Modeling Host-Virus Interactions in Viral Infectious Diseases Using Stem-Cell-Derived Systems and CRISPR/Cas9 Technology.

Jihoon Kim,Bon-Kyoung Koo,Ki-Jun Yoon

doi:10.3390/v11020124

Abstract

Pathologies induced by viral infections have undergone extensive study, with traditional model systems such as two-dimensional (2D) cell cultures and in vivo mouse models contributing greatly to our understanding of host-virus interactions. However, the technical limitations inherent in these systems have constrained efforts to more fully understand such interactions, leading to a search for alternative in vitro systems that accurately recreate in vivo physiology in order to advance the study of viral pathogenesis. Over the last decade, there have been significant technological advances that have allowed researchers to more accurately model the host environment when modeling viral pathogenesis in vitro, including induced pluripotent stem cells (iPSCs), adult stem-cell-derived organoid culture systems and CRISPR/Cas9-mediated genome editing. Such technological breakthroughs have ushered in a new era in the field of viral pathogenesis, where previously challenging questions have begun to be tackled. These include genome-wide analysis of host-virus crosstalk, identification of host factors critical for viral pathogenesis, and the study of viral pathogens that previously lacked a suitable platform, e.g., noroviruses, rotaviruses, enteroviruses, adenoviruses, and Zika virus. In this review, we will discuss recent advances in the study of viral pathogenesis and host-virus crosstalk arising from the use of iPSC, organoid, and CRISPR/Cas9 technologies.

Highlights

Viruses are obligatory intracellular pathogens that rely on host cell surface receptors to enter the cell, and co-opt host cellular machineries to replicate, assemble, and release new virus particles
A number of studies using 3D human stem-cell-derived systems, including neurosphere culture and brain organoid models, revealed in detail the cellular phenotypes related to human microcephaly and neurological disorders that result upon Zika virus (ZIKV) infection [18,43,44,45,46,47]
2D and 3D induced pluripotent stem cells (iPSCs)- and ESC-derived model systems have been applied in multiple ways to provide significant insight into the host factors, pathogenesis and underlying biological mechanisms involved in virus infection as well as platforms for drug testing

Summary

Introduction

Viruses are obligatory intracellular pathogens that rely on host cell surface receptors to enter the cell, and co-opt host cellular machineries to replicate, assemble, and release new virus particles. Development of CRISPR/Cas genome editing enables the rapid introduction of targeted mutations or genome-wide screening in stem-cell-derived systems [20,21,22]. The combination of these technologies provides versatile and patient-specific human model systems to study virus infection and pathogenesis [19,23,24,25,26]. We review recent progress in our understanding of host-virus interaction mechanisms in human viral diseases using human stem-cell-derived model systems, combined with CRISPR/Cas genome editing technology (Figure 1).

Modeling of Viral Disease Using iPSC Technology

Modeling of Viral Pathogenesis Using Adult Stem-Cell-Derived Organoid Systems

Targeted Approaches to Identify Host Factors Regulating Infection

Conclusions and Future Perspectives