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

Abstract

BackgroundHematophagous 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.ResultsA 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.ConclusionsMidge 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.

Ecological Dynamics Impacting Bluetongue Virus Transmission in North America

“…Culicoides feeding can cause physiologic and immunologic responses in mouse models resulting in the recruitment of leukocytic cells to bite sites (114). Recruitment of susceptible cell populations to the position of deposited virus occurs within hours of feeding and may explain a single infected midge's ability to transmit BTV to naive sheep with an efficiency of 80-100% (114,115). BTV preferentially infects endothelial cells that line the walls of blood vessels, mononuclear phagocytic cells, and dendritic cells (114).…”

“…Recruitment of susceptible cell populations to the position of deposited virus occurs within hours of feeding and may explain a single infected midge's ability to transmit BTV to naive sheep with an efficiency of 80-100% (114,115). BTV preferentially infects endothelial cells that line the walls of blood vessels, mononuclear phagocytic cells, and dendritic cells (114). After replication, BTV is released into the bloodstream where it interacts with blood cells (platelets, erythrocytes).…”

Equine keratinocytes in the pathogenesis of insect bite hypersensitivity: Just another brick in the wall?

“…nubeculosus WBE ( Table 1 ). The concentration of the ligands used in the study was based on previous work [ 34 , 37 ], while concentrations of the recombinant Culicoides allergens used were based on previously published studies [ 11 , 38 ].…”

“…Immunologically, equine IBH is described as an IgE mediated, Type I hypersensitivity reaction to salivary gland proteins of Culicoides insects [ 8 – 10 ]. While feeding, Culicoides cause significant mechanical damage to the skin and inject a pool of various salivary gland proteins which act as allergens in predisposed horses [ 11 ]. Many of these allergens are enzymes such as proteases, hyaluronidase and maltase, while the biological function of others is still not known.…”

Vesicular Stomatitis Virus Transmission: A Comparison of Incriminated Vectors

“…Recent investigations of the biting midge salivary proteome have identified several immunomodulatory proteins [106] and shown a dramatic effect of midge saliva on innate mammalian immune responses post blood-feeding [106,107,108]. Recently, orbiviruses dissemination has been shown to be highly favored when delivered during midge feeding [109]. Vector saliva may be promoting infection through co-feeding processes by impacting the immune response at the local site of feeding [105,110].…”