Bioengineered Liver Cell Models of Hepatotropic Infections

Arez, Francisca; Rodrigues, Ana Paula Leite; Brito, Catarina; Alves, Paula M.

doi:10.3390/v13050773

Cited by 5 publications

(4 citation statements)

References 158 publications

(248 reference statements)

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“…While the tissue host tropism of HEV can be identified and innate immune responses characterized cells in a dish, these were unable to provide a complete picture of the human body’s response to HEV infection. Future perspectives would be designed to a suitable experimental model system resembling in vivo tissue architecture such as organoids, spheroids, bioprinted microtissues, and organ on-chip systems [ 141 ].…”

Section: In Vitro Modelsmentioning

confidence: 99%

Animal Models for Studying Congenital Transmission of Hepatitis E Virus

Yadav

Kenney

2023

Microorganisms

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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.

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Section: In Vitro Modelsmentioning

confidence: 99%

Animal Models for Studying Congenital Transmission of Hepatitis E Virus

Yadav

Kenney

2023

Microorganisms

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“…Pluripotent stem cells (PSCs) are a renewable source of cells and can be obtained via different protocols [ 59 ]. Since the cells derived from PSCs would be functional and similar to primary cells, they may be suggested as an ideal replacement for currently used cell-based models [ 60 ]. In 2012 and 2015, 2D cultures of HLCs derived from human PSCs were shown to support the entry and replication of HCVcc [ 61 , 62 ].…”

Section: In Vitro Modelsmentioning

confidence: 99%

“…Nevertheless, although great efforts are directed toward improving differentiation protocols to achieve better maturation, little progress has been achieved so far. Therefore, there is a need to provide a suitable niche that is more similar to the in vivo architecture, such as spheroids, organoids, bioprinted microtissues, and microfluidic chip devices [ 60 ].…”

Section: In Vitro Modelsmentioning

confidence: 99%

Modeling Hepatotropic Viral Infections: Cells vs. Animals

Rad

Zahmatkesh

Bikmulina

et al. 2021

Cells

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The lack of an appropriate platform for a better understanding of the molecular basis of hepatitis viruses and the absence of reliable models to identify novel therapeutic agents for a targeted treatment are the two major obstacles for launching efficient clinical protocols in different types of viral hepatitis. Viruses are obligate intracellular parasites, and the development of model systems for efficient viral replication is necessary for basic and applied studies. Viral hepatitis is a major health issue and a leading cause of morbidity and mortality. Despite the extensive efforts that have been made on fundamental and translational research, traditional models are not effective in representing this viral infection in a laboratory. In this review, we discuss in vitro cell-based models and in vivo animal models, with their strengths and weaknesses. In addition, the most important findings that have been retrieved from each model are described.

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“…In malaria, volunteer infection studies (VIS) are widely used for drug and vaccine development to achieve early proof-of-principle [ 4 ]. For the liver stage of Plasmodium infection, the generation of data to feed Population Pharmacokinetics (PopPK) models to set the clinical starting dose essentially relies on in vivo mouse models, due to limited availability of human-based in vitro models [ 5 – 7 ].…”

Section: Introductionmentioning

confidence: 99%

Translation of liver stage activity of M5717, a Plasmodium elongation factor 2 inhibitor: from bench to bedside

Khandelwal

Arez

Alves

et al. 2022

Malar J

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Background Targeting the asymptomatic liver stage of Plasmodium infection through chemoprevention could become a key intervention to reduce malaria-associated incidence and mortality. Methods M5717, a Plasmodium elongation factor 2 inhibitor, was assessed in vitro and in vivo with readily accessible Plasmodium berghei parasites. In an animal refinement, reduction, replacement approach, the in vitro IC99 value was used to feed a Population Pharmacokinetics modelling and simulation approach to determine meaningful effective doses for a subsequent Plasmodium sporozoite-induced volunteer infection study. Results Doses of 100 and 200 mg would provide exposures exceeding IC99 in 96 and 100% of the simulated population, respectively. Conclusions This approach has the potential to accelerate the search for new anti-malarials, to reduce the number of healthy volunteers needed in a clinical study and decrease and refine the animal use in the preclinical phase. Graphical Abstract

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Bioengineered Liver Cell Models of Hepatotropic Infections

Cited by 5 publications

References 158 publications

Animal Models for Studying Congenital Transmission of Hepatitis E Virus

Animal Models for Studying Congenital Transmission of Hepatitis E Virus

Modeling Hepatotropic Viral Infections: Cells vs. Animals

Translation of liver stage activity of M5717, a Plasmodium elongation factor 2 inhibitor: from bench to bedside

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