title: Production and differentiation of myeloid cells driven by proinflammatory cytokines in response to acute pneumovirus infection in mice.
abstract: Respiratory virus infections are often pathogenic, driving severe inflammatory responses. Most research has focused on localized effects of virus infection and inflammation. However, infection can induce broad-reaching, systemic changes that are only beginning to be characterized. In this study, we assessed the impact of acute pneumovirus infection in C57BL/6 mice on bone marrow hematopoiesis. We hypothesized that inflammatory cytokine production in the lung upregulates myeloid cell production in response to infection. We demonstrate a dramatic increase in the percentages of circulating myeloid cells, which is associated with pronounced elevations in inflammatory cytokines in serum (IFN-γ, IL-6, CCL2), bone (TNF-α), and lung tissue (TNF-α, IFN-γ, IL-6, CCL2, CCL3, G-CSF, osteopontin). Increased hematopoietic stem/progenitor cell percentages (Lineage(-)Sca-I(+)c-kit(+)) were also detected in the bone marrow. This increase was accompanied by an increase in the proportions of committed myeloid progenitors, as determined by colony-forming unit assays. However, no functional changes in hematopoietic stem cells occurred, as assessed by competitive bone marrow reconstitution. Systemic administration of neutralizing Abs to either TNF-α or IFN-γ blocked expansion of myeloid progenitors in the bone marrow and also limited virus clearance from the lung. These findings suggest that acute inflammatory cytokines drive production and differentiation of myeloid cells in the bone marrow by inducing differentiation of committed myeloid progenitors. Our findings provide insight into the mechanisms via which innate immune responses regulate myeloid cell progenitor numbers in response to acute respiratory virus infection.
authors.affiliation: Priority Research Centre for Asthma and Respiratory Diseases, University of Newcastle, Callaghan, New South Wales 2308, Australia; Department of Microbiology and Immunology, School of Biomedical Sciences and Pharmacy, Faculty of Health, University of Newcastle, Callaghan, New South Wales 2308, Australia; Hunter Medical Research Institute, New Lambton Heights, New South Wales 2305, Australia; and steven.maltby@newcastle.edu.au paul.foster@newcastle.edu.au.
authors.forename: Steven
authors.initials: S
authors.lastname: Maltby
authors.affiliation: Priority Research Centre for Asthma and Respiratory Diseases, University of Newcastle, Callaghan, New South Wales 2308, Australia; Department of Microbiology and Immunology, School of Biomedical Sciences and Pharmacy, Faculty of Health, University of Newcastle, Callaghan, New South Wales 2308, Australia; Hunter Medical Research Institute, New Lambton Heights, New South Wales 2305, Australia; and.
authors.forename: Nicole G
authors.initials: NG
authors.lastname: Hansbro
authors.affiliation: Priority Research Centre for Asthma and Respiratory Diseases, University of Newcastle, Callaghan, New South Wales 2308, Australia; Department of Microbiology and Immunology, School of Biomedical Sciences and Pharmacy, Faculty of Health, University of Newcastle, Callaghan, New South Wales 2308, Australia; Hunter Medical Research Institute, New Lambton Heights, New South Wales 2305, Australia; and.
authors.forename: Hock L
authors.initials: HL
authors.lastname: Tay
authors.affiliation: Priority Research Centre for Asthma and Respiratory Diseases, University of Newcastle, Callaghan, New South Wales 2308, Australia; Department of Microbiology and Immunology, School of Biomedical Sciences and Pharmacy, Faculty of Health, University of Newcastle, Callaghan, New South Wales 2308, Australia; Hunter Medical Research Institute, New Lambton Heights, New South Wales 2305, Australia; and.
authors.forename: Jessica
authors.initials: J
authors.lastname: Stewart
authors.affiliation: Priority Research Centre for Asthma and Respiratory Diseases, University of Newcastle, Callaghan, New South Wales 2308, Australia; Department of Microbiology and Immunology, School of Biomedical Sciences and Pharmacy, Faculty of Health, University of Newcastle, Callaghan, New South Wales 2308, Australia; Hunter Medical Research Institute, New Lambton Heights, New South Wales 2305, Australia; and.
authors.forename: Maximilian
authors.initials: M
authors.lastname: Plank
authors.affiliation: Priority Research Centre for Asthma and Respiratory Diseases, University of Newcastle, Callaghan, New South Wales 2308, Australia; Department of Microbiology and Immunology, School of Biomedical Sciences and Pharmacy, Faculty of Health, University of Newcastle, Callaghan, New South Wales 2308, Australia; Hunter Medical Research Institute, New Lambton Heights, New South Wales 2305, Australia; and.
authors.forename: Bianca
authors.initials: B
authors.lastname: Donges
authors.affiliation: Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Helene F
authors.initials: HF
authors.lastname: Rosenberg
authors.affiliation: Priority Research Centre for Asthma and Respiratory Diseases, University of Newcastle, Callaghan, New South Wales 2308, Australia; Department of Microbiology and Immunology, School of Biomedical Sciences and Pharmacy, Faculty of Health, University of Newcastle, Callaghan, New South Wales 2308, Australia; Hunter Medical Research Institute, New Lambton Heights, New South Wales 2305, Australia; and steven.maltby@newcastle.edu.au paul.foster@newcastle.edu.au.
authors.forename: Paul S
authors.initials: PS
authors.lastname: Foster
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000008:administration & dosage / Q000276:immunology; D001854:Bone Marrow Cells / Q000166:cytology; D002454:Cell Differentiation / Q000276:immunology*; D049109:Cell Proliferation; D016207:Cytokines / Q000097:blood / Q000276:immunology*; D006410:Hematopoiesis; D007113:Immunity, Innate; D007249:Inflammation / Q000276:immunology; D018836:Inflammation Mediators / Q000276:immunology; D007371:Interferon-gamma / Q000276:immunology; D008168:Lung / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D023461:Myeloid Progenitor Cells / Q000166:cytology*; D018111:Pneumovirus; D018186:Pneumovirus Infections / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology
chemical_list: D057134:Antibodies, Neutralizing; D016207:Cytokines; D018836:Inflammation Mediators; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma