Neutrophil extracellular traps offer a new therapeutic target for elephant endotheliotropic herpes hemorrhagic disease (EEHV-HD)

Abstract

Elephant survival is threatened by a devastating hemorrhagic disease called elephant endotheliotropic herpes virus-hemorrhagic disease (EEHV-HD). Once clinical signs are observed in elephants, the disease progresses rapidly and frequently results in death. EEHV-HD negatively impacts elephant conservation because very young, reproductively immature elephants are most at risk for death. Ongoing efforts to understand disease pathogenesis and progression may identify treatment targets and improve clinical outcomes. In some lethal EEHV-HD cases, microthrombosis has been observed in organ tissues similar to other hemorrhagic diseases in humans and animals where sticky webs of protein-coated DNA strands called neutrophil extracellular traps (NETs) exacerbate thrombosis and hemorrhage associated with disseminated intravascular coagulation (DIC). In this study, we sought to identify if NET formation occurs in elephants and could contribute to poor outcomes in EEHV-HD. Our study demonstrated NET release for the first time from elephant heterophils (neutrophils) that occurred in response to various stimuli, including plasma from EEHV-HD affected elephants. EEHV-HD affected tissues contained extensive NETs suggesting that dysregulated NET formation contributes to pathogenesis of this disease. Importantly, elephant neutrophils were blocked from releasing NETs in response to EEHV-HD plasma using known NET inhibitors. The ability to stop NETs in EEHV-HD offers a new therapeutic approach that could be combined with current therapies to improve survival for affected elephants and to positively impact conservation efforts.