Increasing evidence suggests that rat hepatitis E virus infects humans more frequently than is realized, raising urgent questions about diagnosis, transmission, and the true global burden of this overlooked infectious disease.
Research: Rocahepevirus ratti: molecular evolution, zoonotic potential and public health implications. Image credit: Rudmer Zwerver / Shutterstock
Recent research published in journals nature communications Rat hepatitis E virus (ratHEV, Rocahepevirus Latti) Ecology, molecular virology, host range, and clinical impact.
Hepatitis E is a well-known cause of acute hepatitis, with 19.5 million cases annually, and its clinical entity was considered synonymous with hepatitis E virus (HEV) infection. HEV is currently classified as Pasulahepevirus balayani in the Hepeviridae family. Other members of the Hepeviridae family were thought to be strictly host-restricted and not involved in human disease. However, this assumption was called into question in 2018 when human infections with Rocahepevirus species were confirmed.
Initially thought to be restricted to rodents, ratHEV remained largely ignored until the first human case was detected in a liver transplant patient with chronic hepatitis of unknown origin in Hong Kong. Active surveillance and retrospective analysis have since confirmed additional cases in Asia and Europe, with cases reported in Canada, revealing ratHEV as a zoonotic virus and prompting a reconsideration of the disease situation. In this study, researchers summarized the ecology, host range, virology, and clinical impact of ratHEV.
RatHEV taxonomy and molecular virology
of rocahepe virus There are two species in the genus within the subfamily Orthohepeviridae of the family Hepeviridae. rocahepevirus eotenonomy and R. Rat (ratHEV). Unassigned or putative rocahepevirus-like viruses have been reported in rodents from South America and Asia. There are five RatHEV genotypes (C1-C5). The C1 genotype circulates in shrews and rats, whereas the C2 genotype is restricted to mustelids (mink and ferrets). Current evidence suggests that genotype C1 is the main lineage with zoonotic potential, whereas C2–C5 appear to have negligible zoonotic potential.
RatHEV is a positive-sense, single-stranded ribonucleic acid (RNA) virus with a 6.6 kb to 7 kb genome that encodes three canonical open reading frames (ORFs). ORF1 encodes a nonstructural polyprotein with RNA-dependent RNA polymerase (RdRp), helicase, and methyltransferase domains. ORF2 encodes the capsid and ORF3 encodes a small phosphoprotein. Genomic analysis showed that ratHEV is substantially different from HEV throughout the ORF.
RatHEV epidemiology and interspecies transmission
ratHEV is widespread in synchronous rat populations and has been detected in black rats, Norway rats, and other species in Asia, Europe, and North America. The prevalence of ratHEV RNA in captive rats ranges from 10% to 30%, with higher prevalence in urban than in rural habitats and in subtropical Asia and southern Europe than in northern temperate regions. Detection of ratHEV in other rodent species is rare.
Occasionally, genotype C1 infections have been recorded in carnivores, almost certainly reflecting environmental contamination or accidental exposure. Domestic pigs are the only non-rodent mammals that exhibit active replication of rat HEV, and viral RNA has been detected in blood and feces, suggesting that pigs may be a temporary host. The review also mentions the detection of genotype C1 in birds of prey and experimental susceptibility in chickens, but their role in natural infection remains unclear. Serological studies have shown evidence of human exposure to ratHEV in Asia and Europe.
In Asia, seroprevalence ranges from less than 1% in urban areas to 22% in rural China, with higher rates associated with rodent contact, older age, and rural residence. In Europe, high seroprevalence rates have been observed among forestry workers and individuals experiencing homelessness. Most infections have been reported in China and Spain, with sporadic cases also found in France, Canada, Germany and Thailand.
Diagnosis, treatment and prevention of RatHEV
Diagnosis of ratHEV infection remains difficult due to the lack of commercially available assays and limited validation of available protocols. Detection of viral RNA is the only reliable marker of active infection. Therefore, molecular testing remains important for patients with cryptogenic hepatitis. The available primer sets do not match all RatHEV clusters, making multiple quantitative polymerase chain reaction (qPCR) protocols the most reliable screening method.
Antibody-based assays serve only an epidemiological role. Cross-reactivity with HEV-specific antibody assays has been reported in 10% to 70% of immunoglobulin G (IgG) samples and 20% to 40% of immunoglobulin M (IgM) samples. Notably, detection of ratHEV-specific IgM was anecdotal, with only three cases, all showing partial HEV cross-reactivity. Therefore, IgG reactivity remains the most reliable evidence of previous exposure.
RatHEV infection follows a clinical course similar to HEV, ranging from subclinical infection to acute hepatitis. In some cases, it may lead to fulminant liver failure and death. In immunocompromised populations, infection can persist and cause chronic hepatitis. Additionally, reports of encephalitis and glomerulonephritis in infected patients suggest extrahepatic involvement.
Currently, management of ratHEV infection is based on experience with HEV. In people with a healthy immune system, the infection usually clears up on its own with supportive care. Ribavirin is considered the main treatment. Other antiviral drugs exhibit in vitro activity but have not been evaluated in humans. Additionally, increasing evidence suggests that HEV genotype 1 vaccines provide partial protection against RatHEV. However, clinical efficacy data are lacking.
RatHEV surveillance and public health implications
Overall, the impact of ratHEV on human health is currently only beginning to be understood, and systematic surveillance remains limited to China and Western Europe. Including RatHEV in HEV guidelines could facilitate increased investment in diagnostics and research. Furthermore, international collaboration will be essential to develop diagnostics, harmonize surveillance efforts, and strengthen early detection of emerging zoonotic threats.
