Article

The Kunitz-Like Modulatory Protein Haemangin Is Vital for Hard Tick Blood-Feeding Success

Stanford University, United States of America
PLoS Pathogens (Impact Factor: 8.06). 08/2009; 5(7):e1000497. DOI: 10.1371/journal.ppat.1000497
Source: PubMed

ABSTRACT Ticks are serious haematophagus arthropod pests and are only second to mosquitoes as vectors of diseases of humans and animals. The salivary glands of the slower feeding hard ticks such as Haemaphysalis longicornis are a rich source of bioactive molecules and are critical to their biologic success, yet distinct molecules that help prolong parasitism on robust mammalian hosts and achieve blood-meals remain unidentified. Here, we report on the molecular and biochemical features and precise functions of a novel Kunitz inhibitor from H. longicornis salivary glands, termed Haemangin, in the modulation of angiogenesis and in persistent blood-feeding. Haemangin was shown to disrupt angiogenesis and wound healing via inhibition of vascular endothelial cell proliferation and induction of apoptosis. Further, this compound potently inactivated trypsin, chymotrypsin, and plasmin, indicating its antiproteolytic potential on angiogenic cascades. Analysis of Haemangin-specific gene expression kinetics at different blood-feeding stages of adult ticks revealed a dramatic up-regulation prior to complete feeding, which appears to be functionally linked to the acquisition of blood-meals. Notably, disruption of Haemangin-specific mRNA by a reverse genetic tool significantly diminished engorgement of adult H. longicornis, while the knock-down ticks failed to impair angiogenesis in vivo. To our knowledge, we have provided the first insights into transcriptional responses of human microvascular endothelial cells to Haemangin. DNA microarray data revealed that Haemangin altered the expression of 3,267 genes, including those of angiogenic significance, further substantiating the antiangiogenic function of Haemangin. We establish the vital roles of Haemangin in the hard tick blood-feeding process. Moreover, our results provide novel insights into the blood-feeding strategies that enable hard ticks to persistently feed and ensure full blood-meals through the modulation of angiogenesis and wound healing processes.

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    • "To date, about 15 single Kunitz-domain peptides from ticks have been functionally characterized. Classical serine protease inhibitors were analyzed from the hard ticks Rhipicephalus microplus (BMCL) [25], Rhipicephalus appendiculatus (TdPI) [26], Rhipicephalus haemaphysaloides (Rhipilin-1) [27], Haemaphysalis longicornis (HlChl, HIMKI and Haemangin) [28-30], Amblyomma cajennense (Amblyomin-X) [31], and Ixodes scapularis (Tryptogalinin) [32]. Protease inhibitors were also characterized from the soft ticks Ornithodoros moubata (TAP) [33] and Ornithodoros savignyi (FXaI) that mainly function as anti-clotting agents. "
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    BMC Evolutionary Biology 01/2014; 14(1):4. DOI:10.1186/1471-2148-14-4 · 3.41 Impact Factor
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    • "Ticks modulate neutrophil attraction by modifying chemokine and cytokine responses; reducing activation and down regulating reactive oxygen intermediates and nitric oxide; and, reducing surface integrin expression as well as endothelium expression of adhesion molecules (Brossard and Wikel, 2008; Kazimirova and Stibraniova, 2013). Wound healing is also modulated by tick saliva binding and inhibition of growth factors, reducing angiogenesis, impairing fibroblast migration, and by the presence of metalloproteases that remodel extracellular matrix (Fukumoto et al., 2006; Ribeiro et al., 2006; Kramer et al., 2008; Francischetti et al., 2009; Islam et al., 2009; Kazimirova and Stibraniova, 2013). Saliva binding and inhibition of transforming growth factor-beta (TGF-β), platelet-derived growth factor (PDGF), and fibroblast growth factor (FGF) reduces wound healing. "
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