Tick Histamine Release Factor Is Critical for Ixodes scapularis Engorgement and Transmission of the Lyme Disease Agent

Abstract

Ticks are distributed worldwide and affect human and animal health by transmitting diverse infectious agents. Effective vaccines against most tick-borne pathogens are not currently available. In this study, we characterized a tick histamine release factor (tHRF) from Ixodes scapularis and addressed the vaccine potential of this antigen in the context of tick engorgement and B. burgdorferi transmission. Results from western blotting and quantitative Reverse Transcription-PCR showed that tHRF is secreted in tick saliva, and upregulated in Borrelia burgdorferi-infected ticks. Further, the expression of tHRF was coincident with the rapid feeding phase of the tick, suggesting a role for tHRF in tick engorgement and concomitantly, for efficient B. burgdorferi transmission. Silencing tHRF by RNA interference (RNAi) significantly impaired tick feeding and decreased B. burgdorferi burden in mice. Interfering with tHRF by actively immunizing mice with recombinant tHRF, or passively transferring tHRF antiserum, also markedly reduced the efficiency of tick feeding and B. burgdorferi burden in mice. Recombinant tHRF was able to bind to host basophils and stimulate histamine release. Therefore, we speculate that tHRF might function in vivo to modulate vascular permeability and increase blood flow to the tick bite-site, facilitating tick engorgement. These findings suggest that blocking tHRF might offer a viable strategy to complement ongoing efforts to develop vaccines to block tick feeding and transmission of tick-borne pathogens.

Deorphanization and target validation of cross-tick species conserved novel Amblyomma americanum tick saliva protein

“…The specificity of Abs to both 24 h and 48 h TSPs as well as the reactivity of mono-specific Abs to r Aam AV422 on western blots of r Aam AV422, tick saliva, haemolymph and dissected tick organs led us to conclude that this protein was ubiquitously expressed and injected into the host within 24 h of tick feeding. In the literature two other cross-tick species conserved TSPs, tick calreticulin (Sanders et al, 1998, 1999; Ferreira et al, 2002; Xu et al, 2004, 2005; Alarcon-Chaidez et al, 2006; Gao et al, 2008; Kaewhom et al, 2008; Parizi et al, 2009) and histamine release factor (Mulenga et al, 2003a Mulenga and Azad, 2005; Dai et al, 2010) have been described. A common feature between tick calreticulin and histamine release factor is that they both have homologs in vertebrates (Mulenga et al, 2003b, Mulenga and Azad, 2005; Coe and Michalak, 2009; Martins et al, 2010).…”

Modulation of host immunity by tick saliva

“…F2 crossbreeds of these two cattle were resistant to R. microplus infestation, with feeding with R. microplus larvae inducing significant increases in dermal mast cell numbers. Mast cells are major producers of the inflammatory mediator histamine, and ticks can affect histamine actions by either binding histamine via histamine-binding lipocalins [93, 94] or by promoting its secretion via histamine release factor [95], further evidence of the ambiguous role for mast cells in tick feeding responses. One explanation for histamine binding followed by its release can be explained by the need to suppress inflammatory responses at the early stage of feeding, followed by an increased need for vascular permeability during the rapid engorgement phase of tick feeding.…”

“…After migration to the site of injury, basophils degranulate and release mediators such as histamine to reject ticks in a host reaction known as cutaneous basophil hypersensitivity [103]. Similar to mast cells, histamine release from basophils can be mediated by tick histamine release factor binding [95]. Several studies have confirmed the role of basophils in acquired immunity against ticks in mice [102, 104, 105].…”

RNA Interference – A Powerful Functional Analysis Tool for Studying Tick Biology and its Control

“…These include salivary proteins such as tick histamine release factor [147], Salp15 [52], and the lectin complement pathway inhibitor (TSLPI) [145]; the latter two provide protection for B. burgdorferi against components of the host immune system. Salivary proteins Salp14 [49], Salp16 [48], and Salp25D [44] have been examined for their function in acquiring A. phagocytophilum or B. burgdorferi through RNAi.…”