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Sequential infection with influenza A virus followed by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) leads to more severe disease and encephalitis in a mouse model of COVID-19.

By Jordan J Clark, Rebekah Penrice-Randal, Parul Sharma, Anja Kipar, Xiaofeng Dong, Shaun Pennington, Amy E Marriott, Stefano Colombo, Andrew D Davidson, Maia Kavanagh Williamson, David Matthews, Lance Turtle, Tessa Prince, Grant L Hughes, Edward I Patterson, Ghada Shawli, Krishanthi Subramaniam, Jo Sharp, Lynn McLaughlin, En-Min Zhou, Joseph D Turner, Giancarlo A Biagini, Andrew Owen, Julian Alexander Hiscox, James P Stewart

Posted 13 Oct 2020
bioRxiv DOI: 10.1101/2020.10.13.334532

COVID-19 is a spectrum of clinical symptoms in humans caused by infection with SARS-CoV-2, a recently emerged coronavirus that has rapidly caused a pandemic. Coalescence of a second wave of this virus with seasonal respiratory viruses, particularly influenza virus is a possible global health concern. To investigate this, transgenic mice expressing the human ACE2 receptor driven by the epithelial cell cytokeratin-18 gene promoter (K18-hACE2) were first infected with IAV followed by SARS-CoV-2. The host response and effect on virus biology was compared to K18-hACE2 mice infected with IAV or SARS-CoV-2 only. Infection of mice with each individual virus resulted in a disease phenotype compared to control mice. Although, SARS-CoV-2 RNA synthesis appeared significantly reduced in the sequentially infected mice, these mice had a more rapid weight loss, more severe lung damage and a prolongation of the innate response compared to singly infected or control mice. The sequential infection also exacerbated the extrapulmonary manifestations associated with SARS-CoV-2. This included a more severe encephalitis. Taken together, the data suggest that the concept of "twinfection" is deleterious and mitigation steps should be instituted as part of a comprehensive public health response to the COVID-19 pandemic.

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