title: Rhadinovirus host entry by co-operative infection.
abstract: Rhadinoviruses establish chronic infections of clinical and economic importance. Several show respiratory transmission and cause lung pathologies. We used Murid Herpesvirus-4 (MuHV-4) to understand how rhadinovirus lung infection might work. A primary epithelial or B cell infection often is assumed. MuHV-4 targeted instead alveolar macrophages, and their depletion reduced markedly host entry. While host entry was efficient, alveolar macrophages lacked heparan - an important rhadinovirus binding target - and were infected poorly ex vivo. In situ analysis revealed that virions bound initially not to macrophages but to heparan⁺ type 1 alveolar epithelial cells (AECs). Although epithelial cell lines endocytose MuHV-4 readily in vitro, AECs did not. Rather bound virions were acquired by macrophages; epithelial infection occurred only later. Thus, host entry was co-operative - virion binding to epithelial cells licensed macrophage infection, and this in turn licensed AEC infection. An antibody block of epithelial cell binding failed to block host entry: opsonization provided merely another route to macrophages. By contrast an antibody block of membrane fusion was effective. Therefore co-operative infection extended viral tropism beyond the normal paradigm of a target cell infected readily in vitro; and macrophage involvement in host entry required neutralization to act down-stream of cell binding.
authors: Sir Albert Sakzewski Virus Research Centre, School of Chemistry and Molecular Biosciences, Royal Children's Hospital and University of Queensland, Brisbane, Australia.
authors: Clara
authors: C
authors: Lawler
authors: Division of Virology, Department of Pathology, University of Cambridge, Cambridge, United Kingdom.
authors: Ricardo
authors: R
authors: Milho
authors: Division of Virology, Department of Pathology, University of Cambridge, Cambridge, United Kingdom.
authors: Janet S
authors: JS
authors: May
authors: Sir Albert Sakzewski Virus Research Centre, School of Chemistry and Molecular Biosciences, Royal Children's Hospital and University of Queensland, Brisbane, Australia; Division of Virology, Department of Pathology, University of Cambridge, Cambridge, United Kingdom.
authors: Philip G
authors: PG
authors: Stevenson
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D004847:Epithelial Cells / Q000821:virology*; D005455:Fluorescent Antibody Technique; D006566:Herpesviridae Infections / Q000821:virology*; D008264:Macrophages / Q000821:virology*; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D011650:Pulmonary Alveoli / Q000821:virology; D018144:Rhadinovirus / Q000472:pathogenicity; D014771:Virion / Q000472:pathogenicity