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

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

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.