Respiratory Enterovirus (like Parainfluenza Virus) Can Cause Chronic Lung Disease if Protection by Airway Epithelial STAT1 Is Lost

Abstract

Epithelial barrier cells are proposed to be critical for host defense, and airway epithelial cell capacity for IFN signal transduction is presumed to protect against respiratory viral infection. However, it has been difficult to fully test these concepts given the absence of tools to analyze IFN signaling specific to airway epithelial cells in vivo. To address these issues, we generated a new line of transgenic mice with Cre-driver genes (Foxj1 and Scgb1a1) for a floxed-Stat1 allele (designated Foxj1-Scgb1a1-Cre-Stat1f/f mice) to target the master IFN signal regulator STAT1 in airway epithelial cells and tested these mice for control of infection because of mouse parainfluenza (Sendai) virus and human enterovirus D68 (EV-D68). Indeed, both types of infections showed increases in viral titers and severity of acute illness in Foxj1-Scgb1a1-Cre-Stat1f/f mice and conventional Stat1−/− mice compared with wild-type mice. In concert, the chronic lung disease that develops after Sendai virus infection was also increased in Foxj1-Scgb1a1-Cre-Stat1f/f and Stat1–/– mice, marked by airway and adjacent parenchymal immune cell infiltration and mucus production for at least 7 wk postinfection. Unexpectedly, relatively mild EV-D68 infection also progressed to chronic lung disease in Foxj1-Scgb1a1-Cre-Stat1f/f and Stat1−/− mice but was limited (like viral replication) to airways. The results thereby provide proof-of-concept for a critical role of barrier epithelial cells in protection from acute illness and chronic disease after viral infection and suggest a specific role for airway epithelial cells given the limitation of EV-D68 replication and acute and chronic manifestations of disease primarily to airway tissue.

Basal epithelial stem cells cross an alarmin checkpoint for postviral lung disease

“…Moreover, increases in basal cell marker levels at 12 d continued to progress to maximal levels at 21-49 d after infection based on RNAseq and corresponding qPCR-assay and was correlated with subsequent mucinous differentiation marked by Muc5ac gene expression (Figure 2A,B). This pattern of gene expression developed in concert with bronchiolar-alveolar sites of mucinous differentiation based on PAShematoxylin staining at 49 d after infection (Figure 2C), consistent with mucous cell formation as reported previously (5). In concert with gene expression data, these remodeling sites also contained Aqp3 + Krt5 + basal cells (Figure 3A).…”

“…To extend this point, the fourth implication of our study derives from the translation of experimental data to clinical conditions exemplified by lung conditions ranging from acute lung injury to chronic remodeling disease. As noted above, the presently identified paradigm for PVLD appears to hold in varying forms across a broad sample of RNA viruses (IAV, SeV, EV-D68, RSV, HRV, and SARS-CoV) as studied in our lab and others (5,10,(58)(59)(60). The present data thereby links acute viral pneumonia to chronic bronchiolization as suggested in descriptive reports of presumed viral infection (11) and documented SARS-CoV-2 infection (27,43).…”

“…Epithelial barrier sites such as skin, gut, and lung are charged with host protection that relies on endoderm-derived epithelial stem cells to repair any possible damage (1)(2)(3). When the injury is due to infection, this barrier is further responsible for a process to contain and help eliminate the pathogen (4,5). For this task, barrier epithelial cells must also communicate upstream and downstream with immune cells to coordinate the host response (6)(7)(8).…”

“…Here we address this issue in studies of a mouse model of PVLD due to the natural rodent pathogen Sendai virus (SeV). We chose this model for several reasons: (1) the pattern of acute illness progresses from proximal to distal airspaces for a bronchiolar-alveolar (centrilobular) pattern that is characteristic of natural infection (5,32); (2) acute infectious illness is linked to progressive and long-term lung remodeling disease in a genetically susceptible but also widely engineered inbred strain (C57BL/6J) (33)(34)(35); (3) these experimental conditions allow application of highly informative single-cell, lineage-tracing, gene-reporter, and conditional gene-knockout technologies; and (4) the disease components detected to date are also routinely found in other experimental models of inflammatory lung disease and in humans with respiratory disease linked to viral infection (5,8,10,(28)(29)(30)36). In the present study, the combination of these advanced approaches reveals a subset of basal-epithelial stem cells (basal-ESCs) that are critical for homeostasis at barrier sites in skin and gut but are also reprogrammed for excessive growth, migration, and immune-activation that drive post-viral disease in the lung.…”

Group 2 Innate Lymphoid Cells Must Partner with the Myeloid–Macrophage Lineage for Long-Term Postviral Lung Disease

“…To address these issues, the current study engaged mice that were bred as Il7ra wt/Cre -Rora fl/fl mice to achieve more selective and efficient deletion of ILC2s. In addition, we employed a mouse model that manifests both acute illness and subsequent progression to chronic inflammatory disease postinfection with the natural mouse pathogen Sendai virus (SeV) (34)(35)(36)(37). To date, the SeV model appears similar to the response to human pathogens, such as IAV and respiratory enterovirus (EV-D68) in mice (17,37) and the type 2 immune response found in humans with lung disease due to asthma and chronic obstructive pulmonary disease (COPD) (34,35,38,39).…”