The Identification of a Circovirus implicated in Human Hepatitis

The Identification of a Circovirus implicated in Human Hepatitis

Hepatitis is a term used to describe liver inflammation that can be caused by a variety of factors, including viral infections. Hepatitis viruses A, B, C, D, and E are the most common viruses associated with human hepatitis. These viruses are members of different viral families, each with its own set of characteristics and modes of transmission.

Researchers from the Institut Pasteur, Necker-Enfants Malades Hospital (AP-HP), Inserm in the Imagine Institute, Université Paris Cité, and the Alfort National Veterinary School (EnvA) have discovered a previously unknown species of circovirus known as human circovirus 1 (HCirV-1).

Circoviruses are a group of small, highly resistant DNA viruses discovered in 1974 in a variety of animal species, where they can cause respiratory, renal, dermatological, and reproductive problems. HCirV-1 is a novel virus that is not related to any known animal circoviruses. It was discovered to be involved in liver damage in a patient receiving immunosuppressive treatment. The journal Emerging Infectious Diseases published the discovery of the first circovirus in humans, which was linked to hepatitis.

Although the transmission of animal viruses to humans is frequently reported in the scientific literature, it is uncommon to find a novel virus in a patient in Europe. But as part of a recent study, scientists and physicians have identified the first circovirus involved in human hepatitis.

The patient was diagnosed with unexplained chronic hepatitis with few symptoms. We had access to a large number of samples over a number of years and were thus able to identify this novel virus, which was completely unexpected.

Marc Eloit

“The patient was diagnosed with unexplained chronic hepatitis with few symptoms.” She had a heart-lung transplant 17 years before and had been closely monitored ever since. “We had access to a large number of samples over a number of years and were thus able to identify this novel virus, which was completely unexpected,” explains Marc Eloit, the study’s last author, Head of the Institut Pasteur’s Pathogen Discovery laboratory, and Professor of Virology at the Alfort National Veterinary School (EnvA). His laboratory specialises in pathogen identification in patients suspected of having a severe infection of unknown origin.

In March 2022, in collaboration with the Department of Clinical Microbiology at Necker-Enfants Malades Hospital (AP-HP), the pathological tissue samples of this 61-year-old female patient receiving immunosuppressive treatment, whose hepatitis had no identifiable cause, were sequenced to search for microbial sequences. The RNA (ribonucleic acid) sequences extracted from the tissues were analyzed and compared with those of known microbes.

“The aim is to identify sequences of interest among all the sequences obtained, which is like searching for a needle in a haystack!” continues the scientist Marc Eloit. These thousands of RNA sequences were analyzed in parallel using mNGS (metagenomic next-generation sequencing) high-throughput sequencing techniques and sophisticated algorithms. After ruling out common etiologies, the analysis led to the identification of a previously unknown species of circovirus, provisionally named human circovirus 1 (HCirV-1). No other viral or bacterial sequence was found.

Discovery of a circovirus involved in human hepatitis

The role of HCirV-1 in hepatitis was then demonstrated by analyzing samples taken from the patient during her post-transplant treatment in previous years. The findings revealed that the HCirV-1 viral genome was undetectable in blood samples from 2017 to 2019, then peaked in September 2021. The virus replicated in liver cells (2 to 3% of liver cells were infected), pointing to the virus’s role in liver damage: once the virus has used the resources in the liver cell to replicate, it destroys the cell.

Following antiviral treatment, the patient’s liver enzymes returned to normal levels beginning in November 2021, indicating the end of hepatic cytolysis.

Diagnosis of unknown aetiology hepatitis remains a major challenge, as evidenced by cases of acute hepatitis reported in children in the United Kingdom and Ireland last April and reported to WHO. “In order to offer appropriate treatment and effectively monitor patients, we need to know the cause of the hepatitis, particularly whether or not it is viral.” “The identification of this novel virus that is pathogenic in humans, as well as the development of a test that can be performed by any hospital laboratory, provides a new tool for diagnosing and monitoring patients with hepatitis,” says Anne Jamet of Necker-Enfants Malades Hospital (AP-HP), who is also affiliated with Inserm and co-last author of the study.

Although some circoviruses are pathogenic to animals and vaccines can be given, particularly to pigs, this is the first known circovirus that is pathogenic to humans. The patient’s symptoms remained mild, and the virus was identified because she was closely monitored after her combined transplant. The virus’s origin, whether it is circulating in humans or in animals, has yet to be determined, as has the source of infection (contact, food, etc.). Following their discovery, the scientists created a specific PCR test that is now available for the etiological diagnosis of unknown hepatitis. A serological test is also in the works.

“These findings demonstrate the utility of this type of sequencing analysis in detecting novel or unexpected pathogens.” Clinicians must always know whether or not an infection is viral in order to tailor treatment accordingly. It is also critical to be able to identify a novel pathogen when an infection is unexplained and to develop a diagnostic test, because any new case of human infection with an emerging pathogen could potentially signal the start of an outbreak,” Marc Eloit concludes. The test is now available to the medical community and can be used to diagnose other cases of unexplained hepatitis.