Human metapneumovirus infection activates the TSLP pathway that drives excessive pulmonary inflammation and viral replication in mice

Eur J Immunol. 2015 Jun;45(6):1680-95. doi: 10.1002/eji.201445021. Epub 2015 Apr 15.

Authors

Affiliations

¹ Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Millennium Institute on Immunology and Immunotherapy, Pontificia Universidad Católica de Chile, Santiago, Chile.
² Departamento de Anatomía Patológica, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile.
³ INSERM U1064, Nantes, France.
⁴ Departamento de Reumatología, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile.

PMID: 25763996
DOI: 10.1002/eji.201445021

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.

Keywords: Dendritic cells; Inflammation; Neutrophils; OX40L; TSLP; Viral replication; hMPV.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antibodies, Monoclonal / administration & dosage
Antibodies, Monoclonal / pharmacology
Cell Line
Cytokines / genetics
Cytokines / metabolism*
Dendritic Cells / immunology
Dendritic Cells / metabolism
Disease Models, Animal
Epithelial Cells / metabolism
Epithelial Cells / virology
Gene Expression
Humans
Interleukin-33
Interleukin-8 / genetics
Interleukin-8 / metabolism
Interleukins / genetics
Interleukins / metabolism
Macrophages, Alveolar / immunology
Macrophages, Alveolar / metabolism
Metapneumovirus / drug effects
Metapneumovirus / physiology*
Mice
Neutrophils / immunology
Neutrophils / metabolism
OX40 Ligand / antagonists & inhibitors
OX40 Ligand / genetics
OX40 Ligand / metabolism
Paramyxoviridae Infections / drug therapy
Paramyxoviridae Infections / genetics
Paramyxoviridae Infections / metabolism*
Paramyxoviridae Infections / pathology
Paramyxoviridae Infections / virology*
Pneumonia, Viral / drug therapy
Pneumonia, Viral / genetics
Pneumonia, Viral / metabolism*
Pneumonia, Viral / pathology
Pneumonia, Viral / virology*
Receptors, Cytokine / antagonists & inhibitors
Receptors, Cytokine / deficiency
Signal Transduction* / drug effects
T-Lymphocyte Subsets / immunology
T-Lymphocyte Subsets / metabolism
T-Lymphocyte Subsets / pathology
Thymic Stromal Lymphopoietin
Virus Replication

Substances

Antibodies, Monoclonal
CRLF2 protein, human
Cytokines
IL33 protein, human
Interleukin-33
Interleukin-8
Interleukins
OX40 Ligand
Receptors, Cytokine
Thymic Stromal Lymphopoietin