears viral infections from our cells and bodies. However, uncontrolled inflammation is dangerous. Therefore, ‘Suppressor of Cytokine Signalling’ (SOCS) regulators are deployed to control and eventually shut down signalling pathways.
The Hepatitis C Ghost
The Trinity scientists discovered that the HCV abuses our immune response by triggering our SOCS regulators.
“We’ve discovered that HCV hijacks this regulatory process by causing the expression of SOCS in our cells. By increasing the expression of SOCS, HCV basically dulls the normal immune response to viral infection. Without a strong signal our body’s cells cannot then mount an effective inflammatory and anti-viral response that clears infection” explained Dr Stevenson.
“This ability shields HCV from our body’s normal, effective anti-viral immune response and creates a perfect environment in which to survive, replicate and infect other cells. Many diseases are mediated by increasing the inflammatory response to an inappropriately high level, but in this case, it is the lack of adequate inflammation that enables HCV to go undiagnosed, leaving it free to rapidly replicate and infect other cells.”
Dr Stevenson explained to HeadStuff that inhibiting the HCV-p7 protein reduces the induction of the SOCS regulator. Therefore, targeting this protein may be an efficient mechanism to restore the effective immune responses against HCV, especially in patients that do not respond to existing therapy.
“If chemists developed effective therapeutics that inhibit HCV-p7, these medicines might be useful in restoring effective immune responses against HCV” added Dr Stevenson.
The Trinity Immunologists
Dr Stevenson’s research aims to decipher the mechanisms by which pathogens target and evade immune responses. They have a specific interest in inflammatory and anti-viral pathways, such as the tumor necrosis factor alpha (TNF) and interferon (IFN)-alpha pathways, respectively.
Dysregulation of TNF production has been implicated in a variety of human diseases including Alzheimer’s disease, cancer, major depression, psoriasis and inflammatory bowel disease (IBD).
His research group investigates specific diseases such as HCV, HIV and Respiratory Syncytial Virus (RSV). RSV blocks immunity and is a major global problem affecting children and the elderly. There are no effective vaccines or therapeutics for this virus.
Tackling HIV’s Immunity
Last year, Dr Stevenson’s lab discovered a mechanism by which HIV evades the immune system, and which shows precisely how the virus avoids elimination. The new research shows that HIV targets and disables the Interferon signalling pathway, thus avoiding the immune response that is designed to cure viral infection.
“We discovered that HIV promotes the destruction of the anti-viral Interferon signalling pathway. Essentially, HIV uses the machinery in our own cells to do this, and the virus is thus able to reduce the production of many important anti-viral molecules. Without these anti-viral molecules, our immune system can’t clear viral infections” explained Dr Stevenson.
“Our new revelation sheds new light on how HIV avoids elimination, which, in turn, may explain why HIV is still not a curable disease. We feel this discovery could mark a paradigm shift in our understanding of how this virus evades our immune response. It should open the door to a new era of HIV research aiming to cure and eradicate this deadly virus.”