Animal Models for Studying Congenital Transmission of Hepatitis E Virus

Abstract

One of the most intriguing issues in the hepatitis E virus (HEV) field is the significant increase in mortality rates of the mother and fetus when infection occurs in the second and third trimesters of gestation. A virus that is normally self-limiting and has a mortality rate of less than one percent in otherwise healthy individuals steeply rises by up to 30% in these pregnant populations. Answering this pivotal question has not been a simple task. HEV, in general, has been a difficult pathogen to understand in the laboratory setting. A historical lack of ability to efficiently propagate the virus in tissue culture models has led to many molecular aspects of the viral lifecycle being understudied. Although great strides have been made in recent years to adapt viruses to cell culture, this field remains behind other viruses that are much easier to replicate efficiently in vitro. Some of the greatest discoveries regarding HEV have come from using animal models for which naturally occurring strains of HEV have been identified, including pigs and chickens, but key limitations have made animal models imperfect for studying all aspects of human HEV infections. In addition to the difficulties working with HEV, pregnancy is a very complicated biological process with an elaborate interplay between many different host systems, including hormones, cardiovascular, kidneys, respiratory, gastrointestinal, epithelial, liver, metabolic, immune, and others. Significant differences between the timing and interplay of these systems are notable between species, and making direct comparisons between animals and humans can be difficult at times. No simple answer exists as to how HEV enhances mortality in pregnant populations. One of the best approaches to studying HEV in pregnancy is likely a combinatorial approach that uses the best combination of emerging in vitro and in vivo systems while accounting for the deficiencies that are present in each model. This review describes many of the current HEV animal model systems and the strengths and weaknesses of each as they apply to HEV pregnancy-associated mortality. We consider factors that are critical to analyzing HEV infection within the host and how, despite no perfect animal model for human pregnancy mortality existing, recent developments in HEV models, both in vitro and in vivo, are advancing our overall understanding of HEV in the pregnant host.

Discovery of Hepatitis E and Its Impact on Global Health: A Journey of 44 Years about an Incredible Human-Interest Story

“…Few cases of HEV-gt3 infections reported in pregnant women have not been associated with severe disease or deaths [ 93 , 94 , 95 ]. As of today, there are no animal models that recapitulate all the clinical manifestations of vertical transmission of HEV as seen in humans [ 88 , 96 , 97 , 98 , 99 , 100 ].…”

A Zoonotic Strain of Rocahepevirus ratti Hepatitis E Virus Does Not Replicate Efficiently within Human Placental JEG-3 Cells

“…However, recent data from China has shown that HEV-gt4 can cause placental injury and obstetric events, but maternal disease is usually asymptomatic and not severe [20]. Despite many HEV studies attempting to elucidate pregnancy mortality, a definitive mechanism contributing to pregnancy pathogenesis has been complex and debated [21,22]. Open reading frame 4 (ORF4) protein expressed in HEV-gt1 during endoplasmic reticulum stress has been suggested as important for enhancing viral replication and could potentially contribute to severe pregnancy morbidity [23][24][25][26].…”

Emerging Pathogens Causing Acute Hepatitis

“…However, the pathogenesis of HEV infection during pregnancy is not fully understood. In this issue, Yadav and Kenney discussed the animal models used to study the congenital transmission of HEV to understand the pathogenesis of HEV during pregnancy [27]. The authors first described the immunological and hormonal changes during pregnancy [27].…”

“…In this issue, Yadav and Kenney discussed the animal models used to study the congenital transmission of HEV to understand the pathogenesis of HEV during pregnancy [27]. The authors first described the immunological and hormonal changes during pregnancy [27]. There is no ideal animal model that can study HEV pathogenesis during pregnancy from all aspects, though non-human primates could be suitable for studying HEV genotypes 1-4 [27].…”

“…The authors first described the immunological and hormonal changes during pregnancy [27]. There is no ideal animal model that can study HEV pathogenesis during pregnancy from all aspects, though non-human primates could be suitable for studying HEV genotypes 1-4 [27]. Rabbits and pigs could be suitable models for studying the effect of chronic HEV infection on pregnancy [27].…”