Identifying the mechanisms by which respiratory viruses predispose to secondary bacterial infections

Antecedent viral infections predispose individuals to secondary bacterial disease, particularly in respiratory tract infections such as pneumonia, chronic obstructive pulmonary disease, otitis media and pharyngitis. Secondary bacterial infections often result in poor clinical outcomes and antibiotic treatment failure, but the mechanisms whereby viruses predispose to bacterial disease are not completely understood. We determined how infection with three ubiquitous human respiratory viruses, respiratory syncytial (RSV), human parainfluenza 3 (HPIV-3) and influenza virus alters the ability of nontypeable Haemophilus influenzae (NTHi) and Streptococcus pneumoniae to adhere to respiratory epithelial cells. RSV and HPIV-3 augmented bacterial adherence to primary bronchial epithelial cells and immortalized cell lines by up-regulating eukaryotic cell receptors for these pathogens, whereas this mechanism was less significant in primary small airway epithelial cells. Influenza virus infection enhanced bacterial adhesion but did not alter receptor expression. These studies demonstrated that the mechanisms by which viruses promote bacterial colonization vary between respiratory pathogens and are cell type-dependent.;In studies to further characterize the mechanisms by which RSV enhances bacterial adhesion, we found that RSV G glycoprotein is a receptor for NTHi and pneumococcus. NTHi and pneumococcus adhered in higher numbers to Chinese hamster ovary (CHO) cells expressing RSV G protein. Pre-incubation of CHO cells expressing RSV G protein with anti-RSV G antibodies reduced bacterial adhesion. Finally, both NTHi and pneumococci bound to RSV virions in an inoculum-dependent manner.;NTHi interacts with a number of molecules on the respiratory epithelium in order to colonize the respiratory tract. We found that NTHi uses intercellular adhesion molecule 1 (ICAM-1) expressed on respiratory epithelial cells as a receptor. NTHi adhered in higher number to CHO cells transfected with human ICAM-1 (CHQ-ICAM-1). Further studies using antibody blocking assays and western blots identified outer membrane protein PS of NTHi as a ligand for ICAM-1. Furthermore, NTHi up-regulated the expression of its own receptor, ICAM-1.;Further examination of the interactions between respiratory bacterial and viral pathogens will clarify the mechanisms responsible for secondary bacterial infections, and strategies to circumvent these processes may help reduce these complications.