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

Abstract

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.

Common laboratory mice are susceptible to infection with SARS-CoV2 beta variant

“…In these areas, the vascular response was more intense, with endothelial cell activation and occasional rolling and emigration of leukocytes. The observed changes are morphologically similar to those observed in K18-hACE2 mice at 3 dpi with a wt strain, though less extensive (12). Bronchial lymph nodes generally exhibited SARS-CoV-2 antigen in several macrophages and/or dendritic cells (Fig.…”

“…The wt SARS-CoV-2 is unable to infect mice due to a receptor mismatch, but accumulating evidence suggests that naturally occurring VOCs might be able to acquire this function (5,13). We probed this hypothesis and show that BALB/c mice are susceptible to infection with the beta variant producing a mild pneumonia reminiscent of what is seen in the K18-hACE2 mice and other species susceptible to SARS-CoV-2 (12). Further studies are needed to determine which other variants are similarly able to infect laboratory mice, the genetic determinants required and whether the acquired ability to infect mice is related to an increased a nity towards mACE-2 speci cally or to ACE-2 across species (including hACE-2); the latter is likely given the evidently increased transmissibility of VOCs in humans (4,13).…”

Double insult: flu bug enhances SARS-CoV-2 infectivity

“…3 In addition, sequential infection with IAV (A/HKx31(X31, H3N2)), followed by SARS-CoV-2, leads to more severe lung damage and encephalitis, while exacerbating extrapulmonary manifestations in K18-hACE2 transgenic mice. 4 The similarity of findings in these different animal models portends that coinfection of IAV and SARS-CoV may also cause more severe disease in human. Therefore, potential coinfection of IAV and SARS-CoV-2 should be a driver of increased clinical awareness.…”

SARS-CoV-2 Infections in Animals: Reservoirs for Reverse Zoonosis and Models for Study

“…The predominantly used mouse model is a transgenic model adapted to express human ACE-2 (K18-hACE-2) [ 71 ]. This model was recently used to demonstrate that infection with influenza followed by a coinfection with SARS-CoV-2 results in a more severe disease [ 72 ]. A further transgenic mouse model used experimentally is the HFH4-hACE-2 mouse [ 73 ].…”