Rat Hepatitis E Virus: A Comprehensive Review of an Emerging Zoonotic Threat

A comprehensive review published in Nature Communications has synthesized current evidence on rat hepatitis E virus (ratHEV), an emerging pathogen with confirmed zoonotic transmission to humans.

Background and Discovery

Hepatitis E virus (HEV), classified as Paslahepevirus balayani in the Hepeviridae family, causes an estimated 19.5 million cases of acute hepatitis annually. Until recently, other members of the Hepeviridae family were considered host-restricted and not a cause of human disease.

This assumption was challenged in 2018 when the first confirmed human infection by a Rocahepevirus species was documented.

The index case was identified in Hong Kong in a liver transplant recipient suffering from chronic hepatitis of unknown origin. Subsequent active surveillance and retrospective analyses have confirmed additional human cases across Asia and Europe, with one case reported in Canada. These findings establish ratHEV as a zoonotic virus capable of transmission to humans.

Taxonomy and Molecular Virology

• The Rocahepevirus genus within the Orthohepevirinae subfamily contains two species: Rocahepevirus eothenomi and R. ratti (ratHEV). Unassigned or putative Rocahepevirus-like viruses have also been reported in South American and Asian rodents.
• Five distinct ratHEV genotypes (C1 to C5) have been identified. Current evidence suggests genotype C1, which circulates in shrews and rats, is the primary lineage with zoonotic potential. Genotype C2 is limited to mustelids (minks and ferrets), while genotypes C2-C5 are currently considered to have negligible zoonotic potential.
• RatHEV is a positive-sense, single-stranded RNA virus with a genome size of 6.6 to 7 kilobases. Genomic analyses indicate ratHEV is substantially divergent from the common hepatitis E virus (HEV) across these genetic regions.

Epidemiology and Cross-Species Transmission

Animal Reservoirs: RatHEV is widespread in synanthropic (human-associated) rat populations, including black rats and Norwegian rats, across Asia, Europe, and North America. Viral RNA prevalence in trapped rats ranges from 10% to 30%, with higher rates observed in urban areas compared to rural habitats.

Other Hosts: Domestic pigs are the only non-rodent mammals documented to show active replication of ratHEV, suggesting they could act as transient hosts. Genotype C1 has also been detected in birds of prey, and experimental studies have shown susceptibility in chickens.

Human Exposure: Serological studies provide evidence of human exposure to ratHEV in both Asia and Europe.

• In Asia, seroprevalence rates range from less than 1% in urban regions to 22% in rural China. Higher rates are associated with rodent contact, older age, and rural residence.
• In Europe, higher seroprevalence has been observed in specific groups, including forestry workers and individuals experiencing homelessness.

Reported Human Infections: The majority of confirmed human infections have been reported in China and Spain, with sporadic cases detected in France, Canada, Germany, and Thailand.

Diagnosis, Clinical Course, and Management

Diagnostic Challenges: Diagnosis remains difficult due to a lack of commercially available assays and limited validation of existing protocols. Viral RNA detection via multiple quantitative polymerase chain reaction (qPCR) protocols is considered the most reliable method for identifying active infection.

Antibody Testing: Antibody assays currently serve primarily an epidemiological role. Cross-reactivity with HEV-specific antibody tests has been reported in 10% to 70% of samples for immunoglobulin G (IgG) and 20% to 40% for immunoglobulin M (IgM).

Clinical Presentation: Infection with ratHEV follows a clinical course similar to 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. Reports of encephalitis and glomerulonephritis in infected patients suggest potential extrahepatic involvement.

Treatment and Prevention: Clinical management is guided by experience with HEV. Infection is generally self-limiting with supportive care in immunocompetent individuals. The antiviral drug ribavirin is considered the main treatment option. Growing evidence suggests the existing HEV genotype 1 vaccine may provide partial protection against ratHEV, though clinical efficacy data are currently lacking.

Public Health Implications and Surveillance Needs

The review describes the current understanding of ratHEV's impact on human health as "nascent."

Systematic surveillance for the virus remains limited primarily to China and Western Europe. The researchers note that including ratHEV in existing HEV clinical and public health guidelines could facilitate increased diagnosis and stimulate further research investment.

International coordination is identified as crucial for developing standardized diagnostics, harmonizing global surveillance efforts, and enhancing the early detection of this and other emergent zoonotic threats.