Abstract
Bacterial infections following rhinovirus (RV), a common cold virus, are well documented, but pathogenic mechanisms are poorly understood. We developed animal and cell culture models to examine the effects of RV on subsequent infection with non-typeable Hemophilus influenzae (NTHi). We focused on NTHI-induced neutrophil chemoattractants expression that is essential for bacterial clearance. Mice infected with RV1B were superinfected with NTHi and lung bacterial density, chemokines and neutrophil counts determined. Human bronchial epithelial cells (BEAS-2B) or mouse alveolar macrophages (MH-S) were infected with RV and challenged with NHTi, TLR2 or TLR5 agonists. Chemokine levels were measured by ELISA and expression of IRAK-1, a component of MyD88-dependent TLR signaling, assessed by immunoblotting. While sham-infected mice cleared all NTHi from the lungs, RV-infected mice showed bacteria up to 72 h post-infection. However, animals in RV/NTHi cleared bacteria by day 7. Delayed bacterial clearance in RV/NTHi animals was associated with suppressed chemokine levels and neutrophil recruitment. RV-infected BEAS-2B and MH-S cells showed attenuated chemokine production after challenge with either NTHi or TLR agonists. Attenuated chemokine responses were associated with IRAK-1 protein degradation. Inhibition of RV-induced IRAK-1 degradation restored NTHi-stimulated IL-8 expression. Knockdown of TLR2, but not other MyD88-dependent TLRs, also restored IRAK-1, suggesting that TLR2 is required for RV-induced IRAK-1 degradation.In conclusion, we demonstrate for the first time that RV infection delays bacterial clearance in vivo and suppresses NTHi-stimulated chemokine responses via degradation of IRAK-1. Based on these observations, we speculate that modulation of TLR-dependent innate immune responses by RV may predispose the host to secondary bacterial infection, particularly in patients with underlying chronic respiratory disorders.
Highlights
Respiratory infection by one pathogen can alter the innate immunity to unrelated pathogens long after resolution of the first infection
RV infection is associated with hospitalizations for lower respiratory tract illness, a significant proportion of which are accompanied by bacterial infections including acute otitis media, sinusitis and pneumonia
We demonstrate for the first time that RV infection promotes bacterial persistence of non-typeable Hemophilus influenzae (NTHi) in vivo, which was associated with reduced expression of neutrophil-attracting chemokines and neutrophil infiltration into the lungs
Summary
Respiratory infection by one pathogen can alter the innate immunity to unrelated pathogens long after resolution of the first infection This can affect the pathogen clearance and increase disease severity [1]. RV triggers exacerbations of chronic obstructive pulmonary disease and cystic fibrosis, conditions in which the airways are chronically colonized with bacteria [6,7] Most studies examining this problem to date have been focused on understanding the molecular mechanisms by which influenza virus predisposes host to secondary bacterial infection. In addition to immunosuppressive molecules, antiviral proteins (such as IFNs) produced during viral infections attenuate initial KC/CXCL-1 and MIP2/ CXCL2 responses to secondary pneumococcal challenge, resulting in increased persistence of bacteria and death in mouse models of infection [15]. Influenza virus desensitizes TLR receptors in vivo and decreases pro-inflammatory cytokine responses to bacterial ligands long after the viral infection resolves [16]
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