Developing human spheroid models as high-throughput compatible screening platforms for therapeutics against emerging and re-emerging viruses with pandemic potential

Authors

• P Bhattacharjee
• S Dvoracsko
• N Rutland
• B Kundu
• L Johnson
• R Cinar
• MR Iyer

Abstract

Members of the Phenuiviridae, Togaviridae and Flaviviridae viral families are associated with severe neuropathology that often leads to public health and economic burden on society. Their continuous threat as emerging and re-emerging viruses has highlighted the need for the development of effective antivirals and therapies against virus-induced disease. Currently, there are no direct acting antivirals on the market for these viral families, and efficacious antiviral discovery is hampered by the lack of predictive, well-characterized infection platforms. The development and standardization of high-throughput screening (HTS) compatible and physiologically relevant antiviral assay platforms is critical for antiviral discovery. Spheroid models derived from differentiated human induced pluripotent stem cells (hiPSCs) may provide a reliable tool for understanding virus infection and the development of HTS-compatible assays for drug discovery, as these spheroid models mimic the complex interactions of human tissues and allow us to use a wider array of readouts including pathogenesis phenotypes to discover both antiviral and cytoprotective compounds. In this study, we utilize human spheroid models to mimic brain tissue in vitro with the goal of including disease phenotypes as readouts for screening antivirals. We evaluated a panel of neurotropic viruses with high pandemic potential, including Rift Valley Fever virus (RVFV) and Chikungunya virus (CHIKV), in functional neural spheroids comprised of hiPSC-neurons and astrocytes. Here, we describe how pathogenesis readouts like intracellular calcium oscillations of the neural spheroids can be used as a functional readout for HTS of antivirals in addition to classical cell viability and infection inhibition.

Scientific Focus Area: Microbiology and Infectious Diseases

This page was last updated on Monday, September 25, 2023