The Absence of Interferon-\u03b2 Promotor Stimulator-1 (IPS-1) Predisposes to Bronchiolitis and Asthma-like Pathology in Response to Pneumoviral Infection in Mice

Kirsten Spann,Simon Phipps,Vivian Zhang,Jason P. Lynch,Rhiannon B. Werder,Jennifer Simpson,Zhixuan Loh

doi:10.1038/s41598-017-02564-9

Kirsten Spann, Simon Phipps + Show 5 more

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https://doi.org/10.1038/s41598-017-02564-9

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Abstract

Respiratory syncytial virus (RSV)-bronchiolitis is a major cause of infant morbidity and mortality and a risk factor for subsequent asthma. We showed previously that toll-like receptor (TLR)7 in plasmacytoid dendritic cells (pDCs) is critical for protection against bronchiolitis and asthma in mice infected with pneumonia virus of mice (PVM), the mouse homolog of RSV. This lack of redundancy was unexpected as interferon-β promotor stimulator-1 (IPS-1) signalling, downstream of RIG-I-like receptor (RLR) and not TLR7 activation, contributes to host defence in hRSV-inoculated adult mice. To further clarify the role of IPS-1 signalling, we inoculated IPS-1−/− and WT mice with PVM in early-life, and again in later-life, to model the association between bronchiolitis and asthma. IPS-1 deficiency predisposed to severe PVM bronchiolitis, characterised by neutrophilic inflammation and necroptotic airway epithelial cell death, high mobility group box 1 (HMGB1) and IL-33 release, and downstream type-2 inflammation. Secondary infection induced an eosinophilic asthma-like pathophysiology in IPS-1−/− but not WT mice. Mechanistically, we identified that IPS-1 is necessary for pDC recruitment, IFN-α production and viral control. Our findings suggest that TLR7 and RLR signalling work collaboratively to optimally control the host response to pneumovirus infection thereby protecting against viral bronchiolitis and subsequent asthma.

Highlights

PRRs and anti-viral mediators are associated with an increased risk of severe Respiratory syncytial virus (RSV) bronchiolitis[10,11,12]
We identify that interferon-β promotor stimulator-1 (IPS-1)-mediated signalling is critical for the recruitment of plasmacytoid dendritic cells (pDCs), leading to the generation of a IFN-αhigh/IL-33lowHMGB1low cytokine microenvironment in the lung that protects against bronchiolitis and subsequent asthma[17, 19]
The coordinated antiviral host response to pneumovirus infection requires both an RIG-I-like receptor (RLR)/IPS-1 signal to induce the recruitment of pDCs, as well as TLR7-mediated activation of the recruited pDC18, explaining the non-redundant role of both PRRs

Summary

Introduction

PRRs and anti-viral mediators are associated with an increased risk of severe RSV bronchiolitis[10,11,12]. The adoptive transfer of TLR7-competent pDCs to TLR7−/− mice in early-life is sufficient to reconstitute the antiviral response, as highlighted by the restoration of type I and III IFN production and accelerated viral clearance, suggesting that TLR7 signalling in pDCs is critical for protection against severe bronchiolitis This lack of redundancy in PRR signalling was unexpected, and appears to contradict work by other investigators who have shown that IPS-1, essential for RLR but not TLR signalling, is necessary for the production of type I IFN (α/β) in adult mice following inoculation with hRSV20–22. The different phenotypes might reflect the limitations of infecting mice with a human pathogen, or the age at which the mice were inoculated, which can have profound effects on the nature of the immune response[25] To assess these possibilities, we explored whether IPS-1 deficiency predisposes toward the development of severe bronchiolitis and subsequent asthma-like pathologies following primary and secondary infection with PVM respectively

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