Hepatitis E virus (HEV) is the leading cause of acute viral hepatitis globally, infecting 20 million people annually and resulting in approximately 60,000 deaths. HEV, part of the Hepeviridae family and the Orthohepevirus genus, comprises four types: HEV-A, B, C, and D. Traditionally, HEV infections have demonstrated clear host specificity across species: HEV-A infects humans, while HEV-B, C1, C2, and D are associated with infections in birds, rats, ferrets, and bats, respectively.Since 2018, however, cases of human infections by rat HEV (HEV-C1) causing viral hepatitis have been reported in various countries, with increasing frequency. Notably, two pediatric cases of unexplained acute hepatitis caused by rat HEV were identified in Spain, raising significant concerns about the public health risks posed by rat HEV. Research into the molecular mechanisms of rat HEV cross-species transmission is therefore crucial for controlling this potential zoonotic threat.
Recently, a collaborative research effort led by Dr. Wenshi Wang’s team from Xuzhou Medical University and Siddharth Sridhar’s team from the University of Hong Kong published a paper in the Proceedings of the National Academy of Sciences of the Sciences of the United States of America (PNAS, IF=9.4), titled “Cell binding tropism of rat hepatitis E virus is a pivotal determinant of its zoonotic transmission to humans.” This study systematically explores the zoonotic infection potential of HEV from various species, examining immune cross-reactivity and identifying cell binding tropism as a key molecular mechanism underlying rat HEV’s ability to cross species and infect humans.
Host susceptibility and cross-species transmission are primarily determined by the virus’s entry mechanisms, which depend on the specific binding between viral particles and host cell surface receptors. HEV exists in two forms: unenveloped virus particles (nHEV), which mediate transmission between hosts, and quasi-enveloped virus particles (eHEV), which circulate within the host’s bloodstream and facilitate intra-host cell-to-cell transmission. The specific binding between nHEV and host cell surface receptors is thus a key factor in determining HEV’s host specificity and cross-species transmission potential.
Dr. Wang’s team utilized the self-assembling property of the HEV capsid protein ORF2 to generate virus-like particles (VLPs) for various HEV types. This approach overcame the challenges of culturing different HEV species in cells, which traditionally hindered viral binding studies. The study revealed that rat HEV VLPs and infectious particles exhibit high-affinity, specific binding to human cells and tissues, allowing entry and replication within human cells. In contrast, HEV VLPs from other species only bound specifically to their homologous host liver tissues without binding to human cells or tissues.
To further investigate the specific amino acid residues on the rat HEV ORF2 capsid protein responsible for binding to human cells, the research team conducted 3D structural analysis of the protein and introduced targeted amino acid mutations. The findings not only identified critical residues influencing ORF2 dimerization and VLP formation but also discovered key residues determining HEV VLP binding to cell surfaces. Additionally, the team found that rat HEV VLPs can bind effectively to various intestinal regions, and rat infection experiments demonstrated the presence of rat HEV in different intestinal segments, suggesting the virus can reach the liver via the gut-liver axis, ultimately causing viral hepatitis.
Antigenic cartography and immune cross-reactivity studies revealed that rat HEV VLPs and HEV-A VLPs induce bidirectional immune cross-reactivity. Serum from HEV-A-infected individuals exhibited cross-reactivity with HEV-C1 VLPs and partially inhibited the binding of rat HEV VLPs to human liver cells. Similarly, serum from individuals vaccinated with the HEV-A vaccine Hecolin® showed cross-immune reactivity with rat HEV VLPs and partially blocked their binding to human liver cells.
In conclusion, the binding tropism between HEV capsids and host cells is a crucial factor in determining the zoonotic potential of HEV across different species. Systematic studies of the antigenic landscape and serological cross-reactivity among different HEV species can provide valuable strategies for developing species-specific HEV diagnostics and establish a critical foundation for effectively controlling zoonotic transmission of HEV.
