Abstract
The key to better understanding complex virus-host interactions is the utilization of robust three-dimensional (3D) human cell cultures that effectively recapitulate native tissue architecture and model the microenvironment. A lack of physiologically-relevant animal models for many viruses has limited the elucidation of factors that influence viral pathogenesis and of complex host immune mechanisms. Conventional monolayer cell cultures may support viral infection, but are unable to form the tissue structures and complex microenvironments that mimic host physiology and, therefore, limiting their translational utility. The rotating wall vessel (RWV) bioreactor was designed by the National Aeronautics and Space Administration (NASA) to model microgravity and was later found to more accurately reproduce features of human tissue in vivo. Cells grown in RWV bioreactors develop in a low fluid-shear environment, which enables cells to form complex 3D tissue-like aggregates. A wide variety of human tissues (from neuronal to vaginal tissue) have been grown in RWV bioreactors and have been shown to support productive viral infection and physiological meaningful host responses. The in vivo-like characteristics and cellular features of the human 3D RWV-derived aggregates make them ideal model systems to effectively recapitulate pathophysiology and host responses necessary to conduct rigorous basic science, preclinical and translational studies.
Highlights
In vitro studies of complex virus-host interactions require robust cell culture models that effectively recapitulate in vivo properties and characteristics
Cells were observed to form cellular structures and features not readily expressed in conventional monolayer cell culture
For these and other reasons, we argue that the 3D cellular aggregates grown in the rotating wall vessel (RWV) bioreactor provide a more in vivo-like simulation of parental tissues, and their susceptibility to virus entry, replication and subsequent pathogenesis support their utilization for the study of these processes in vitro
Summary
In vitro studies of complex virus-host interactions require robust cell culture models that effectively recapitulate in vivo properties and characteristics. Cells grown in conventional monolayer cell cultures, often lack polarization and the architectural features of in vivo tissues and, may improperly represent key virus-host interactions [1,2,3]. Mucin production at mucosal epithelial sites influences virus-host interactions at the epithelial barrier and impacts viral infection and transmission [5,6,7] While some of these features may be present in conventional monolayer cell cultures, they often lack the polarity and other topographic features that are present in vivo. The RWV bioreactor was found to create a modeled microgravity, low fluid-shear environment that provides the necessary oxygenation and nutrients for development and polarization In this environment, cells were observed to form cellular structures and features not readily expressed in conventional monolayer cell culture. NHNP, normal human neural progenitor; VZV, Varicella zoster virus; HIV, human immunodeficiency virus; HCV, hepatitis C virus; EBV, Epstein–Barr virus; HEV, hepatitis E virus; CBV, Coxsackie B virus; HCMV, human cytomegalovirus; VSV, Vesicular stomatitis virus; HSV, herpes simplex virus; RSV, respiratory syncytial virus; PIV3, parainfluenza virus type 3; SARS- CoV, severe acute respiratory syndrome coronavirus; HuNoV, human norovirus; CPE, cytopathic effects; ND, not determined
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