A growing body of evidence suggests that rat hepatitis E virus is spilling into humans more often than recognized, raising urgent questions about diagnosis, transmission, and the true global burden of this overlooked infection.
Study: Rocahepevirus ratti: molecular evolution, zoonotic potential and public health impact. Image Credit: Rudmer Zwerver / Shutterstock
A recent study published in the journal Nature Communications reviewed the current evidence on rat hepatitis E virus (ratHEV, Rocahepevirus ratti) ecology, molecular virology, host range, and clinical impact.
Hepatitis E is a well-known cause of acute hepatitis, with 19.5 million cases yearly, and its clinical entity was deemed synonymous with hepatitis E virus (HEV) infection. HEV is now classified as Paslahepevirus balayani in the Hepeviridae family. Other Hepeviridae members were considered strictly host-restricted, with no role in human disease. However, this assumption was challenged in 2018, when human infection by a Rocahepevirus species was confirmed.
Initially considered to be restricted to rodents, ratHEV remained largely overlooked until the first human case was detected in Hong Kong in a liver transplant recipient with chronic hepatitis of unknown origin. Subsequently, active surveillance and retrospective analyses have confirmed additional cases in Asia and Europe, with a case also reported in Canada, revealing that ratHEV is a zoonotic virus transmitted to humans and prompting a rethinking of the disease landscape. In the present study, researchers summarized ratHEV ecology, host range, virology, and clinical impact.
RatHEV Taxonomy and Molecular Virology
The Rocahepevirus genus within the Orthohepevirinae subfamily of the Hepeviridae family has two species, Rocahepevirus eothenomi and R. ratti (ratHEV). Unassigned or putative Rocahepevirus-like viruses have been reported in South American and Asian rodents. There are five ratHEV genotypes (C1 to C5): the C1 genotype circulates in shrews and rats, while the C2 genotype is limited to mustelids (minks 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 non-structural polyprotein with RNA-dependent RNA polymerase (RdRp), helicase, and methyltransferase domains. ORF2 encodes the capsid, and ORF3 encodes a small phosphoprotein. Genomic analyses have shown that ratHEV is substantially divergent from HEV across ORFs.
RatHEV Epidemiology and Cross-Species Transmission
ratHEV is widespread in synanthropic rat populations and has been detected in black rats, Norwegian rats, and other species across Asia, Europe, and North America. ratHEV RNA prevalence ranges from 10% to 30% in trapped rats, with higher prevalence in urban areas 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.
Occasional genotype C1 infections have been documented in carnivores, almost certainly reflecting environmental contamination or incidental exposure. Domestic pigs are the only non-rodent mammals to show active replication of ratHEV, with viral RNA detected in blood and feces, suggesting that pigs could be transient hosts. The review also notes detection of genotype C1 in birds of prey and experimental susceptibility in chickens, although their role in natural transmission remains uncertain. Serological studies have shown evidence of human exposure to ratHEV in Asia and Europe.
In Asia, seroprevalence rates range from less than 1% in urban regions to 22% in rural China, with higher rates associated with rodent contact, older age, and rural residence. In Europe, higher seroprevalence has been observed in forestry workers and individuals experiencing homelessness. Most infections have been reported in China and Spain, with cases sporadically detected in France, Canada, Germany, and Thailand.
RatHEV Diagnosis, Treatment, and Prevention
The diagnosis of ratHEV infection remains challenging due to the lack of commercial assays and limited validation of available protocols. Viral RNA detection is the only reliable marker of active infection. As such, molecular testing remains crucial in patients with hepatitis of unknown etiology. Since available primer sets do not align with all ratHEV clusters, multiple quantitative polymerase chain reaction (qPCR) protocols constitute the most reliable screening method.
Assays based on antibodies serve only an epidemiological role. Cross-reactivity with HEV-specific antibody assays has been reported in 10% to 70% of samples for immunoglobulin G (IgG) and 20% to 40% of samples for immunoglobulin M (IgM). Notably, ratHEV-specific IgM detection is anecdotal, with only three cases, all showing partial HEV cross-reactivity. As such, IgG reactivity remains the most robust evidence of previous exposure.
Infection with ratHEV follows a similar clinical course to that with HEV, ranging from sub-clinical infection to acute hepatitis. In some cases, it may lead to fulminant liver failure and death. In immunocompromised populations, infection can be persistent, leading to chronic hepatitis. Moreover, reports of encephalitis and glomerulonephritis in infected patients suggest extrahepatic involvement.
Currently, management of ratHEV infection is guided by experience with HEV. Infection is generally self-limiting with supportive care in immunocompetent people. Ribavirin is considered the main treatment; other antivirals exhibit in vitro activity but have not been assessed in humans. Further, growing evidence suggests that the HEV genotype 1 vaccine provides partial protection against ratHEV. However, clinical efficacy data are lacking.
RatHEV Surveillance and Public Health Implications
Together, the current understanding of ratHEV's impact on human health is nascent, and systematic surveillance remains limited to China and Western Europe. Including ratHEV in HEV guidelines could facilitate increased diagnosis and research investment. Further, international coordination will be crucial to developing diagnostics, harmonizing surveillance efforts, and enhancing early detection of emergent zoonotic threats.
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