The Role of Endothelial Cell-Derived Inflammatory and Vasoactive Mediators in the Pathogenesis of Bluetongue

Abstract

Bluetongue is an insect-transmitted disease of sheep and wild ruminants that is caused by bluetongue virus (BTV). Cattle are asymptomatic reservoir hosts of BTV. Infection of lung microvascular endothelial cells (ECs) is central to the pathogenesis of BTV infection of both sheep and cattle, but it is uncertain as to why sheep are highly susceptible to BTV-induced microvascular injury, whereas cattle are not. Thus, to better characterize the pathogenesis of bluetongue, the transcription of genes encoding a variety of vasoactive and inflammatory mediators was quantitated in primary ovine lung microvascular ECs (OLmVECs) exposed to BTV and/or inflammatory mediators. BTV infection of OLmVECs increased the transcription of genes encoding interleukin- (IL) 1 and IL-8, but less so IL-6, cyclooxygenase-2, and inducible nitric oxide synthase. In contrast, we previously have shown that transcription of genes encoding all of these same mediators is markedly increased in BTV-infected bovine lung microvascular ECs and that BTV-infected bovine ECs produce substantially greater quantities of prostacyclin than do sheep ECs. Thus, sheep and cattle were experimentally infected with BTV to further investigate the role of EC-derived vasoactive mediators in the pathogenesis of bluetongue. The ratio of thromboxane to prostacyclin increased during BTV infection of both sheep and cattle, but was significantly greater in sheep (P = 0.001). Increases in the ratio of thromboxane to prostacyclin, indicative of enhanced coagulation, coincided with the occurrence of clinical manifestations of bluetongue in BTV-infected sheep. The data suggest that inherent species-specific differences in the production and activities of EC-derived mediators contribute to the sensitivity of sheep to BTV-induced microvascular injury.

Sensing and Control of Bluetongue Virus Infection in Epithelial Cells via RIG-I and MDA5 Helicases

“…Bovine aortic primary endothelial cell (EC) cultures were obtained from an Aubrac breed heifer as previously described (9). Cultures of ECs were purified by fluorescence-activated cell sorting (FACS) on FL2/FL3, with a BD Aria II FACS apparatus as already described (8).…”

Bluetongue virus: virology, pathogenesis and immunity

“…Infection of bovine and ovine microvascular endothelial cells induces the transcription of interleukin 1 (IL-1), IL-8, IL-6, cyclooxygenase-2, and inducible nitric oxide synthase [19]. These mediators have been involved in the pathogenesis of severe viral haemorragic fevers.…”

“…These mediators have been involved in the pathogenesis of severe viral haemorragic fevers. Infection of sheep and cattle with BTV induces a plasmatic increase of prostacyclin and thromboxane [19]. Thromboxane is a strong pro-coagulant factor whereas prostacyclin is a potent vasodilatator and inhibitor of platelet aggregation.…”

“…Thromboxane is a strong pro-coagulant factor whereas prostacyclin is a potent vasodilatator and inhibitor of platelet aggregation. There is a much higher prostacyclin/thromboxane ratio in cattle, which may explain the lower sensitivity of cattle to BTV induced microvascular injury and thrombosis [19].…”

Experimental reproduction of bluetongue virus serotype 8 clinical disease in calves

“…Although the pathogenesis of bluetongue is similar in sheep and cattle (MacLachlan et al, 1990), it is uncertain as to why BTV infection causes extensive microvascular injury in sheep, but less in cattle. Recently the role of species-specific endothelial cell-derived inflammatory and vasoactive mediators has been shown (DeMaula et al, 2002).…”