Type 2 and interferon inflammation strongly regulate SARS-CoV-2 related gene expression in the airway epithelium

Satria P. Sajuthi; Peter DeFord; Nathan D. Jackson; Michael T. Montgomery; Jamie L. Everman; Cydney L. Rios; Elmar Pruesse; James D. Nolin; Elizabeth G. Plender; Michael E. Wechsler; Angel CY Mak; Celeste Eng; Sandra Salazar; Vivian Medina; Eric M. Wohlford; Scott Huntsman; Deborah A. Nickerson; Soren Germer; Michael C. Zody; Gonçalo Abecasis; Hyun Min Kang; Kenneth M. Rice; Rajesh Kumar; Sam Oh; Jose Rodriguez-Santana; Esteban G. Burchard; Max A. Seibold

A particularly vexing question regards the mechanisms that underlie the unusual 500 severity of illness associated with SARS-CoV-2, especially when compared to most 501 circulating respiratory viruses. Clearly, severe disease often entails development of 502 pneumonia, possibly resulting from an expanded tropism of SARS-CoV-2 to include 503 lower lung airway and alveolar cells. The most severe patients also appear to 504 experience an exuberant immune response, characterized a "cytokine storm" 24 , 505 occurring with and possibly driving the development of acute respiratory distress 506 syndrome (ARDS). Supposing that aspects of epithelial response to coronavirus family 507 members would be shared, including with SARS-CoV-2, we examined in vivo 508 coronavirus infection among the GALA II children. We found that CoV infections elicit a 509 broad airway transcriptome response, similar to HRV infections, and we identified a 510 panel of cytokines and transcription factors that likely regulate these responses. In 511 particular, we found that IL-6 was predicted to regulate responses to CoV and was itself 512 upregulated with these infections. These data support the recent investigation of 513 . CC-BY-NC-ND 4.0 International license author/funder. It is made available under a The copyright holder for this preprint (which was not peer-reviewed) is the . https://doi.org/10.1101/2020.04.09.034454 doi: bioRxiv preprint tocilizumab (IL-6R blocking antibody) for the treatment of COVID-19 illnesses 24 . 514 Strikingly our analysis revealed an increased cytotoxic immune response with CoV 515 infection, driven by the differential presence and activity of cytotoxic CD8+ T cells and 516 NK cells, as compared to the more heavily neutrophil-based responses to HRV 517 infection. Although preliminary, this finding, if similarly occurring with SARS-CoV-2 518 infection, could partly explain the dramatic inflammation observed in SARS-CoV-2 519 patients, which can extend to the distal lung. 520