Hypothetical model of EHV5 pathogenesis in the horse. Drawings are based on SMART servier medical art templates. The horse’s respiratory tract is designated in blue, the circulatory system in red and the upper airway lymph nodes in orange. (1) EHV5 virions are propelled by the mucociliary escalator towards the tonsillar crypts, embedded in the nasopharynx. Here, EHV5 directly infects lymphocytes residing in lymphoid follicles (LF). Infected lymphocytes then transport the virus either directly to the bloodstream or via the lymph vessels and (2) the draining lymph nodes (especially the retropharyngeal lymph nodes) to the bloodstream. In the lymphoid follicles or draining lymph nodes, EHV5 spreads to neighbouring lymphocytes via cell–cell transfer. EHV5-infected lymphocytes might either succumb due to apoptosis or survive and function as a life-long reservoir for EHV5. Via the bloodstream or via lymphocyte-homing, EHV5-infected lymphocytes (re)route to different parts of the respiratory tract, e.g. the nasal cavities or the trachea (3a) or the lungs (3b). (3a) EHV5-infected lymphocytes might transfer infection to epithelial cells, which could amplify the infection and shed a high viral load in respiratory secretions. (3b) EHV5 infects alveolar cells and spreads to neighbouring cells via cell–cell transfer. Viral replication, together with host-specific predisposing factors might eventually trigger the onset of fibrosis and EMPF due to yet unknown reasons.