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

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Clark, Jordan ORCID: 0000-0003-1790-7883, Penrice-Randal, Rebekah ORCID: 0000-0002-0653-2097, Sharma, Parul, Kipar, Anja, Dong, Xiaofeng, Pennington, Shaun, Marriott, Amy, Colombo, Stefano, Davidson, Andrew, Williamson, Maia Kavanagh et al (show 16 more authors) , Matthews, David ORCID: 0000-0003-4611-8795, Turtle, Lance ORCID: 0000-0002-0778-1693, Prince, Tessa ORCID: 0000-0002-8796-2629, Hughes, Grant, Patterson, Edward, Shawli, Ghada, Mega, Daniele, Subramaniam, Krishanthi, Sharp, Jo ORCID: 0000-0001-8482-5736, McLaughlin, Lynn, Zhou, En-Min, Turner, Joseph, Biagini, Giancarlo ORCID: 0000-0001-6356-6595, Owen, Andrew, Hiscox, Julian and Stewart, James ORCID: 0000-0002-8928-2037 (2020) 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. bioRxiv. 2020.10.13.334532-.

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Abstract

COVID-19 is a spectrum of clinical symptoms in humans caused by infection with SARS-CoV-2, a recently emerged coronavirus that rapidly caused a pandemic. Coalescence of this virus with seasonal respiratory viruses, particularly influenza virus is a 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, they exhibited 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 encephalitic manifestations associated with SARS-CoV-2 infection. Conversely, prior infection with a commercially available, multivalent live-attenuated influenza vaccine (Fluenz tetra) elicited the same reduction in SARS-CoV-2 RNA synthesis albeit without the associated increase in disease severity. This suggests that the innate immune response stimulated by infection with IAV is responsible for the observed inhibition of SARS-CoV-2, however, infection with attenuated, apathogenic influenza vaccine does not result in an aberrant immune response and enhanced disease severity. 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.

Item Type:	Article
Uncontrolled Keywords:	Infectious Diseases, Biodefense, Influenza, Pneumonia & Influenza, Pneumonia, Emerging Infectious Diseases, Vaccine Related, Lung, Prevention, Immunization, 2.1 Biological and endogenous factors, 2 Aetiology, Infection, 3 Good Health and Well Being
Depositing User:	Symplectic Admin
Date Deposited:	19 Oct 2020 09:30
Last Modified:	14 Mar 2024 19:09
DOI:	10.1101/2020.10.13.334532
Open Access URL:	https://www.biorxiv.org/content/10.1101/2020.10.13...
Related URLs:	Publisher
URI:	https://livrepository.liverpool.ac.uk/id/eprint/3104422