Rhadinovirus Host Entry by Co-operative Infection

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. © 2015 lawler et al.