Anti-Bacterial Innate Responses Enhance Paramyxovirus Replication

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DESCRIPTION (provided by applicant): The human upper airway and associated tissues harbor a diverse microbial flora. There is increasing evidence that polymicrobial infections involving bacteria and paramyxoviruses are a significant factor in human patients with chronic bronchitis, sinusitis and otitis media. Sequelae of recurrent otitis media include hearing and speech impairment that significantly impact the quality of life of both children and their parents/caregivers. Thus, there is a gap in our understanding of interactions between viral and bacterial infections as well as the impact of these microbes on immune responses. Traditionally, TLR signaling pathways have been categorized as anti-microbial, since in most cases their activation leads to innate immune responses and to restricted bacterial or viral growth. This application is based on our remarkable finding that exposure of primary human monocyte-derived cells to bacterial Toll- like receptor (TLR) agonists leads to: 1) enhanced paramyxovirus gene expression and 2) a reversal of virus-induced apoptosis. We propose that activation of TLR pathways by bacterial components does not always lead to strictly anti-microbial responses, but rather, can actually create cell environments that enhance virus replication. The central hypotheses to be tested here are that bacterially-derived TLR agonists enhance RNA virus replication through i) activation of cell survival/proliferation pathways, or ii) suppression of antiviral pathways. In Aim 1, we will test these two mechanistic hypotheses by which bacterial components enhance paramyxovirus gene expression and rescue virus-induced apoptosis. In Aim 2, we will extend these studies to determine if our preliminary results apply to other clinically-relevant RNA viruses such as respiratory syncytial virus, human parainfluenza virus, human metapneumovirus, influenza virus, and rhinovirus. In Aim 3, we will establish in vitro bacterial biofilms with nontypeable Haemophilus influenzae (NTHi) or with Streptococcus pneumoniae (pneumococcus) and determine the viral replication potential in immune and epithelial cells exposed to bacterial biofilms or biofilm-derived components. Our studies are innovative, as they show that "anti-microbial" signaling can actually create environments that promote virus replication, particularly for viral mutants which would otherwise be restricted. At the completion of this project, we will have established a firm baseline to study interactions between bacteria, viruses and the host cell signaling pathways that can modulate their replication potential. PUBLIC HEALTH RELEVANCE: There is increasing evidence that polymicrobial infections involving bacteria and paramyxoviruses are a significant factor in human patients with chronic bronchitis, sinusitis and otitis media, and the sequelae of recurrent otitis media can include hearing and speech impairment. We will test the hypotheses that bacterially-derived TLR agonists enhance RNA virus replication through i) activation of cell survival/proliferation pathways, or ii) suppression of antiviral pathways. Our studies are innovative, as they show that "anti-microbial" signaling can actually create environments that promote virus replication, particularly for viral mutants which would otherwise be restricted.