Abstract
Influenza B virus (IBV) is an acute, respiratory RNA virus that has been assumed to induce the eventual death of all infected cells. We and others have shown however, that infection with apparently cytopathic viruses does not necessarily lead to cell death; some cells can intrinsically clear the virus and persist in the host long-term. To determine if any cells can survive direct IBV infection, we here generate a recombinant IBV capable of activating a host-cell reporter to permanently label all infected cells. Using this system, we demonstrate that IBV infection leads to the formation of a survivor cell population in the proximal airways that are ciliated-like, but transcriptionally and phenotypically distinct from both actively infected and bystander ciliated cells. We also show that survivor cells are critical to maintain respiratory barrier function. These results highlight a host response pathway that preserves the epithelium to limit the severity of IBV disease.
Highlights
Influenza B virus (IBV) is an acute, respiratory RNA virus that has been assumed to induce the eventual death of all infected cells
In order to determine if any cells could survive direct IBV infection, we generated a Cre recombinase reporter virus in the B/Malaysia/
We accomplished this by encoding Cre recombinase in the polymerase (PB1) segment of the viral genome (Fig. 1a), an approach that we have previously published to be appropriate for exogenous gene expression in IBV21
Summary
Influenza B virus (IBV) is an acute, respiratory RNA virus that has been assumed to induce the eventual death of all infected cells. We show that survivor cells are critical to maintain respiratory barrier function These results highlight a host response pathway that preserves the epithelium to limit the severity of IBV disease. Influenza viruses cause widespread cell death and changes to the structure and composition of the epithelium[13,14] This tissue damage, combined with the rapid influx of immune cells and inflammatory cytokines, underlies the clinical symptoms of influenza disease. Upon depletion of the survivor cell population, we observe increased epithelial permeability, decreased pulmonary compliance, and delayed recovery from infection Based on these data, we propose a model in which nonlytic clearance of IBV and subsequent cellular survival is a hostadaptive process to preserve critical respiratory barrier function during an acute viral infection
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