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Rat Hepatitis E virus is a potential zoonotic pathogen to humans

  • Author Footnotes
    # Z. Q, X. H and Y. X contributed equally to this work.
    Zhongyao Qian
    Footnotes
    # Z. Q, X. H and Y. X contributed equally to this work.
    Affiliations
    Medical Faculty, Kunming University of Science and Technology, Yunnan Provincal Key Laboratory of Clinical Virology, 727 Jingming Road, Kunming, China
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  • Author Footnotes
    # Z. Q, X. H and Y. X contributed equally to this work.
    Xianhui Hao
    Footnotes
    # Z. Q, X. H and Y. X contributed equally to this work.
    Affiliations
    Medical Faculty, Kunming University of Science and Technology, Yunnan Provincal Key Laboratory of Clinical Virology, 727 Jingming Road, Kunming, China
    Search for articles by this author
  • Author Footnotes
    # Z. Q, X. H and Y. X contributed equally to this work.
    Yueping Xia
    Footnotes
    # Z. Q, X. H and Y. X contributed equally to this work.
    Affiliations
    Medical Faculty, Kunming University of Science and Technology, Yunnan Provincal Key Laboratory of Clinical Virology, 727 Jingming Road, Kunming, China
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  • Wenhai Yu
    Correspondence
    Corresponding authors. Addresses: Institute of Medical Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Kunming, PR China
    Affiliations
    Institute of Medical Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Kunming, PR China
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  • Fen Huang
    Correspondence
    Medical Faculty, Kunming University of Science and Technology, 727 Jingming Road, Kunming, China.
    Affiliations
    Medical Faculty, Kunming University of Science and Technology, Yunnan Provincal Key Laboratory of Clinical Virology, 727 Jingming Road, Kunming, China
    Search for articles by this author
  • Author Footnotes
    # Z. Q, X. H and Y. X contributed equally to this work.

