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 hMPVinduced 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-CL 2 MBP) 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.

Hydrogen Sulfide Is an Antiviral and Antiinflammatory Endogenous Gasotransmitter in the Airways. Role in Respiratory Syncytial Virus Infection

“…To determine whether this finding was true in vivo, mice were inoculated with UV-treated RSV (which was non-replicating as assessed in HEp-2 cells by a plaque assay) and treated with GYY4137 or control vehicle, and BAL samples were collected to measure concentration of cytokines and chemokines. As expected, UV-RSV induced secretion of cytokines known to be also released by cells such as alveolar macrophages that do not require viral replication, including IL-1β, IL-6, TNF-α, MCP-1, MIP-1β and RANTES (13,19). As shown in Figure 5, treatment of UV-RSV inoculated mice with GYY4137 significantly reduced levels of these cytokines in BAL, suggesting that H 2 S exerted immunomodulatory and antiinflammatory activities in the lung, which are distinct from its inhibitory activity on viral replication.…”

Partial Attenuation of Respiratory Syncytial Virus with a Deletion of a Small Hydrophobic Gene Is Associated with Elevated Interleukin-1β Responses

“…Of note, in our hands, epithelial cells and macrophages supported transcription of the viral genome, but neutrophils did not. While we (26,35) and other groups (36,37) have explored the role of alveolar macrophages in initiating the immune response to RSV infection by cytokine production, the role of neutrophils in RSV infection is not known. Studies have shown IL-9 (38), TNF (39), and chemokine (40) production by neutrophils in response to RSV.…”

Role of MicroRNA in the Lung's Innate Immune Response

“…Depletion of resident macrophages impairs host defense against a range of bacterial pathogens, including S. aureus , K. pneumoniae , and some P. aeruginosa isolates, as well as viral pathogens, respiratory syncytial virus and influenza A [39][40][41][42][43] . These cells are also capable of promoting tissue damage during infections by pathogens such as ExoS+ P. aeruginosa and metapneumovirus [44,45] .…”