Alveolar macrophage‐derived extracellular vesicles inhibit endosomal fusion of influenza virus. (9th July 2020)

• Record Type: Journal Article
• Authors: Schneider, Daniel J; Smith, Katherine A; Latuszek, Catrina E; Wilke, Carol A; Lyons, Danny M; Penke, Loka R; Speth, Jennifer M; Marthi, Matangi; Swanson, Joel A; Moore, Bethany B; Lauring, Adam S; Peters‐Golden, Marc
• Is Part Of: EMBO journal. Volume 39:Number 16(2020)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2020-07-09
• Subjects: alveolar macrophage -- endosome fusion -- epithelial cell -- extracellular vesicles -- influenza; Molecular biology -- Periodicals; 572.805
• DOI: 10.15252/embj.2020105057
• Languages: English
• ISSNs: 0261-4189

Abstract

Abstract: Alveolar macrophages (AMs) and epithelial cells (ECs) are the lone resident lung cells positioned to respond to pathogens at early stages of infection. Extracellular vesicles (EVs) are important vectors of paracrine signaling implicated in a range of (patho)physiologic contexts. Here we demonstrate that AMs, but not ECs, constitutively secrete paracrine activity localized to EVs which inhibits influenza infection of ECs in vitro and in vivo . AMs exposed to cigarette smoke extract lost the inhibitory activity of their secreted EVs. Influenza strains varied in their susceptibility to inhibition by AM‐EVs. Only those exhibiting early endosomal escape and high pH of fusion were inhibited via a reduction in endosomal pH. By contrast, strains exhibiting later endosomal escape and lower fusion pH proved resistant to inhibition. These results extend our understanding of how resident AMs participate in host defense and have broader implications in the defense and treatment of pathogens internalized within endosomes. Synopsis: Extracellular vesicles are emerging as homeostatic vectors, but poorly understood in influenza infection. Here, alveolar macrophage‐derived extracellular vesicles inhibit influenza‐endosome fusion in a strain‐specific, and pH‐dependent manner. Following initial infection of epithelial cells, the influenza virus traffics within host cell endosomes which undergo progressive acidification. Prior to gaining entry into the nucleus for its replication, influenza virus must fuse with endosome membranes—an event initiated at a strain‐specific pH. Alveolar macrophages secrete extracellular vesicles which, when internalized by epithelial cells, lead to accelerated acidification of endosomes. Infection of epithelial cells by influenza strains which preferentially fuse with endosome membranes at high pH is inhibited by extracellular vesicles. Infection by influenza strains which fuse at low pH is unaffected by extracellular vesicles. Abstract : Extracellular vesicles secreted from alveolar macrophages can promote acidification of endosomes in influenza virus‐infected epithelial cells to inhibit viral replication.