Resolved Influenza A Virus Infection Has Extended Effects on Lung Homeostasis and Attenuates Allergic Airway Inflammation in a Mouse Model.

Qingyu Wu,Olivia Kershaw,Ilka Jorde,Sabine Stegemann-Koniszewski,Jens Schreiber,Andreas Jeron,Dunja Bruder

doi:10.3390/microorganisms8121878

Abstract

Allergic airway inflammation (AAI) involves T helper cell type 2 (Th2) and pro-inflammatory responses to aeroallergens and many predisposing factors remain elusive. Influenza A virus (IAV) is a major human pathogen that causes acute respiratory infections and induces specific immune responses essential for viral clearance and resolution of the infection. Beyond acute infection, IAV has been shown to persistently affect lung homeostasis and respiratory immunity. Here we asked how resolved IAV infection affects subsequently induced AAI. Mice infected with a sublethal dose of IAV were sensitized and challenged in an ovalbumin mediated mouse model for AAI after resolution of the acute viral infection. Histological changes, respiratory leukocytes, cytokines and airway hyperreactivity were analyzed in resolved IAV infection alone and in AAI with and without previous IAV infection. More than five weeks after infection, we detected persistent pneumonia with increased activated CD4+ and CD8+ lymphocytes as well as dendritic cells and MHCII expressing macrophages in the lung. Resolved IAV infection significantly affected subsequently induced AAI on different levels including morphological changes, respiratory leukocytes and lymphocytes as well as the pro-inflammatory cytokine responses, which was clearly diminished. We conclude that IAV has exceptional persisting effects on respiratory immunity with substantial consequences for subsequently induced AAI.

Highlights

Due to constant interactions of the lungs and airways with the outside environment, there is a strong need for the regulation of respiratory immune responses [1]
In the bronchoalveolar lavage (BAL) and the lung, we detected significantly increased total cell numbers in airway inflammation (AAI) alone as well as in AAI preceded by Influenza A virus (IAV) infection as compared to uninfected, mock-sensitized controls (Figure 5a,b)
In a combined mouse model for sublethal IAV infection and AAI we show that IAV infection has extended effects on the immunological microenvironment of the lung and that it significantly affects the lymphoid and myeloid cellular composition and the pro-inflammatory cytokine response in subsequent allergic inflammation

Summary

Introduction

Due to constant interactions of the lungs and airways with the outside environment, there is a strong need for the regulation of respiratory immune responses [1]. In acute IAV infection, enhanced susceptibility to secondary bacterial infections is a major complication, which at least in part is attributed to the antiviral immune and especially the cytokine response [11,12,13,14]. In secondary bacterial infections following IAV infection, inadequate inflammatory responses are frequently observed and can be both dampened as well as overshooting [13,15]. We and others have shown that IAV infection affects the lung and the respiratory immune system for extended periods of time following clearance of the virus and resolution of the infection [12,16,17,18,19,20]. Lasting effects on patient lung function have been reported up to one year following IAV infections [21,22,23,24]

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Results

Conclusion