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Worldwide, the Hepatitis E virus (HEV) is the main pathogen of acute viral hepatitis, with an extremely high mortality in pregnant women. However, the pathogenesis of HEV infection in pregnant women remains largely unknown. We established an HEV-infected pregnant mice animal model to explore the adverse pregnancy outcomes of HEV infection. Mice wer...
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... mice in the early pregnancy group were not pregnant, and one mouse in the middle group and one mouse in the late pregnancy were not pregnant, as defined by unchanged estrogen and/or progesterone (Figure 1, Figure 2A,B). Interestingly, HEV RNA was detected in the feces at 3~5 dpi and in the serum at 5~7 dpi ( Figure 2C-E, Table 1). Viremia was observed in all infected pregnant mice (Figure 2). ...Context 2
... viral titer in the serum of the HEV-infected miscarriage mice was compared with that of the non-pregnant mice and delivery mice at 7 dpi in the early and middle groups ( Figure 2F). A negative strand of HEV RNA was also detected in the serum (Table 1). The relative expression of negative-strand HEV RNA in the serum was compared among non-pregnant, normal delivery and miscarriage mice at 7 dpi in the early and middle pregnancy groups ( Figure 2G). ...Context 3
... mild antiviral effects were obtained in the liver and uterus of mice treated with RBV compared with the untreated mice ( Figure 2H). In addition, positive and negative strands of HEV RNA were also detected in the liver, spleen, kidney, and colon of HEV-infected pregnant mice ( Figure 2I-K, Table 1). All pregnant mice infected with HEV in the early pregnancy (5/5) or the late pregnancy (8/8) has a normal delivery, while only one mouse infected with HEV in the middle pregnancy had a normal delivery (1/8). ...Similar publications
Hepatitis E virus (HEV) is associated with acute hepatitis disease, which may lead to chronic disease in immunocompromised individuals. The disease is particularly severe among pregnant women (20–30% mortality). The only licensed vaccine against HEV, which is available in China, is the Escherichia coli purified recombinant virus-like particles (VLP...
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... 1 However, it leads to chronic infection in immunocompromised patients, such as organ-transplanted recipients 2 or patients with human immunodeficiency virus (HIV) infection. 3 Although HEV predominantly replicates in the liver, multiple extrahepatic HEV replication sites, including the brain, 4,5 placenta, 6,7 uterus, 8,9 testes, and epididymis, 10,11 have been identified. HEV RNA first detected in the sperm is associated with infertility. ...
Hepatitis E virus (HEV) persists in the male genital tract that associates with infertility. However, the presence of HEV in the female genital tract is unreported. Vaginal secretions, cervical smears, and cervix uteri were collected to explore the presence of HEV in the female genital tract. HEV RNA and/or antigens were detected in the vaginal secretions, cervical smears, and the cervix uteri of women. The infectivity of HEV excreted into vaginal secretions was further validated in vitro. In addition, HEV replicates in the female genital tract were identified in HEV‐infected animal models by vaginal injection or vaginal mucosal infection to imitate sexual transmission. Serious genital tract damage and inflammatory responses with significantly elevated mucosal innate immunity were observed in women or animals with HEV vaginal infection. Results demonstrated HEV replicates in the female genital tract and causes serious histopathological damage and inflammatory responses.
... Pregnant gilts experimentally infected with HEV-gt3 did not transmit the virus to their offspring [86,[94][95][96][97][98]. ...
The story of the discovery of hepatitis E originated in the late 1970s with my extreme belief that there was a hidden saga in the relationship between jaundice and pregnancy in developing countries and the opportunity for a massive epidemic of viral hepatitis, which hit the Gulmarg Kashmir region in November 1978. Based on data collected from a door-to-door survey, the existence of a new disease, epidemic non-A, non-B hepatitis, caused by a hitherto unknown hepatitis virus, was announced. This news was received by the world community with hype and skepticism. In the early 1980s, the world watched in awe as an extreme example of human self-experimentation led to the identification of VLP. In 1990, a cDNA clone from the virus responsible for epidemic non-A, non-B hepatitis was isolated. Over the years, we traversed three eras of ambiguity, hope, and hype of hepatitis E research and conducted several seminal studies to understand the biology of HEV and manifestations of hepatitis E. Many milestones have been reached on the long and winding road of hepatitis E research to understand the structure, biology, and diversity of the agent, changing the behavior of the pathogen in developed countries, and the discovery of a highly effective vaccine.
... However, an in vivo study conducted in HEV-infected pregnant mice showed a shift in the immune response from Th2 tolerogenic response, which is essential for maintaining pregnancy, to the pro-inflammatory Th1profile [97]. This immune response alteration has also been seen in HEV-infected pregnant women who have hepatic failure, which could be considered a biomarker for miscarriage [99] (Figure 1). ...
