Key result
Neurotrophic factors and PYC-12 significantly suppressed virus infection, apoptosis, and inflammatory responses in influenza-infected human brain organoids.
Why the study?
Human pluripotent stem cell-derived brain organoids provide an opportunity as an in vitro model for modeling virus infection and drug screening.
hPSC-derived brain organoids can serve as a tractable model for studying viral infections and screening antiviral and neuroprotective compounds.
Brain organoids enable antiviral screening; leaves open clinical translation for influenza neuroprotection.
Human pluripotent stem cell (hPSC)-derived brain organoids offer an unprecedented opportunity for various applications as an in vitro model, such as modeling virus infection and drug screening. In this study, we present an experimental brain organoid platform for modeling infection with multiple viruses (e.g., influenza virus or enterovirus). Brain organoids challenged by influenza viruses (H1N1-WSN and H3N2-HKT68) had decreased overall organoid size, similar to ZIKA virus infection, while enteroviruses (EV68 and EV71) infected brain organoids displayed the opposite result. Then, we studied the molecular events in WSN-infected organoids, and we found that WSN could widely infect multiple cell types, and preferentially infected MAP2+ neurons compared to SOX2+ neural stem cells (NSCs) and GFAP+ astrocytes in brain organoids, and induced apoptosis of NSCs and neurons, but not astrocytes. The inflammatory responses in organoids observed to occur (Tumor necrosis factor alpha, interferon gamma, and interleukin 6) after WSN infection may further facilitate brain damage. Furthermore, transcriptional profiling revealed several upregulated genes ( CSAG3 and OAS2 ) and downregulated genes ( CDC20B, KCNJ13, OTX2-AS1, CROCC2 , and F5 ) after WSN infection for 24 hpi and 96 hpi, implicating antiviral drugs development responses to WSN. Finally, we explored neurotrophic factors (e.g., BDNF, GDNF, and NT3) and PYC-12 as antiviral and neuroprotective reagents, which could significantly suppress virus infection, apoptosis, and inflammatory responses. Collectively, we established a tractable experimental model system to investigate the impact and mechanism of virus infection on human brain development, and provide a platform for rapidly screening therapeutic compounds, advancing the development of antiviral strategies.
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Zhang et al. (2022) studied Virus infection in brain organoids. Neurotrophic factors (BDNF, GDNF, NT3) and PYC-12 was evaluated on Virus infection, apoptosis, and inflammatory responses. Neurotrophic factors and PYC-12 significantly suppressed virus infection, apoptosis, and inflammatory responses in influenza-infected human brain organoids.
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