Increased virulence of Culicoides midge cell-derived bluetongue virus in IFNAR mice

Authors: Drolet, Barbara; Reister-Hendricks, Lindsey; MAYO, CHRISTIE - Colorado State University; RODGERS, CASE - Colorado State University; Molik, David; MCVEY, DAVID - University Of Nebraska

Submitted to: Viruses
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 9/13/2024
Publication Date: 9/17/2024
Citation: Drolet, B.S., Reister-Hendricks, L.M., Mayo, C., Rodgers, C., Molik, D.C., McVey, D.S. 2024. Increased virulence of Culicoides midge cell-derived bluetongue virus in IFNAR mice. Viruses. 16(9). Article 1474. https://doi.org/10.3390/v16091474.
DOI: https://doi.org/10.3390/v16091474

Interpretive Summary: Bluetongue (BT) is a disease of livestock and wildlife that spreads by the bite of a small biting fly called a midge. The disease is severe in sheep and deer and leads to large financial losses in animal production and trade restrictions. To understand how the virus causes disease and test vaccine candidates to prevent disease, scientists conduct infection studies in mice and in target animals. Because it is difficult to work with midges and control how much virus they are delivering into an animals skin when they blood feed, scientists grow virus in an animal cell line that is very efficient in making the virus, hamster cells, and then inject that into the animals. But replicating the disease's severity this way is difficult for many types of the virus, even when very large doses are given to the animal. We looked into whether injecting virus that was made in midge cells would more closely mimic the clinical disease seen in animals when the virus comes from a midge bite. Mice injected with the midge-made virus got sick sooner, had more severe symptoms, and more died compared to those injected with the virus made from the hamster cells. Our findings suggest using midge cell-based virus could help recreate a more realistic infection scenario in labs and in the animals affected by the disease, without having to work directly with live biting midges.

Technical Abstract: Bluetongue (BT) is a Culicoides midge-borne hemorrhagic disease affecting cervids and ruminant livestock species, resulting in significant economic losses from animal production and trade restrictions. Experimental animal infections using the a/ß interferon receptor knockout IFNAR mouse model and susceptible target species are critical for understanding viral pathogenesis, virulence, and evaluating vaccines. However, conducting experimental vector-borne transmission studies with the vector itself are logistically difficult and experimentally problematic. Therefore, experimental infections are induced by hypodermic injection with virus typically derived from baby hamster kidney (BHK) cells. Unfortunately, for many U.S. BTV serotypes, it is difficult to replicate the severity of the disease seen in natural, midge-transmitted infections by injecting BHK-derived virus into target host animals. Using the IFNAR BTV murine model, we compared the virulence of traditional BHK cell-derived BTV-17 with C. sonorensis midge (W8) cell-derived BTV-17 to determine whether using cells of the transmission vector would provide an in vitro virulence aspect of vectortransmitted virus. At both low and high doses, mice inoculated with W8-BTV-17 had an earlier onset of viremia, earlier onset and peak of clinical signs, and significantly higher mortality compared to mice inoculated with BHK-BTV-17. Our results suggest using a Culicoides W8 cell-derived inoculum may provide an in vitro vector-enhanced infection to more closely represent disease levels seen in natural midge-transmitted infections while avoiding the logistical and experimental complexity of working with live midges.