Viral infections in pregnancy are major causes of maternal and fetal morbidity and mortality. Infections can develop in the neonate transplacentally, perinatally, or postnatally (from breast milk or other sources) and lead to different clinical manifestations, depending on the viral agent and the gestational age at exposure. Viewing the peculiar tolerogenic status which characterizes pregnancy, viruses could exploit this peculiar immunological status to spread or affect the maternal immune system, adopting several evasion strategies. In fact, both DNA and RNA virus might have a deep impact on both innate and acquired immune systems. For this reason, investigating the interaction with these pathogens and the host’s immune system during pregnancy is crucial not only for the development of most effective therapies and diagnosis but mostly for prevention. In this review, we will analyze some of the most important DNA and RNA viruses related to gestational infections.
... As expected, the negative control mice demonstrated HEV negative. Hence, their findings firmly suggest that HEV can replicate in pregnant BALB/c mice [114]. ...
... Fine modulation of Th1/Th2 stability is a crucial cause for the safeguarding of fetuses as opposed to abortions in mice [115]. They reported a higher Th1/Th2 ratio (9.48 fold) in HEV-infected miscarriage mice than in uninfected mice with normal delivery [114]. ...
... More work with the BALB/C model is necessary to evaluate its ability to sustain gt1, gt2, and gt3 infections and what contribution they play to pregnancy mortality in this model. Th1/Th2 ratio (9.48 fold) in HEV-infected miscarriage mice than in uninfected mice with normal delivery [114]. They also reported the vertical spread of HEV from the mother to the fetus. ...
A comprehensive review of the animal models utilized to assess hepatitis E virus pregnancy disease.
... Therefore, the regulations of farm, slaughterhouses, pork meat industries need to be strengthened. In addition, animal models for HEV infection might be important for further studies [85][86][87]. ...
Hepatitis E virus (HEV) is an important public health problem and is responsible for both acute and chronic viral hepatitis. Public health implications of HEV are derived from its transmission route, either water-borne or food-borne, and its zoonotic potential. Not only in developing countries, but HEV cases are also found in a high number in developed countries. The spread of HEV to the environment might pollute surface waters, which could act as the source of infection for both humans and animals. Identification of the virus in animal products suggests the circulation of HEV within water and food chains. High seroprevalence and circulation of HEV in livestock, in particular pigs, as well as in environmental samples warrants further investigation into pig markets. HEV virulence in different environments and meat supply chains could shed light on the possible sources of infection in humans and the degree of occupational risk. The purpose of this review is to discuss HEV infections with an emphasis on livestock- and environment-related risk factors, and food-borne, water-borne, and zoonotic transmissions.
... Therefore, the regulations of farm, slaughterhouses, pork meat industries need to be strengthened. In addition, animal models for HEV infection might be important for further studies [85][86][87]. ...
Hepatitis E virus (HEV) is an important public health problem and is responsible for both acute and chronic viral hepatitis. Public health implications of HEV are derived from its transmission route, either water-borne or food-borne, and its zoonotic potential. Not only in developing countries, but HEV cases are also found in a high number in developed countries. The spread of HEV to the environment might pollute surface waters, which could act as the source of infection for both humans and animals. Identification of the virus in animal products suggests the circulation of HEV within water and food chains. High seroprevalence and circulation of HEV in livestock, in particular pigs, as well as in environmental samples warrants further investigation into pig markets. HEV virulence in different environments and meat supply chains could shed light on the possible sources of infection in humans and the degree of occupational risk. The purpose of this review is to discuss HEV infections with an emphasis on livestock-and environment-related risk factors, and food-borne, water-borne, and zoonotic transmissions.
... Similarly, in this study, higher levels of fibrosis were identified in the liver of positive control pigs than those in negative control and vaccinated pigs. Several studies have shown that HEV infects not only the liver but also other organs, such as the S.I, L.I, lymph nodes, and uterus [68][69][70]. In addition, it has been reported that hepatitis B causes not only infection but also inflammation in the intestine [71]. ...
We investigated the cross-species transmission of rabbit hepatitis E virus (rb HEV) to pigs and evaluated the cross-protection of a swine (sw) HEV-3 virus-like particle (VLP) vaccine against rb HEV infection in pigs. Twelve 4-week-old conventional pigs were divided into negative control (n = 3), positive control (rb HEV-infected, n = 4), and vaccinated (vaccinated and rb HEV-challenged, n = 5) groups. The vaccine was administered at weeks 0 and 2, and viral challenge was conducted at week 4. Serum HEV RNA, anti-HEV antibody, cytokine, and liver enzyme levels were determined. Histopathological lesions were examined in abdominal organs. Viral RNA was detected and increased anti-HEV antibody and alanine aminotransferase (ALT) levels were observed in positive control pigs; liver fibrosis, inflammatory cell infiltration in the lamina propria of the small intestine and shortened small intestine villi were also observed. In vaccinated pigs, anti-HEV antibody and Th1 cytokine level elevations were observed after the second vaccination; viral RNA was not detected, and ALT level elevations were not observed. The results verified the cross-species transmission of rb HEV to pigs and cross-protection of the sw HEV-3 VLP vaccine against rb HEV infection in pigs. This vaccine may be used for cross-protection against HEV infection in other species.
