Abstract
Ticks, blood-feeding arthropods, and secrete immunosuppressive molecules that inhibit host immune responses and provide survival advantages to pathogens. In this study, we characterized the immunosuppressive function of a novel tick salivary protein, DsCystatin, from Dermacentor silvarum of China. DsCystatin directly interacted with human Cathepsins L and B and inhibited their enzymatic activities. DsCystatin impaired the expression of inflammatory cytokines such as IL1β, IFNγ, TNFα, and IL6 from mouse bone marrow-derived macrophages (BMDMs) that had been stimulated with LPS or Borrelia burgdorferi. Consistently, DsCystatin inhibited the activation of mouse BMDMs and bone marrow-derived dendritic cells by downregulating the surface expression of CD80 and CD86. Mechanically, DsCystatin inhibited LPS- or B. burgdorferi-induced NFκB activation. For the first time, we identified that DsCystatin-attenuated TLR4 signaling by targeting TRAF6. DsCystatin enhanced LPS-induced autophagy, mediated TRAF6 degradation via an autophagy dependent manner, thereby impeded the downstream phosphorylation of IκBα and the nuclear transport of NFκB. Finally, DsCystatin relieved the joint inflammation in B. burgdorferi or complete Freund’s adjuvant induced mouse arthritis models. These data suggested that DsCystatin is a novel immunosuppressive protein and can potentially be used in the treatment of inflammatory diseases.
Highlights
Ticks are blood-feeding arthropods that can be temporarily parasitic on the surface of vertebrate
Sequence analysis indicated that DsCystatin ORF was 387 bp long, encoding a 128-amino acid peptide
A putative signal peptide cleavage site at amino acid position 21 was found in DsCystatin (Figure 1A)
Summary
Ticks are blood-feeding arthropods that can be temporarily parasitic on the surface of vertebrate. Ticks transmit various pathogens that cause human diseases including Lyme disease, tick-borne encephalitis, and human granulocytic anaplasmosis, among others [1, 2]. Unlike other vectors that feed in a very rapid process, ticks spend a relatively long period of time feeding on animals. Soft ticks feeding lasts several hours, whereas hard ticks feeding lasts for 6–9 days [1]. Tick saliva contains a large number of biological active molecules, which interfere with host defense response and benefit for tick feeding and pathogen transmission [3, 4]
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