title: Human metapneumovirus infection activates the TSLP pathway that drives excessive pulmonary inflammation and viral replication in mice.
abstract: Human metapneumovirus (hMPV) is a leading cause of acute respiratory tract infections in children and the elderly. The mechanism by which this virus triggers an inflammatory response still remains unknown. Here, we evaluated whether the thymic stromal lymphopoietin (TSLP) pathway contributes to lung inflammation upon hMPV infection. We found that hMPV infection promotes TSLP expression both in human airway epithelial cells and in the mouse lung. hMPV infection induced lung infiltration of OX40L(+) CD11b(+) DCs. Mice lacking the TSLP receptor deficient mice (tslpr(-/-) ) showed reduced lung inflammation and hMPV replication. These mice displayed a decreased number of neutrophils as well a reduction in levels of thymus and activation-regulated chemokine/CCL17, IL-5, IL-13, and TNF-α in the airways upon hMPV infection. Furthermore, a higher frequency of CD4(+) and CD8(+) T cells was found in tslpr(-/-) mice compared to WT mice, which could contribute to controlling viral spread. Depletion of neutrophils in WT and tslpr(-/-) mice decreased inflammation and hMPV replication. Remarkably, blockage of TSLP or OX40L with specific Abs reduced lung inflammation and viral replication following hMPV challenge in mice. Altogether, these results suggest that activation of the TSLP pathway is pivotal in the development of pulmonary pathology and pulmonary hMPV replication.
authors.affiliation: Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Millennium Institute on Immunology and Immunotherapy, Pontificia Universidad Católica de Chile, Santiago, Chile.
authors.forename: Margarita K
authors.initials: MK
authors.lastname: Lay
authors.affiliation: Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Millennium Institute on Immunology and Immunotherapy, Pontificia Universidad Católica de Chile, Santiago, Chile.
authors.forename: Pablo F
authors.initials: PF
authors.lastname: Céspedes
authors.affiliation: Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Millennium Institute on Immunology and Immunotherapy, Pontificia Universidad Católica de Chile, Santiago, Chile.
authors.forename: Christian E
authors.initials: CE
authors.lastname: Palavecino
authors.affiliation: Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Millennium Institute on Immunology and Immunotherapy, Pontificia Universidad Católica de Chile, Santiago, Chile.
authors.forename: Miguel A
authors.initials: MA
authors.lastname: León
authors.affiliation: Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Millennium Institute on Immunology and Immunotherapy, Pontificia Universidad Católica de Chile, Santiago, Chile.
authors.forename: Rodrigo A
authors.initials: RA
authors.lastname: Díaz
authors.affiliation: Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Millennium Institute on Immunology and Immunotherapy, Pontificia Universidad Católica de Chile, Santiago, Chile.
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Salazar
authors.affiliation: Departamento de Anatomía Patológica, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile.
authors.forename: Gonzalo P
authors.initials: GP
authors.lastname: Méndez
authors.affiliation: Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Millennium Institute on Immunology and Immunotherapy, Pontificia Universidad Católica de Chile, Santiago, Chile.|INSERM U1064, Nantes, France.
authors.forename: Susan M
authors.initials: SM
authors.lastname: Bueno
authors.affiliation: Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Millennium Institute on Immunology and Immunotherapy, Pontificia Universidad Católica de Chile, Santiago, Chile.|INSERM U1064, Nantes, France.|Departamento de Reumatología, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile.
authors.forename: Alexis M
authors.initials: AM
authors.lastname: Kalergis
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000494:pharmacology; D002460:Cell Line; D016207:Cytokines / Q000235:genetics / Q000378:metabolism*; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000378:metabolism / Q000821:virology; D015870:Gene Expression; D006801:Humans; D000067596:Interleukin-33; D016209:Interleukin-8 / Q000235:genetics / Q000378:metabolism; D007378:Interleukins / Q000235:genetics / Q000378:metabolism; D016676:Macrophages, Alveolar / Q000276:immunology / Q000378:metabolism; D029121:Metapneumovirus / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D009504:Neutrophils / Q000276:immunology / Q000378:metabolism; D053278:OX40 Ligand / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D018184:Paramyxoviridae Infections / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000821:virology*; D011024:Pneumonia, Viral / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000821:virology*; D018121:Receptors, Cytokine / Q000037:antagonists & inhibitors / Q000172:deficiency; D015398:Signal Transduction / Q000187:drug effects; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D014779:Virus Replication; D000094632:Thymic Stromal Lymphopoietin
chemical_list: D000911:Antibodies, Monoclonal; C498762:CRLF2 protein, human; D016207:Cytokines; C506536:IL33 protein, human; D000067596:Interleukin-33; D016209:Interleukin-8; D007378:Interleukins; D053278:OX40 Ligand; D018121:Receptors, Cytokine; D000094632:Thymic Stromal Lymphopoietin
keywords: Dendritic cells; Inflammation; Neutrophils; OX40L; TSLP; Viral replication; hMPV