... House mice have a very low rate of mosaic aneuploidy in preimplantation embryos (about 25% of embryos, compared to 70% in humans) (Lightfoot et al., 2006), which plays a role in their negligible rate of naturally conceived miscarriages of less than 1% (Li et al., 2011;Yang et al., 2019;Sandalinas et al., 2001;Rubio et al., 2007). Also, in contrast to the much higher rate observed in humans, the spontaneous occurrence of aneuploidy in mice is rare, affecting less than 1% of embryos (Lightfoot et al., 2006;Bond et al., 1983). ...
Centrioles are subcellular organelles essential for normal cell function and development; they form the cell’s centrosome (a major cytoplasmic microtubule organization center) and cilium (a sensory and motile hair-like cellular extension). Centrioles with evolutionarily conserved characteristics are found in most animal cell types but are absent in egg cells and exhibit unexpectedly high structural, compositional, and functional diversity in sperm cells. As a result, the centriole’s precise role in fertility and early embryo development is unclear. The centrioles are found in the spermatozoan neck, a strategic location connecting two central functional units: the tail, which propels the sperm to the egg and the head, which holds the paternal genetic material. The spermatozoan neck is an ideal site for evolutionary innovation as it can control tail movement pre-fertilization and the male pronucleus’ behavior post-fertilization. We propose that human, bovine, and most other mammals–which exhibit ancestral centriole-dependent reproduction and two spermatozoan centrioles, where one canonical centriole is maintained, and one atypical centriole is formed–adapted extensive species-specific centriolar features. As a result, these centrioles have a high post-fertilization malfunction rate, resulting in aneuploidy, and miscarriages. In contrast, house mice evolved centriole-independent reproduction, losing the spermatozoan centrioles and overcoming a mechanism that causes miscarriages.
... It was reported that wild-type and immunodeficient mice were not susceptible to humanderived HEV-1, human-derived HEV-3, wild boar-derived HEV-3 and HEV-4 (Li et al., 2008;Schlosser et al., 2014;Sayed and Meuleman, 2017;Sayed et al., 2017a,b). However, Balb/c and Balb/c nude mice could be infected by HEV-4 isolated from a pig stool isolated in China (Zhou et al., 2017;Yang et al., 2019). HEV RNA and HEV Ag were detected in liver, spleen, kidney, brain, uterus and intestine of infected mice. ...
The hepatitis E virus (HEV) is responsible for 20 million infections worldwide per year. Although, HEV infection is mostly self-limiting, immunocompromised individuals may evolve toward chronicity. The lack of an efficient small animal model has hampered the study of HEV and the discovery of anti-HEV therapies. Furthermore, new HEV strains, infectious to humans, are being discovered. Human liver-chimeric mice have greatly aided in the understanding of HEV, but only two genotypes (HEV-1 and HEV-3) have been studied in this model. Moreover, the immunodeficient nature of this mouse model does not allow full investigation of the virus and all aspects of its interaction with the host. Recent studies have shown the susceptibility of regular and nude Balb/c mice to a HEV-4 strain (KM01). This model should allow the investigation of the interplay between HEV and the adaptive immune system of its host, and potential immune-mediated complications. Here, we assess the susceptibility of human liver-chimeric and non-humanised mice to a different HEV-4 strain (BeSW67HEV4-2008). We report that humanised mice could be readily infected with this isolate, resulting in an infection pattern comparable to HEV-3 infection. Despite these results and in contrast to KM01, non-humanised mice were not susceptible to infection with this viral strain. Further investigation, using other HEV-4 isolates, is needed to conclusively determine HEV-4 tropism and mouse susceptibility.
... 85 Huangfen et al. used a mouse model to evaluate the adverse outcomes of HEV during pregnancy in HEV-infected pregnant mice. 86 They found HEV-RNA and antigens in the uterus and placental cells implying that the virus replicated in those tissues. 86 Miscarriage occurred in 87% (7/8) of the cases. ...
... 86 They found HEV-RNA and antigens in the uterus and placental cells implying that the virus replicated in those tissues. 86 Miscarriage occurred in 87% (7/8) of the cases. 86 ...
... 86 Miscarriage occurred in 87% (7/8) of the cases. 86 ...
Intrauterine viruses can infect the decidua and placenta and cause adverse effects on the fetus during gestation. This review discusses the contribution of various viral infections to miscarriage and the molecular mechanisms by which viruses can cause devastating effects on healthy fetuses and induce miscarriage. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) as newly emerged coronavirus was considered here, due to the concerns about its role during pregnancy and inducing miscarriage, as well. in this narrative review, an extensive literature search was conducted to find all studies investigating viral infections in miscarriage and their molecular mechanisms published over the past 20 years.
The results of various studies investigating the roles of 20 viral infections in miscarriage is presented. Then, the mechanisms of pregnancy loss in viral infections were addressed, including alteration of trophoblast invasion and placental dysfunction, inducing excessive maternal immune response, and inducing apoptosis in the placental tissue. Viruses may cause pregnancy loss through different mechanisms and our knowledge about these mechanisms can be helpful for controlling or preventing viral infections and achieving a successful pregnancy.
