1. Human metapneumovirus infection activates the TSLP pathway that drives excessive pulmonary inflammation and viral replication in mice
- Author
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Lay, Margarita, Céspedes, Pablo, Palavecino, Christian, León, Miguel, Díaz, Rodrigo, Salazar, Francisco, Méndez, Gonzalo, Bueno, Susan, Kalergis, Alexis, Departamento de Microbiologıa y Genetica Molecular [Santiago, Chile] (Facultad de Ciencias Biologicas), Pontificia Universidad Católica de Chile (UC), Departamento de Anatomia Patologica [Santiago, Chile] (Facultad de Medicina), Centre de Recherche en Transplantation et Immunologie (U1064 Inserm - CRTI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Departamento de Inmunologıa Clınica y Reumatologıa [Santiago, Chile] (Escuela de Medicina), Authors are supported by grant numbers 3120019, 3140455, 1070352, 1050979, 1040349, 1100926, 1110397, 1100971 and 1110604 from the National Fund for Scientific and Technological Development (FONDECYT) program of the ministry of Education of Chile, and by grant P09-016-F from theMillennium Institute in Immunology and Immunotherapy of the ministry of Economy of Chile. AMK is a Chaire De La Région Pays De La Loire De Chercheur ´Etranger D’excellence., and Le Bihan, Sylvie
- Subjects
Neutrophils ,viruses ,Immunology ,Pneumonia, Viral ,Gene Expression ,Inflammation ,OX40 Ligand ,Virus Replication ,Cell Line ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Thymic Stromal Lymphopoietin ,T-Lymphocyte Subsets ,Macrophages, Alveolar ,Viral replication ,Immunology and Allergy ,Animals ,Humans ,Receptors, Cytokine ,030304 developmental biology ,0303 health sciences ,[SDV.MHEP] Life Sciences [q-bio]/Human health and pathology ,Paramyxoviridae Infections ,Interleukins ,Interleukin-8 ,virus diseases ,Antibodies, Monoclonal ,Epithelial Cells ,Dendritic Cells ,Interleukin-33 ,OX40L ,respiratory tract diseases ,3. Good health ,Disease Models, Animal ,TSLP ,hMPV ,Cytokines ,Metapneumovirus ,[SDV.MHEP]Life Sciences [q-bio]/Human health and pathology ,030215 immunology ,Signal Transduction - Abstract
International audience; 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 r hMPV r Inflammation r Neutrophils r OX40L r TSLP r Viral replication.
- Published
- 2014