Rhinovirus Attenuates Non-typeable Hemophilus influenzae-stimulated IL-8 Responses via TLR2-dependent Degradation of IRAK-1

PLoS Pathogens

Umadevi S. Sajjan¹  Shyamala Ganesan²  Adam T. Comstock²  Benjamin L. Unger²  Andrea N. Faris²  Marc B. Hershenson² 

[1] Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan, United States of America;Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, Michigan, United States of America

关键词: Epithelial cells;    Chemokines;    Bacterial diseases;    Alveolar macrophages;    Small interfering RNAs;    Neutrophils;    Rhinovirus infection;    Analysis of variance;   

DOI  :  10.1371/journal.ppat.1002969

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY