Scientists from Institut Pasteur, Necker-Enfants Malades Hospital (AP-HP), Inserm im Imagine Institute, Université Paris Cité and Alfort National Veterinary School (EnvA) have identified a previously unknown species of circovirus tentatively named Human Circovirus 1 (HCirV-1). Circoviruses are a family of small, highly resistant DNA viruses first identified in various animal species in 1974, where they can cause respiratory, kidney, skin and reproductive problems. HCirV-1 is a novel virus far removed from known animal circoviruses. It has been shown to be involved in damage to the liver of a patient undergoing immunosuppressive treatment. This discovery of the first human circovirus implicated in hepatitis was published in the journal Emerging infectious diseases on January 3, 2023.
Although transmission of animal viruses to humans is regularly reported in the scientific literature, it is rare for a novel virus to be identified in a patient in Europe. But in a recent study, scientists and doctors have identified the first circovirus implicated in human hepatitis. “The patient had unexplained chronic hepatitis with few symptoms. She had received a heart-lung transplant 17 years ago and has been monitored regularly ever since. We had access to a large number of samples over several years and were therefore able to identify this novel virus, which was completely unexpected,” explains Marc Eloit, senior author of the study, head of the Pathogen Discovery Laboratory at the Institut Pasteur and Professor of Virology at Alfort National Veterinary School (EnvA) Its laboratory specializes in identifying pathogens in patients suspected of having a serious infection of unknown origin.
In March 2022, in collaboration with the Department of Clinical Microbiology of Necker-Enfants Malades Hospital (AP-HP), the pathological tissue samples of this 61-year-old patient on 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 to those of known microbes. “The aim is to identify interesting sequences among all the sequences obtained, it’s like looking for a needle in a haystack!” continues scientist Marc Eloit. These thousands of RNA sequences were analyzed in parallel using mNGS high-throughput sequencing techniques (next-generation metagenomic sequencing) and sophisticated algorithms. After excluding common etiologies, the analysis led to the identification of a previously unknown circovirus species tentatively named Human Circovirus 1 (HCirV-1). No other viral or bacterial sequence was found.
The involvement of HCirV-1 in the hepatitis was then demonstrated by analysis of samples taken from the patient at earlier years as part of her post-transplant treatment. The results showed that the HCirV-1 viral genome was undetectable in the blood samples from 2017 to 2019, then its concentration peaked in September 2021. Viral replication in liver cells was demonstrated (2 to 3% of liver cells were infected), suggesting the role of HCirV-1 in liver damage: once the virus has used the resources in the liver cell to replicate, it destroys the cell.
As of November 2021, the patient’s liver enzymes returned to normal levels after antiviral treatment, indicating the end of hepatic cytolysis.
The diagnosis of hepatitis of unknown etiology remains a major challenge, as demonstrated by the cases of acute hepatitis in children reported last April in the United Kingdom and Ireland and reported by the WHO. “We need to know the cause of hepatitis, and specifically whether it is viral or not, in order to provide appropriate treatment and effectively monitor patients. The identification of this novel virus, which is pathogenic to humans, and the development of a test that can be performed by any hospital laboratory, offers a new tool to diagnose and monitor patients with hepatitis,” emphasizes Anne Jamet of the Department of Clinical Microbiology at Necker -Enfants Malades Hospital (AP-HP), which is also affiliated with Inserm and co-senior author on the study.
Although some circoviruses are pathogenic to animals and vaccines can be administered, particularly in pigs, this is the first known circovirus pathogenic to humans. The patient’s symptoms remained mild; the virus was identified because she was closely monitored after her combined transplant. The origin of the virus – whether it is circulating in humans or of animal origin – has yet to be identified, and the source of infection (contact, food, etc.) remains unknown. Following their discovery, scientists developed a specific PCR test that is now available for the etiological diagnosis of hepatitis of unknown origin. A serological test is also being developed.
“These results demonstrate the value of this type of sequence analysis in identifying new or unexpected pathogens. It is always important for clinicians to know whether an infection is viral or not so that they can adjust treatment accordingly. It is also crucial to be able to identify a new pathogen when an infection remains unexplained and to develop a diagnostic test, as each new case of human infection with an emerging pathogen potentially signals the beginning of an outbreak.” , concludes Marc Eloit.The test is now available to the medical community and can now easily be used in other cases of unexplained hepatitis.