Hepatitis C virus hides in the immune system increasing the expression of SOCS


Scientists from Trinity College Dublin have discovered how the highly infectious and sometimes deadly Hepatitis C virus (HCV) “ghosts” our immune system and remains undiagnosed in many people.

They report their findings in the international FASEB journal.

HCV’s main route of transmission is via infected blood but over the past 40 years, it has accidentally been given to many patients across the world via infected blood products.

The virus replicates particularly well in the liver, and the damage it causes makes it a leading cause of liver disease worldwide.

Even though HCV can be deadly, initial infection is rarely accompanied by any obvious clinical symptoms for reasons that have – until now – remained unknown.

As a result, it often goes undiagnosed for the first 6-12 months following infection.

If left untreated HCV spreads throughout the liver, stimulating a low-level inflammatory response.

Over several months, these mild responses – accompanied by subsequent liver repair – result in fibrotic scarring of the liver.

The liver’s main job is to filter out toxins, but during HCV infection the build-up of fibrotic, non-functioning liver tissue, results in reduced liver function.

Without a fully functioning liver, one major side-effect is the build-up of toxins, often referred to as “jaundice”.

If patients do not realise they are infected with HCV, their first noticeable symptoms are the side-effects of liver fibrosis (such as jaundice).

While the majority of HCV infections are now treatable with new medicines, early detection would avoid the damaging progression to liver disease.

Therefore, a group of scientists led by Assistant Professor in Immunology at Trinity, Nigel Stevenson, set out to understand how the virus avoids being discovered for months after infection.

HCV suppresses the immune response

Under normal circumstances, our cells communicate with each other with molecules called cytokines, which work by activating specific cascades of other molecules within our cells called signalling pathways.

These cytokines and their signalling pathways trigger the expression of hundreds of molecules within our cells to increase inflammation and anti-viral activity.

This immune response is capable of killing and clearing viral infections from our cells and bodies.

Uncontrolled inflammation would be dangerous, however, so to ensure our immune response to infection is appropriately regulated, several cytokine signalling pathways are controlled by immune regulators called “Suppressor Of Cytokine Signalling (SOCS)” regulators.

After a period of time following an initial response, pro-inflammatory cytokine signalling pathways are shut down by SOCS.

This is a computerized drawing of the Hep C virus

The Hepatitis C Virus (HCV), circulating in the blood before it infects cells. The image is credited to Nexu Science Communication.

The Trinity scientists found that HCV “ghosts” our immune response, by triggering our own SOCS regulators; a specific part of the virus is responsible for increasing a specific SOCS molecule – in both liver and immune cells.

Dr Stevenson said: “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 the infection.”

“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.”

TNF‐α is an important proinflammatory cytokine produced in response to infection.

Excess levels of TNF‐α are implicated in a range of inflammatory conditions, including rheumatoid arthritis, septic shock, inflammatory bowel disease, and viral hepatitis [13].

A key role for TNF‐α in the pathology associated with chronic inflammation is emphasized by successful targeting of arthritis and inflammatory bowel disease with therapeutic anti‐TNF‐α [4].

The effects of TNF‐α are mediated through TNFR1 and TNFR2, leading to proliferation, inflammation, and apoptosis [5].

Upon receptor binding, TNF‐α signals through a variety of cytosolic proteins, including TRADD [6] and TRAF2 [7], leading to IκB degradation and the subsequent release and nuclear translocation of NF‐κB.

Binding of NF‐κB to gene promoters initiates transcription of numerous proinflammatory cytokines, including IL‐6, IL‐8, TNF‐α, and CXCL‐10 [89].

Interestingly, CXCL‐10 can also be induced by TNF‐α via the MAPK pathway [10].

TNF‐α signaling is known to be regulated by the deubiquitinating enzyme, A20, which removes Lys‐63‐linked, nondegradative ubiquitin chains from the receptor‐interacting protein and promotes its Lys‐48‐linked polyubiquitination, thus targeting it for proteasomal degradation [11].

However, unchecked TNF‐α signaling results in chronic inflammation, cell death, and tumorigenesis, as demonstrated in A20‐deficient mice [12].

Whereas ubiquitination is a critical regulatory mechanism of the TNF‐α pathway, it is likely that this essential proinflammatory cytokine pathway is controlled by other unknown mechanisms to ensure an appropriate response to infection.

SOCS, a family of eight inhibitory intracellular proteins (CIS and SOCS1–7), are rapidly induced in response to numerous cytokines and microbial products, including IFN‐γ, growth hormone, IL‐2, fMLP, and LPS [1315].

SOCS act in a negative‐feedback loop to regulate inflammatory responses and were discovered initially as inhibitors of the JAK/STAT pathway but are increasingly believed to regulate other pathways [1617].

Many patients (50–85%) fail to clear HCV, resulting in chronic infection [18].

Acute HCV disease progression is mediated by the expression of proinflammatory cytokines, such as IL‐8, IL‐6, and TNF‐α; however, significant pathology is uncommon in these patients, meaning that infection often remains undetected for many years [1920].

The mechanism by which pathology is limited during HCV infection is unknown.

A role for SOCS proteins during HCV infection has been suggested [2124], which led us to investigate whether HCV‐induced SOCS could regulate proinflammatory cytokine induction, thus contributing to the mild pathology associated with HCV infection [25].

In this study, we demonstrate that SOCS1 and SOCS3 are induced by TNF‐α and inhibit its NF‐κB signal transduction.

We also found that SOCS3 levels are elevated in PBMCs from HCV‐infected patients, which may be responsible for the observed reduction in TNF‐α‐mediated IκB degradation and proinflammatory cytokine production.

Furthermore, HCV induced SOCS3 in Huh7 hepatocytes, which directly inhibited TNF‐α‐induced, proinflammatory IL‐8 expression, possibly by blocking the NF‐κB pathway through direct association with TRAF2.

These findings suggest a novel mechanism by which HCV suppresses inflammatory responses, possibly explaining the mild pathology often associated with acute HCV infection.

Media Contacts: 
Thomas Deane – TCD
Image Source:
The image is credited to Nexu Science Communication.

Original Research: Closed access
“The hepatitis C virus (HCV) protein, p7, suppresses inflammatory responses to tumor necrosis factor (TNF)-α via signal transducer and activator of transcription (STAT)3 and extracellular signal-regulated kinase (ERK)–mediated induction of suppressor of cytokine signaling (SOCS)3”. Orla Convery, Siobhan Gargan, Michelle Kickham, Martina Schroder, Cliona O’Farrelly, and Nigel J. Stevenson.
FASEB Journal. doi:10.1096/fj.201800629RR


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