      Keywords

      Linked Article

      To the Editor:
      We read with interest the manuscript “Orthohepevirus C infection as an emerging cause of acute hepatitis in Spain: First report in Europe” by Rivero-Juarez A et al.
      • Rivero-Juarez A.
      • Frias M.
      • Perez A.B.
      • Pineda J.A.
      • Reina G.
      • Fuentes-Lopez A.
      • et al.
      Orthohepevirus C infection as an emerging cause of acute hepatitis in Spain: first report in Europe.
      A total of 267 patients with acute hepatitis were divided into 2 cohorts, i.e. cohort 1 (without hepatotropic virus infection, n = 169) and 2 (with HEV infection, n = 98) to detect rat HEV (Orthohepevirus C; HEV-C1) RNA. A total of 2 individuals with mild acute hepatitis in cohort 1 and 1 individual (anti-HEV IgM positive) with severe acute hepatitis in cohort 2 were positive for HEV-C1 RNA. Although the first case of rat HEV-infected human was reported in a liver transplant recipient with chronic HEV infection in Hong Kong in 2018,
      • Sridhar S.
      • Yip C.C.Y.
      • Wu S.
      • Cai J.
      • Zhang A.J.
      • Leung K.H.
      • et al.
      Rat hepatitis E virus as cause of persistent hepatitis after liver transplant.
      this study is the first to report HEV-C1 infection in Europe in acute HEV-infected patients. Rat HEV was previously thought to infect rodents and cannot infect humans exclusively. However, the HEV-C1 infection has emerged in Hong Kong,
      • Sridhar S.
      • Yip C.C.Y.
      • Wu S.
      • Cai J.
      • Zhang A.J.
      • Leung K.H.
      • et al.
      Rat hepatitis E virus as cause of persistent hepatitis after liver transplant.
      central Africa,
      • Andonov A.
      • Robbins M.
      • Borlang J.
      • Cao J.
      • Hatchette T.
      • Stueck A.
      • et al.
      Rat hepatitis E virus linked to severe acute hepatitis in an immunocompetent patient.
      and Spain
      • Rivero-Juarez A.
      • Frias M.
      • Perez A.B.
      • Pineda J.A.
      • Reina G.
      • Fuentes-Lopez A.
      • et al.
      Orthohepevirus C infection as an emerging cause of acute hepatitis in Spain: first report in Europe.
      recently. Non-human primates have been identified as susceptible to rat HEV,
      • Yang F.
      • Li Y.
      • Li Y.
      • Jin W.
      • Duan S.
      • Xu H.
      • et al.
      Experimental cross-species transmission of rat hepatitis E virus to rhesus and cynomolgus monkeys.
      indicating the possibility of transmission of rat HEV to humans. Rats, which closely and frequently come into contact with humans and domestic animals, have become a natural reservoir of HEV. Thus, the prevalence of HEV-C1 in these regions where HEV is highly prevalent in humans and domestic animals should be investigated.
      A total of 68 wild rats (Rattus norvegicus, 31 females and 37 males) were collected for HEV-C1 detection in Dali City, Yunnan Province, Southwest China, where a high prevalence of genotype 4 HEV has been reported in humans, cows, and goats because of the traditional mixed farming of domestic animals.
      • Huang F.
      • Li Y.
      • Yu W.
      • Jing S.
      • Wang J.
      • Long F.
      • et al.
      Excretion of infectious hepatitis E virus into milk in cows imposes high risks of zoonosis.
      ,
      • Long F.
      • Yu W.
      • Yang C.
      • Wang J.
      • Li Y.
      • Li Y.
      • et al.
      High prevalence of hepatitis E virus infection in goats.
      Notably, 19.1% (13/68) liver, 19.1% (13/68) intestine, 16.2% (11/68) spleen, 10.3% (7/68) kidney, 16.1% (5/31) uterus, and 21.6% (8/37) testis samples were positive for HEV-C1 RNA by quantitative real-time PCR (Fig. 1A). The liver, which is the most important replication site of HEV, had the highest HEV-C1 titer (5.4×105 ± 4.1×105 copies/g, Fig. 1B). In addition, HEV antigens were observed in the liver, spleen, kidney, intestine, uterus, and testis on immunohistochemical assays in our previous study,
      • Long F.
      • Yu W.
      • Yang C.
      • Wang J.
      • Li Y.
      • Li Y.
      • et al.
      High prevalence of hepatitis E virus infection in goats.
      whereas no signal is noted in HEV-C1 RNA-negative mock rats (Fig. 1C). Both HEV-C1 RNA and HEV antigens positive were determined to be HEV-C1 infection. Considering that rat HEV has been identified to be infectious to non-human primates and BALB/c mice are susceptible to human- or swine-derived HEV, cross-species transmission is conceivable.
      Figure thumbnail gr1
      Fig. 1HEV-C1 detection in rats captured from Dali City, where HEV-A is highly prevalent.
      (A) Positive rate of HEV-C1 RNA in the liver, spleen, kidney, intestine, uterus, or testis of 68 wild rats. (B) Genomic copy number of HEV in the liver, spleen, kidney, intestine, uterus, and testis of rats captured from the farmers’ house. (C) HEV antigens in the liver, spleen, kidney, intestine, uterus, and testis of rats were observed by IHC assay. Rats negative to HEV-C1 RNA serve as mock control.
      The Orthohepevirus A (HEV-A) infection causes a self-limited disease in immunocompetent individuals and chronicity in immunosuppressed patients. Up to now, 20 cases of HEV-C1-infected humans, including 16 in Hong Kong,
      • Sridhar S.
      • Yip C.C.Y.
      • Wu S.
      • Cai J.
