The Effects of Pharmacological and Lentivirus-Induced Immune Suppression on Orbivirus Pathogenesis: Assessment of Virus Burden in Blood Monocytes and Tissues by Reverse Transcription-In Situ PCR

Abstract

We investigated the effects of pharmacological and lentivirus-induced immunosuppression on bluetongue virus (BTV) pathogenesis as a mechanism for virus persistence and induction of clinical disease. Immunologically normal and immunosuppressed sheep were infected subcutaneously with BTV serotype 3 (BTV-3), a foreign isolate with unknown pathogenicity in North American livestock, and with North American serotype 11 (BTV-11). Erythrocyte-associated BTV RNA was detected earlier and at greater concentrations in sheep treated with immunosuppressive drugs. Similarly, viral RNA and infectious virus were detected in blood monocytes earlier and at higher frequency in immunosuppressed animals: as many as 1 in 970 monocytes revealed BTV RNA at peak viremia, compared to <1 in 105 monocytes from immunocompetent sheep. Animals infected with BTV-3 had a higher virus burden in monocytes and lesions of greater severity than those infected with BTV-11. BTV RNA was detected by in situ hybridization in vascular endothelial cells and cells of monocyte lineage, but only in tissues from immunocompromised animals, and was most abundant in animals infected with BTV-3. In contrast, reverse transcription-in situ PCR showed BTV RNA from both viral serotypes in high numbers of tissue leukocytes and vascular endothelial cells from both immunosuppressed and, to a lesser extent, immunocompetent animals. Collectively, these findings show that BTV infection is widely distributed during acute infection but replication is highly restricted in animals with normal immunity. These findings also suggest that in addition to virulence factors that define viral serotypes, immunosuppression could play a role in the natural history of orbivirus infection, allowing for higher virus burden, increased virus persistence, and greater potential for acquisition of virus by the arthropod vector.

Comprehensive immune profiling reveals that Orbivirus infection activates immune checkpoints during acute T cell immunosuppression

“…Monocytes are one of the main targets of BTV infection in ovine and bovine PBMCs ( 17 , 47 ). No significant changes in cell percentage or number of monocytes (CD14 + ) were observed during BTV infection ( Figure 2C , Supplementary Figure 6E ).…”

Transmission of Bluetongue Virus Serotype 8 by Artificial Insemination with Frozen–Thawed Semen from Naturally Infected Bulls

“…Variations in pathogenesis, duration and clinical outcome of BTV-infections have been observed among individual animals, but the underlying mechanisms are still not fully understood [65][66][67]. Despite the fact that the animals in this study were of similar age and breed, and within the groups all subject to the same treatment, they did respond differently to the virus.…”

Potential of Using Capripoxvirus Vectored Vaccines Against Arboviruses in Sheep, Goats, and Cattle

“…In sheep, clinical signs of disease are fever, nasal discharge, drooling, facial edema, and muscle weakness, accompanied by viremia (27,35,36). Animals surviving acute infection still remain at risk for long-term effects such as chronic dermatitis and the presence of lesions at mucosal and interdigital surfaces (37). Mortality rates of BTV vary significantly between outbreaks; these outbreaks occur due to integration of susceptible sheep breeds into BTV endemic areas or through the spread of virus to BTV free sheep from infected sheep in areas between endemic and non-endemic areas (34).…”