The Pathogenesis and Immune Evasive Mechanisms of Equine Herpesvirus Type 1

Abstract

Equine herpesvirus type 1 (EHV-1) is an alphaherpesvirus related to pseudorabies virus (PRV) and varicella-zoster virus (VZV). This virus is one of the major pathogens affecting horses worldwide. EHV-1 is responsible for respiratory disorders, abortion, neonatal foal death and equine herpes myeloencephalopathy (EHM). Over the last decade, EHV-1 has received growing attention due to the frequent outbreaks of abortions and/or EHM causing serious economical losses to the horse industry worldwide. To date, there are no effective antiviral drugs and current vaccines do not provide full protection against EHV-1-associated diseases. Therefore, there is an urgent need to gain a better understanding of the pathogenesis of EHV-1 in order to develop effective therapies. The main objective of this review is to provide state-of-the-art information on the pathogenesis of EHV-1. We also highlight recent findings on EHV-1 immune evasive strategies at the level of the upper respiratory tract, blood circulation and endothelium of target organs allowing the virus to disseminate undetected in the host. Finally, we discuss novel approaches for drug development based on our current knowledge of the pathogenesis of EHV-1.

Keywords: Equine Herpesvirus type 1; immune evasion; pathogenesis; prevention; therapies.

FIGURE 1

Schematic representation of the pathogenesis of EHV-1 in the horse. (1) Primary EHV-1 replication in the epithelial cells of the upper respiratory tract: (a) EHV-1 infection (green); (b) Viral spread within the respiratory epithelium and viral shedding; (c) EHV-1 crosses the basement membrane (BM) and penetrates the lamina propria via the use of single infected leukocytes; (d) EHV-1 reaches the blood circulation and draining lymph nodes; (e) EHV-1 enters nerve endings of the peripheral nervous system and spreads in the retrograde direction to the trigeminal ganglia (TG). (2) EHV-1 replication in the draining lymph nodes and establishment of a cell-associated viremia in peripheral blood mononuclear cells (PBMC). (3) Establishment of EHV-1 latency in TG neurons and respiratory lymphoid tissues. (4) Via a cell-associated viremia in PBMC, EHV-1 is transported to target organs such as the pregnant uterus (4a), the central nervous system (CNS) (4b) or the eye (4c), where it initiates a secondary replication in the endothelial cells lining the blood vessels of this organ. gray, respiratory tract; red, blood circulation; yellow, lymph nodes; blue, TG; green, spinal cord. Drawings are partially based on SMART servier medical art templates.

FIGURE 2

EHV-1 immune evasive strategies. (1) Restricted replication at the URT: (a) EHV-1 infects respiratory epithelial cells; (b) Infected epithelial cells produce type I IFN to limit viral spread within the upper respiratory tract (URT); (c) Infected epithelial cells produce pro-inflammatory cytokines and chemokines to recruit immune cells to the site of infection; (d) CD172a⁺ cells and T lymphocytes migrate to the URT. EHV-1 uses these cells to cross the basement membrane (BM) and penetrate the lamina propria. (2) Hijacking leukocytes for viral dissemination. EHV-1 silences its replication in immune cells to avoid detection by neutralizing antibodies in the blood circulation and draining lymph nodes. EHV-1 only expresses immediate-early and early proteins in CD172a⁺ cells. All classes of EHV-1 proteins are expressed in T lymphocyte but viral assembly is blocked, and no progeny virions are released. (3) Cell-to-cell spread in the endothelium of target organs: EHV-1 infected immune cells are transported via the blood circulation to the pregnant uterus (a) and CNS (b). The adhesion of infected immune cells to the endothelial cells lining the blood vessels of target organs activates viral replication. New EHV-1 progeny virions are released from infected immune cells and transferred to endothelial cells via (micro)fusion events. Dashed arrows represent further spread of virus particles through connective tissues or CNS. Drawings are partially based on SMART servier medical art templates.