      • Zhang A.J.
      • Leung K.H.
      • et al.
      Rat hepatitis E virus as cause of persistent hepatitis after liver transplant.
      ,
      • Sridhar S.
      • Yip C.C.
      • Lo K.H.
      • Wu S.
      • Situ J.
      • Chew N.F.
      • et al.
      Hepatitis E virus species C infection in humans, Hong Kong.
      ,
      • Sridhar S.
      • Yip C.C.
      • Wu S.
      • Chew N.F.
      • Leung K.H.
      • Chan J.F.
      • et al.
      Transmission of rat hepatitis E virus infection to humans in Hong Kong: a clinical and epidemiological analysis.
      3 in Spain,
      • Rivero-Juarez A.
      • Frias M.
      • Perez A.B.
      • Pineda J.A.
      • Reina G.
      • Fuentes-Lopez A.
      • et al.
      Orthohepevirus C infection as an emerging cause of acute hepatitis in Spain: first report in Europe.
      and 1 in central Africa,
      • Andonov A.
      • Robbins M.
      • Borlang J.
      • Cao J.
      • Hatchette T.
      • Stueck A.
      • et al.
      Rat hepatitis E virus linked to severe acute hepatitis in an immunocompetent patient.
      have been reported. HEV-C1 hepatitis is recognized to be milder than HEV-A hepatitis.
      • Sridhar S.
      • Yip C.C.
      • Wu S.
      • Chew N.F.
      • Leung K.H.
      • Chan J.F.
      • et al.
      Transmission of rat hepatitis E virus infection to humans in Hong Kong: a clinical and epidemiological analysis.
      However, the clinical features of HEV-C1 infections are still largely unclear. Elevated ALT may be an important indicator in HEV-C1-infected patients, whereas no significant increase in ALT is observed in HEV-C1-infected rhesus and cynomolgus monkey models.
      • Yang F.
      • Li Y.
      • Li Y.
      • Jin W.
      • Duan S.
      • Xu H.
      • et al.
      Experimental cross-species transmission of rat hepatitis E virus to rhesus and cynomolgus monkeys.
      In addition, most of these HEV-C1-infected patients are immunocompromised or co-infected with other hepatitis viruses and they usually progress to chronicity (7/9, 77.8%)
      • Sridhar S.
      • Yip C.C.
      • Lo K.H.
      • Wu S.
      • Situ J.
      • Chew N.F.
      • et al.
      Hepatitis E virus species C infection in humans, Hong Kong.
      or liver failure (1/3, 33.33%).
      • Rivero-Juarez A.
      • Frias M.
      • Perez A.B.
      • Pineda J.A.
      • Reina G.
      • Fuentes-Lopez A.
      • et al.
      Orthohepevirus C infection as an emerging cause of acute hepatitis in Spain: first report in Europe.
      Thus, it will be crucial to improve the diagnosis and treatment of HEV-C1, and ideally to develop an effective vaccine.
      HEV-C1 is highly divergent from HEV-A, with only 55%–60% homology.
      • Sridhar S.
      • Yip C.C.Y.
      • Wu S.
      • Cai J.
      • Zhang A.J.
      • Leung K.H.
      • et al.
      Rat hepatitis E virus as cause of persistent hepatitis after liver transplant.
      HEV-A, including 8 genotypes that infect humans, pigs, wild boar, cows, deer, rabbits, and camels, primarily causes human infection. The zoonotic transmission of HEV-A genotypes 3 and 4 from animals to humans by consumption of raw/undercooked pork or milk have been reported.
      • Huang F.
      • Li Y.
      • Yu W.
      • Jing S.
      • Wang J.
      • Long F.
      • et al.
      Excretion of infectious hepatitis E virus into milk in cows imposes high risks of zoonosis.
      ,
      • Wang J.
      • Li N.
      • Zhang H.
      • Li F.
      • Fanning S.
      • Jiang T.
      Detection of hepatitis E virus in the pig livers and retail pork samples collected in selected cities in China.
      HEV-C1 was first identified in Rattus norvegicus from Germany in 2010, and it has been detected in Rattus rattus and Rattus norvegicus in the USA, China, Indonesia, Vietnam, and many European countries.
      • Reuter G.
      • Boros A.
      • Pankovics P.
      Review of hepatitis E virus in rats: evident risk of species Orthohepevirus C to human zoonotic infection and disease.
      HEV-C1 transmission from rats to humans was first reported in a liver transplant recipient whose house is adjacent to a refuse chute (increasing the risk of accidental contact with rodents).
      • Sridhar S.
      • Yip C.C.Y.
      • Wu S.
      • Cai J.
      • Zhang A.J.
      • Leung K.H.
      • et al.
      Rat hepatitis E virus as cause of persistent hepatitis after liver transplant.
      Consistently, we detect HEV-C1 RNA in the Rattus norvegicus captured from the farmers’ house, where humans, swine, cows, goats, and dogs live together, aggravating the possibility of cross-species transmission. The high prevalence of HEV-C1 in rats in Dali City may be associated with the high prevalence of HEV-A in humans and domestic animals. The lessons from SARS and COVID-19 remind us to keep alert to zoonotic diseases. Therefore, HEV-C1 investigation should be performed in the future in these regions, where HEV-A is prevalent, to assess the potential risk of HEV-C1 to humans. However, the absence of sensitive and commercial HEV-C1 detection kits may hamper such investigations.
      In summary, rat HEV can be transmitted across species to humans. The high prevalence of HEV-C1 in these traditional mixed farming regions will aggravate the zoonotic transmission of HEV.

