title: Alveolar macrophages contribute to the pathogenesis of human metapneumovirus infection while protecting against respiratory syncytial virus infection.
abstract: Human metapneumovirus (hMPV) and respiratory syncytial virus (RSV) are leading causes of upper and lower respiratory tract infections in young children and among elderly and immunocompromised patients. The pathogenesis of hMPV-induced lung disease is poorly understood. The lung macrophage population consists of alveolar macrophages (AMs) residing at the luminal surface of alveoli and interstitial macrophages present within the parenchymal lung interstitium. The involvement of AMs in innate immune responses to virus infections remains elusive. In this study, BALB/c mice depleted of AMs by intranasal instillation of dichloromethylene bisphosphonate (L-CL2MBP) liposomes were examined for disease, lung inflammation, and viral replication after infection with hMPV or RSV. hMPV-infected mice lacking AMs exhibited improved disease in terms of body weight loss, lung inflammation, airway obstruction, and hyperresponsiveness compared with AM-competent mice. AM depletion was associated with significantly reduced hMPV titers in the lungs, suggesting that hMPV required AMs for early entry and replication in the lung. In contrast, AM depletion in the context of RSV infection was characterized by an increase in viral replication, worsened disease, and inflammation, with increased airway neutrophils and inflammatory dendritic cells. Overall, lack of AMs resulted in a broad-spectrum disruption in type I IFN and certain inflammatory cytokine production, including TNF and IL-6, while causing a virus-specific alteration in the profile of several immunomodulatory cytokines, chemokines, and growth factors. Our study demonstrates that AMs have distinct roles in the context of human infections caused by members of the Paramyxoviridae family.
authors.affiliation: 1 Department of Pediatrics.
authors.forename: Deepthi
authors.initials: D
authors.lastname: Kolli
authors.forename: Meera R
authors.initials: MR
authors.lastname: Gupta
authors.forename: Elena
authors.initials: E
authors.lastname: Sbrana
authors.forename: Thangam S
authors.initials: TS
authors.lastname: Velayutham
authors.forename: Hong
authors.initials: H
authors.lastname: Chao
authors.forename: Antonella
authors.initials: A
authors.lastname: Casola
authors.forename: Roberto P
authors.initials: RP
authors.lastname: Garofalo
mesh_terms: D000402:Airway Obstruction / Q000276:immunology / Q000503:physiopathology / Q000821:virology; D000818:Animals; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D008168:Lung / Q000276:immunology* / Q000378:metabolism / Q000503:physiopathology / Q000821:virology; D016676:Macrophages, Alveolar / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D029121:Metapneumovirus / Q000276:immunology / Q000472:pathogenicity*; D008807:Mice, Inbred BALB C; D018184:Paramyxoviridae Infections / Q000276:immunology* / Q000378:metabolism / Q000503:physiopathology / Q000821:virology; D011014:Pneumonia / Q000276:immunology / Q000503:physiopathology / Q000821:virology; D018357:Respiratory Syncytial Virus Infections / Q000276:immunology* / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control / Q000821:virology; D012136:Respiratory Syncytial Viruses / Q000276:immunology / Q000472:pathogenicity*; D013997:Time Factors; D014779:Virus Replication
chemical_list: D016207:Cytokines; D018836:Inflammation Mediators
keywords: alveolar macrophages; human metapneumovirus; pathogenesis; respiratory syncytial virus; viral infection
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