Rapid community-driven development of a SARS-CoV-2 tissue simulator

Yafei Wang; Randy Heiland; Morgan Craig; Courtney L. Davis; Ashlee N Ford Versypt; Adrianne Jenner; Jonathan Ozik; Nicholson Collier; Chase Cockrell; Andrew Becker; Gary An; James A. Glazier; Aarthi Narayanan; Amber M Smith; Paul Macklin

While infected cells (e.g., type 1 or type 2 alveolar cells in the lung) cannot recover, they can respond to slow replication and reduce infection of nearby cells. Infected can secrete type I interferons (IFN-⍺,β), which diffuse and bind to receptors on nearby cells to slow viral replication, activate an inflammatory response, and induce gene transcription 14 , to slow cycling or induce apoptosis in these cells 15 . Secreted interferons can also modulate the function of innate and adaptive cellular immunity 15 . 6 Inflammatory and immune responses Lethal SARS and MERS in humans has been correlated with elevated IFN-⍺,β 20 , myeloid activity, and impaired T and B cells 21, 22 , although the timing of Type 1 IFN is critical 23, 24 . Type I IFNs secreted by infected cells or by immune cells diffuse to surrounding cells and recruit innate immune cells, such as macrophages and neutrophils, to the area. In COVID-19 patients, decreased numbers of T cells, natural killer (NK) cells, and, to a lesser extent, B cells occur, and the extent of T cell depletion has been correlated with disease severity 2,3,25 . Excessive IFN-⍺,β activation results in increased macrophage and neutrophil presence, which correlates with lung dysfunction 26, 27 . Delayed IFN-⍺,β production also promotes inflammatory macrophage recruitment that contributes to vascular leakage and impaired T-cell function 23, 24 . Activated macrophages also produce other proinflammatory cytokines like IL-1, IL-6, and TNF-⍺, among others, that enhance infiltration of immune cells and interact with endothelial cells to cause vasodilation 28 . Moreover, epithelial tissue death can reduce tissue integrity, contributing to further immune infiltration, fluid leakage and edema, and acute respiratory distress 29-31 .