      Financial support

      This study was supported by Natural Science Foundation for Distinguished Young Scholars of Yunnan Province ( 202001AV070005 ), Program for Innovative Research Team (in Science and Technology) in University of Yunnan Province (2020), Yunnan Provincal Key Laboratory of Clinical Virology ( 202205AG070053 ), CAMS Innovation Fund for Medical Sciences ( 2021-I2M-1-024 ), Scientific and Technological Innovation Talents of Yunnan Province ( 202205AD160008 ) and Program for Cultivating Reserve Talents in Medical Disciplines from the Health Committee of Yunnan Province ( H-2019043 ).

      Authors’ contributions

      Z. Q and X. H participated in the data acquisition, analysis, and interpretation and drafted the initial manuscript. Y. X participated in the acquisition of the data. W. Y collected the samples and provided technical and financial support. F. H was the guarantor and designed the study.

      Conflict of interest

      The authors declare no conflicts of interest that pertain to this work.
      Please refer to the accompanying ICMJE disclosure forms for further details.

      Acknowledgement

      We thank Huchun Peng and local farmers for their collection of rats.

      Supplementary data

      The following are the supplementary data to this article:

      References

        • Rivero-Juarez A.
        • Frias M.
        • Perez A.B.
        • Pineda J.A.
        • Reina G.
        • Fuentes-Lopez A.
        • et al.
        Orthohepevirus C infection as an emerging cause of acute hepatitis in Spain: first report in Europe.
        J Hepatol. 2022; 77: 326-331
        • Sridhar S.
        • Yip C.C.Y.
        • Wu S.
        • Cai J.
        • Zhang A.J.
        • Leung K.H.
        • et al.
        Rat hepatitis E virus as cause of persistent hepatitis after liver transplant.
        Emerg Infect Dis. 2018; 24: 2241-2250
        • Andonov A.
        • Robbins M.
        • Borlang J.
        • Cao J.
        • Hatchette T.
        • Stueck A.
        • et al.
        Rat hepatitis E virus linked to severe acute hepatitis in an immunocompetent patient.
        J Infect Dis. 2019; 220: 951-955
        • Yang F.
        • Li Y.
        • Li Y.
        • Jin W.
        • Duan S.
        • Xu H.
        • et al.
        Experimental cross-species transmission of rat hepatitis E virus to rhesus and cynomolgus monkeys.
        Viruses. 2022; 14
        • Huang F.
        • Li Y.
        • Yu W.
        • Jing S.
        • Wang J.
        • Long F.
        • et al.
        Excretion of infectious hepatitis E virus into milk in cows imposes high risks of zoonosis.
        Hepatology. 2016 Aug; 64: 350-359
        • Long F.
        • Yu W.
        • Yang C.
        • Wang J.
        • Li Y.
        • Li Y.
        • et al.
        High prevalence of hepatitis E virus infection in goats.
        J Med Virol. 2017; 89: 1981-1987
        • Sridhar S.
        • Yip C.C.
        • Lo K.H.
        • Wu S.
        • Situ J.
        • Chew N.F.
        • et al.
        Hepatitis E virus species C infection in humans, Hong Kong.
        Clin Infect Dis. 2021 Oct 27; ciab919
        • Sridhar S.
        • Yip C.C.
        • Wu S.
        • Chew N.F.
        • Leung K.H.
        • Chan J.F.
        • et al.
        Transmission of rat hepatitis E virus infection to humans in Hong Kong: a clinical and epidemiological analysis.
        Hepatology. 2021; 73: 10-22
        • Wang J.
        • Li N.
        • Zhang H.
        • Li F.
        • Fanning S.
        • Jiang T.
        Detection of hepatitis E virus in the pig livers and retail pork samples collected in selected cities in China.
        Foodborne Pathog Dis. 2021; 18: 97-103
        • Reuter G.
        • Boros A.
        • Pankovics P.
        Review of hepatitis E virus in rats: evident risk of species Orthohepevirus C to human zoonotic infection and disease.
        Viruses. 2020; 12