Human Organs-on-Chips for Virology

Abstract

While conventional in vitro culture systems and animal models have been used to study the pathogenesis of viral infections and to facilitate development of vaccines and therapeutics for viral diseases, models that can accurately recapitulate human responses to infection are still lacking. Human organ-on-a-chip (Organ Chip) microfluidic culture devices that recapitulate tissue-tissue interfaces, fluid flows, mechanical cues, and organ-level physiology have been developed to narrow the gap between in vitro experimental models and human pathophysiology. Here, we describe how recent developments in Organ Chips have enabled re-creation of complex pathophysiological features of human viral infections in vitro.

Keywords: microfluidics; microphysiological system; organ-on-a-chip; viral infections; virus.

Figure 1

Application of Organ Chips to Virology. Organ Chips are emerging as a platform for viral disease models. It is expected that they could uncover signatures in virus evolution and transmission and provide opportunities for personalized response analysis and novel therapeutic drug development. This is difficult in conventional models or heterogeneous patient populations.

Figure 2

Human Liver Sinusoid Chip for HBV Infection Analysis. (A) Schematic of the human liver sinusoid model, in which the medium is recirculated via a pneumatically driven micro-pump and the collagen-coated scaffold ensures cell adherence. (B,C) The 3D chip model produces higher levels of albumin and Cyp450 compared to 2D culture models. (D) Chip models can be infected with patient-derived HBV. Adapted from [32] with permission. Abbreviations: DAPI, 4′,6-diamidino-2-phenylindole dihydrochloride; HBV, hepatitis B virus; PHH, primary human hepatocyte.

Figure 3

3D Printed Nervous System on a Chip for Pseudorabies Virus (PRV) Infection and Transmission. (A) Fabrication of the 3D printed model nervous system on a chip. (B) Schematic of central nervous system (CNS), showing CNS neuronal component in chamber 1, peripheral nervous system (PNS) neuronal component in chamber 2, and peripheral nerve component containing axons and Schwann cells in chamber 3. Direct infection of PNS neurons by PRV led to replication as indicated by fluorescence micrograph of immature (red capsid) and mature virus particles (yellow puncta) in the nucleus and axons (C), and spread of viral particles to the CNS neurons and Schwann cells (D). However, CNS neurons (D-1) and Schwann cells (D-3) exhibited only single primary colors, and not a multicolor profile in PNS neurons (D-2), suggesting a bottleneck in virus transmission. Adapted from [49] with permission from The Royal Society of Chemistry.

Figure 4

Human Lung Airway Chip Enables Study of Influenza Virus Drug-resistance Evolution. (A) Schematic diagram of a cross-section through the human airway chip. (B) Schematic diagram of the method used to generate and identify drug-resistant virus strains by human chip-to-chip transmission under drug pressure. (C) Titers of progeny viruses at the first and eighth passage (P) in control versus amantadine-treated chips. (D) Sequencing graphs showing three mutants (M2-S31N, M2-S31N/G34E, and M2-S31N/L46P) detected in the amantadine-resistant virus pool. Adapted from [69] with permission from the authors.

Figure 5

Viral Hemorrhagic Syndrome (VHS) Modeled On-chip to Study Ebola Virus (EBOV)-induced Loss of Vascular Integrity and Efficacy of Drugs. (A) A minimal design for Ebola VHS-on-a-chip. (B) Endothelial processes involved in VHS. (C) Apparent permeability (P_app) of microvessels in response to Ebola virus-like particles (VLPs). Microvessels were treated for 2 h with the indicated concentrations of VLPs, followed by a permeability assay. (D) Dose response to a drug candidate (melatonin) in microvessels exposed to 1 μg/ml Ebola VLPs for 2 h, followed by a permeability assay. Abbreviations: ECM, extracellular matrix; HUVECs, human umbilical vein endothelial cells. Adapted from [80] with permission.