Pulmonary C-fiber degeneration downregulates IFN-γ receptor 1 via IFN-α induction to attenuate RSV-induced airway hyperresponsiveness

Abstract

Respiratory syncytial virus (RSV) is a leading cause of respiratory infection in infants. Unfortunately, no effective vaccine or treatment against RSV is currently available. Pulmonary C-fibers (PCFs) are critical for regulating pulmonary inflammation and airway hyperresponsiveness (AHR). We previously reported that IFN-γ partially mediated RSV-induced airway disorders. In this study, we found that PCF degeneration alleviated RSV-induced airway inflammation, especially AHR by downregulating IFN-γ receptor 1 (IFNGR1), but had no effect on IFN-γ induction. In contrast, PCF degeneration actually increased IFN-α/β levels, as were the levels of STAT1 and phosphorylated STAT1 (pSTAT1). Exogenous IFN-α treatment induced STAT1 activation and downregulated IFNGR1 expression. These results suggest that PCFs affect IFNGR1 expression by inducing IFN-α to regulate IFN-γ-mediated airway inflammation and AHR. Thus, targeting PCFs activation may help control RSV-induced airway disorders, especially AHR, even with the presence of inflammation.

Sodium Tanshinone IIA Sulfonate Promotes RSV Replication by Type I Interferon-Independent Mechanism in Vitro

“…Antiviral response characterized by the induction of IFN-α, IFN-β and ISGs such as IP-10 are critical in inhibition viral replication [23,24], and are known in related to viral load and disease severity in RSV infection [5][6][7]. However, we found that STS treatment oppositely increased the induction of both IFN-α, IFN-β at 48 hours in response to RSV.…”

“…Helical nucleocapsids is the template for RSV polymerase transcription and replication, which are formed by viral RNA encapsidated by the nucleocapsid(N) protein [4]. The heightened viral load caused by the massive replication of RSV is closely related to the disease severity [5][6][7]. However, there is no available vaccine nor antiviral treatment against RSV [4,5].Therefore, identi cation of drug that regulates viral replication may contribute to clinical management of disease.…”

“…Type I interferon (IFN) response is the critical pathway that defense cells against virus infection by inducing the expression of hundreds of IFNstimulated genes(ISGs) such as interferon gamma-induced protein IP-10 [23,24]. IFN in the response to RSV infection is related to viral load rate of virus clearance and the severity of disease [5][6][7].…”

“…All RSV infections were carried out by RSV A2 strain, which was obtained from Prof. Enmei Liu Children's Hospital of Chongqing Medical University . The RSV A2 strain was prepared in HEp-2 cells as previously described [7]. Brie y HEp-2 cells inoculated with RSV A2 were incubated with DMEM containing 2% FBS at 37 °C (5% CO2) until the cells exhibited >90% cytopathic effect (CPE).…”

Exploring Key Genes and Mechanisms in Respiratory Syncytial Virus-Infected BALB/c Mice via Multi-Organ Expression Profiles

“…The BALB/c mice were infected with 60 μl of RSV-A2 via intranasal inoculation under 2%–5% isoflurane. Based on our previous study of lung tissue from RSV-infected mice, where antiviral interferon-α/β expression peaked at 12 h after infection ( Ye et al., 2017 ), we chose the 12-h time point for sampling. At 12 h post-RSV infection, mice were anesthetized with CO 2 and sacrificed by cervical dislocation.…”