In a very elegant study, Valenzuela [47] described the characterization of a novel salivary anticomplement protein from your American tick [47]. tissue or to facilitate blood feeding. Finally, complement inhibition by hematophagous parasites may also contribute to their success as pathogen vectors. and has been proven. The putative C2-binding protein is a 286 amino acid protein designated CRIT (for complement C2 receptor inhibiting trispanning) [29]. The recombinant extracellular domain of CRIT has been reported to inhibit classical pathway-mediated hemolysis of sheep red blood cells in a dose-dependent manner. In addition, peptides derived from the C-terminus of CRIT were demonstrated to inhibit complement activation [29]. To inhibit complement as proposed, CRIT must be exposed at the host-interactive surface but this molecule has not been detected in recent proteomic analysis of parasite surface membrane extracts [32]. The presence of a schistosome C3-binding protein at the parasite surface is controversial. Some groups reported the presence of a C3-binding molecule on intravascular parasites while others fail to confirm this [24C26, 28]. Nonetheless, labelled surface extracts were reported to contain a surface-associated 130 kDa protein that bound to C3 sepharose [31]. This molecule remains uncharacterized. A ~ 94 kDa schistosome C8 and C9 binding protein (originally designated schistosome complement inhibitory protein-1 (SCIP-1)), with antigenic and functional similarities to the human complement inhibitor protein CD59 (also called protectin), was reported to bind to purified human C8 and C9 and inhibit lysis of sheep and rabbit red blood cells by human complement [30]. Sequence analysis of purified SCIP-1 revealed it to be the previously described, 97 kDa myofibrillar protein, paramyosin. Native and recombinant paramyosin can bind ITIC human C8 and C9 and inhibit C9 polymerization onto red blood cells. The C9 binding domain has been mapped to the carboxyl terminus [30]. A second mechanism whereby paramyosin could impede complement activation was suggested by earlier work, in which the molecule was identified as a surface, Fc-binding protein to which host immunoglobulin bound [33]. Such binding would limit Fc domain access to complement components and therefore the ability of immunoglobulin to activate the classical pathway. However, the ability to detect paramyosin at the schistosome surface where it could engage immunoglobulin and complement is controversial and has not been confirmed in other studies [24]. Furthermore, paramyosin has not been detected in recent proteomic analysis of parasite surface membrane preparations [32]. Adding to the controversy is the inability of other workers to even detect immunoglobulin bound to the parasite surface (either bound their Fc receptors or otherwise) [24]. These latter studies suggest that schistosomes may not permit antibody to bind to their surface in any manner – an ideal outcome for the parasites to avoid complement activation the classical pathway. In addition to molecules that the parasites S5mt themselves produce to inhibit complement activation, schistosomes are reported to possess the remarkable property of acquiring molecules from their hosts for this purpose. One study has reported that the host complement-regulating protein DAF (delay accelerating factor) is found at the parasite surface where it may dissociate C3 convertase, and thereby impede the complement cascade [34]. Exactly how host DAF might be acquired by schistosomes is not known and proteomic analysis of the schistosome tegument has not detected DAF [32]. Pertinent host molecules that have been detected by proteomics at the tegumental surface of living worms include the alpha chain C3c/C3dg fragment of C3 [32]. This suggests that C3 can be both activated by C3 convertase and covalently linked to the parasite surface, but subsequently becomes inactivated by RCAs that are presumably recruited by schistosomes from host plasma. Complement receptor-related protein y (Crry) is one such regulatory protein and this has also been detected in adult schistosome tegumental membranes extracts by proteomic analysis [32]. In summary, intravascular schistosomes possess a host-interactive covering of low intrinsic immunogenicity as well as a collection of molecules that are proposed to impede complement action, should components of the complement cascade manage to ITIC bind to that covering. Therefore, it is perhaps no surprise that there is no significant difference in parasite development in C3-deficient transgenic mice compared with wild-type mice [35]. A study of development in C-5 deficient mice similarly concluded that C5 plays no role in defence against a primary infection in mice [36]. Ticks and complement Ticks are obligate blood feeding ectoparasites. They are vectors of viral, bacterial, protozoan and nematode pathogens of medical and veterinary importance. There are two main families of ticks, the or soft ticks and the or hard ticks. typically feed for a few hours whereas mouthparts remain embedded in host ITIC skin for up to two weeks. The long blood meal of ticks implies that they are ITIC able to deregulate host physiological processes such as hemostasis, vasoconstriction, inflammation, pain perception and immunity. These processes are targeted by bioactive molecules secreted in tick saliva [37]. Below, we describe the molecules involved in complement inhibition (Fig..