Physiological and immunological responses to Culicoides sonorensis blood feeding: A murine model

Authors: Lehiy, Christopher; Reister-Hendricks, Lindsey; RUDER, MARK - University Of Georgia; McVey, David; Drolet, Barbara

Submitted to: Parasites & Vectors
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 6/5/2018
Publication Date: 6/20/2018
Citation: Lehiy, C.J., Reister-Hendricks, L.M., Ruder, M., McVey, D.S., Drolet, B.S. 2018. Physiological and immunological responses to Culicoides sonorensis blood feeding: A murine model. Parasites & Vectors. 11(1):358-370. https://doi.org/10.1186/s13071-018-2935-0.
DOI: https://doi.org/10.1186/s13071-018-2935-0

Interpretive Summary: Culicoides are tiny biting flies that feed on livestock and wildlife and can transmit viruses in their saliva that cause bluetongue and epizootic hemorrhagic disease. Animals can become infected from the bite of a single midge, yet if virus is injected experimentally with a syringe, it can take 100,000 times more virus to cause the same amount of disease. This ‘vector-enhanced transmission’ is poorly understood because not much is known about the basic effects of midge feeding on animals, let alone how the act of blood feeding might affect the ability of virus to infect. Here, using a mouse model, we describe the mammalian immune responses that are triggered when midges bite to take a blood meal and how these responses likely enhance the ability of these viruses to establish infection and spread throughout the animal.

Technical Abstract: Background: Hematophagous Culicoides spp. biting midges are of great agricultural importance as livestock, equine, and wildlife pests and as vectors of the orbiviruses bluetongue, epizootic hemorrhagic disease and African horse sickness. To obtain a blood meal, midges deposit saliva containing allergens, proteases, and anti-hemostatic factors, into the dermis to facilitate feeding. Infected midges deposit virus along with the myriad of salivary proteins during feeding. The extreme efficiency with which midges are able to transmit orbiviruses is not clearly understood, as much is still unknown about the physiological trauma of the bite and immune responses to saliva deposited during feeding. Of particular interest are the first few hours and days after the bite; a critical time period for any midge-transmitted virus to quickly establish a localized infection and disseminate, while avoiding the hosts’ immune responses. Results: A mouse-midge feeding model using colonized Culicoides sonorensis midges was used to characterize innate mammalian immune responses to blood-feeding. Histological analysis of skin, and cellular and cytokine profiles of draining lymph nodes show Culicoides midge feeding elicited a potent pro-inflammatory Th-mediated cellular response with significant mast cell activation, subcutaneous hematomas, hypodermal edema and dermal capillary vasodilation, and rapid infiltration of leukocytes to the bite sites. Mast cell degranulation, triggered by bite trauma and specifically by midge saliva, was key to physiological and immunological responses and the ability of midges to feed to repletion. Conclusions: Midge feeding causes physiological and immunological responses that would be highly favorable for rapid infection and systemic dissemination orbiviruses if delivered during blood-feeding. Recruitment of leukocytic cells to bitten skin brings susceptible cell populations in proximity of deposited virus within hours of feeding. Infected cells would drain to lymph nodes, which become hyperplastic in response to saliva, and result in robust viral replication in expanding cell populations and dissemination via the lymph system. Additionally, saliva-induced vasodilation and direct breaches in dermal capillaries by biting mouthparts exposes susceptible vascular endothelial cells, thereby providing immediate sites of virus replication and a dissemination route via the circulatory system. This research provides insights into the efficiency of Culicoides midges as orbivirus vectors.