title: Activation of human macrophages by bacterial components relieves the restriction on replication of an interferon-inducing parainfluenza virus 5 (PIV5) P/V mutant.
abstract: Macrophages regulate immune responses during many viral infections, and can be a major determinant of pathogenesis, virus replication and immune response to infection. Here, we have addressed the question of the outcome of infection of primary human macrophages with parainfluenza virus 5 (PIV5) and a PIV5 mutant (P/V-CPI-) that is unable to counteract interferon (IFN) responses. In cultures of naïve monocyte-derived macrophages (MDMs), WT PIV5 established a highly productive infection, whereas the P/V-CPI- mutant was restricted for replication in MDMs by IFN-beta. Restricted replication in vitro was relieved in MDM that had been activated by prior exposure to heat killed Gram positive bacteria, including Listeria monocytogenes, Streptococcus pyogenes, and Bacillus anthracis. Enhanced replication of the P/V mutant in MDM previously activated by bacterial components correlated with a reduced ability to produce IFN-beta in response to virus infection, whereas IFN signaling was intact. Activated MDM were found to upregulate the synthesis of IRAK-M, which has been previously shown to negatively regulate factors involved in TLR signaling and IFN-beta production. 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.
authors.affiliation: Department of Microbiology and Immunology, Wake Forest University, School of Medicine, Medical Center Blvd., Winston-Salem, NC 27157-1064, United States.
authors.forename: Caitlin M
authors.initials: CM
authors.lastname: Briggs
authors.forename: Robert C
authors.initials: RC
authors.lastname: Holder
authors.forename: Sean D
authors.initials: SD
authors.lastname: Reid
authors.forename: Griffith D
authors.initials: GD
authors.lastname: Parks
mesh_terms: D000818:Animals; D002522:Chlorocebus aethiops; D015967:Gene Expression Regulation, Viral; D006094:Gram-Positive Bacteria / Q000737:chemistry / Q000276:immunology; D006801:Humans; D016899:Interferon-beta / Q000378:metabolism*; D053592:Interleukin-1 Receptor-Associated Kinases / Q000378:metabolism; D008262:Macrophage Activation / Q000276:immunology*; D008264:Macrophages / Q000276:immunology / Q000378:metabolism / Q000821:virology; D009154:Mutation; D018108:Respirovirus / Q000235:genetics / Q000378:metabolism; D010253:Respirovirus Infections / Q000276:immunology* / Q000821:virology; D015398:Signal Transduction; D014709:Vero Cells; D014779:Virus Replication
chemical_list: D016899:Interferon-beta; C507771:IRAK3 protein, human; D053592:Interleukin-1 Receptor-Associated Kinases