Anti-Bacterial Innate Responses Enhance Paramyxovirus Replication

Summary

Principal Investigator: Griffith D Parks
Abstract: 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.
Funding Period: -------------------- - --------------------
more information: NIH RePORT

Top Publications

  1. pmc Mumps virus inhibits migration of primary human macrophages toward a chemokine gradient through a TNF-alpha dependent mechanism
    Caitlin M Briggs
    Department of Microbiology and Immunology, Wake Forest School of Medicine, Winston Salem, NC 27157 1064, USA
    Virology 433:245-52. 2012
  2. pmc Replication-independent activation of human plasmacytoid dendritic cells by the paramyxovirus SV5 Requires TLR7 and autophagy pathways
    Mary J Manuse
    Department of Microbiology and Immunology, School of Medicine, Wake Forest University, Winston Salem, NC 27157 1064, USA
    Virology 405:383-9. 2010
  3. pmc Activation of human macrophages by bacterial components relieves the restriction on replication of an interferon-inducing parainfluenza virus 5 (PIV5) P/V mutant
    Caitlin M Briggs
    Department of Microbiology and Immunology, Wake Forest University, School of Medicine, Medical Center Blvd, Winston Salem, NC 27157 1064, United States
    Microbes Infect 13:359-68. 2011

Detail Information

Publications3

  1. pmc Mumps virus inhibits migration of primary human macrophages toward a chemokine gradient through a TNF-alpha dependent mechanism
    Caitlin M Briggs
    Department of Microbiology and Immunology, Wake Forest School of Medicine, Winston Salem, NC 27157 1064, USA
    Virology 433:245-52. 2012
    ..MuV infection enhanced secretion of TNF-α, but not macrophage inhibitory factor (MIF). Antibody inhibition and add-back experiments demonstrated that TNF-α was both necessary and sufficient for MuV-mediate chemotaxis inhibition...
  2. pmc Replication-independent activation of human plasmacytoid dendritic cells by the paramyxovirus SV5 Requires TLR7 and autophagy pathways
    Mary J Manuse
    Department of Microbiology and Immunology, School of Medicine, Wake Forest University, Winston Salem, NC 27157 1064, USA
    Virology 405:383-9. 2010
    ..These results have implications for control of SV5 infections in vivo and for development of SV5 as a vaccine vector...
  3. pmc Activation of human macrophages by bacterial components relieves the restriction on replication of an interferon-inducing parainfluenza virus 5 (PIV5) P/V mutant
    Caitlin M Briggs
    Department of Microbiology and Immunology, Wake Forest University, School of Medicine, Medical Center Blvd, Winston Salem, NC 27157 1064, United States
    Microbes Infect 13:359-68. 2011
    ..We discuss these results in terms of the implications for mixed bacteria-virus infections and for the use of live RNA virus vectors that have been engineered to be attenuated for IFN sensitivity...