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. 2016 May;32(5):368-377.
doi: 10.1016/ Epub 2016 Jan 30.

All For One and One For All on the Tick-Host Battlefield

Free PMC article

All For One and One For All on the Tick-Host Battlefield

Jindřich Chmelař et al. Trends Parasitol. .
Free PMC article


The saliva of ixodid ticks contains a mixture of bioactive molecules that target a wide spectrum of host defense mechanisms to allow ticks to feed on the vertebrate host for several days. Tick salivary proteins cluster in multigenic protein families, and individual family members display redundancy and pluripotency in their action to ameliorate or evade host immune responses. It is now clear that members of different protein families can target the same cellular or molecular pathway of the host physiological response to tick feeding. We present and discuss our hypothesis that redundancy and pluripotency evolved in tick salivary immunomodulators to evade immune recognition by the host while retaining the immunomodulatory potential of their saliva.

Keywords: immunomodulation; multigenic protein families; pluripotency; redundancy; silent antigens; tick salivary proteins.


Figure 1
Figure 1. Redundancy and pluripotency in the action of tick salivary proteins on host cellular processes
Different members of different tick protein families target the same host immune function, or the same protein targets different modules of the host immune response. (A) By inhibiting different immune cell-derived proteases with specific inhibitors, Ixodes spp. ticks can block multiple defense mechanisms. The anti-inflammatory serpin IRS-2 (Ixodes ricinus serpin-2) inhibits mast cell chymase and neutrophil cathepsin G. Both proteases are known to be involved in promoting inflammation. The second of the three major neutrophil serine proteases involved in inflammatory responses, elastase, is inhibited by another serpin, Iris (Ixodes ricinus immunosuppressor). Sialostatin L and L2 are inhibitors of the intracellular cysteine proteases cathepsin L and cathepsin S that contribute to NLRP3 inflammasome activation and the production of the pro-inflammatory cytokines interleukin-1β (IL-1β) and IL-18 in macrophages and dendritic cells (DCs). (B) The cystatin from Ixodes scapularis, sialostatin L, was shown to inhibit production of proinflammatory cytokines from DCs, the proliferation of T cells, and the production of IL-9 from Th9 cells and mast cells. Another member of an I. scapularis protein family, Salp (Salivary protein) 15, inhibited proliferation of T cells and the production of pro-inflammatory cytokines from DCs. Finally, the tick salivary serpin Iris also inhibited T cell proliferation. (C) Redundant inhibition of different modules of the interferon-β (IFN-β) signaling pathway by two members of the same multigenic family. Sialostatin L, unlike sialostatin L2, inhibits IFN-β production by DCs. Sialostatin L2, however, inhibits the phosphorylation of STAT-3 in the JAK/STAT signaling pathway and subsequent expression of several genes downstream from IFN-β-dependent DC activation.
Figure 2
Figure 2. Redundancy in a single multigenic family and antigenic variability
(A) Five members of the anti-complement protein multigenic family IxAC-B1-5 affect the same process: they bind to properdin and thus inhibit the stabilization of the C3 convertase complex which, in consequence, inhibits the activation of the alternative pathway of complement. Since there is a divergence in primary structure of individual members of IxAC-B family, it is likely that there is epitope variability and, therefore, different antigenicity across family members, while all members exert the same function on the host. Indeed, the study of Couvreur and colleagues supports such a suggestion, as the sera, raised against IxAC-B1 did not recognize other members of the family [35]. The observed functional (but not antigenical) identity results in a lower amount of protein required for each family member to achieve the inhibition of host complement, which in consequence leads to lower immunogenicity and helps to evade effective recognition by the host immune system (amount effect). On the other hand, when a single recombinant family member (e.g. IxAC-B4, Figure 2A) is tested in a functional bioassay, its concentration would have to be higher to achieve an observable effect, according to our hypothesis. E1-E5 – Epitope 1-5. (B) The sequential expression of members from one multigenic family throughout feeding results in continuous antigenic shift, while the targeted host process remains blocked. Due to this change in epitope exposure, an effective and timely antigen-specific response cannot be mounted against the tick salivary immunomodulators. Similar to other parasites such as Plasmodium spp., Trypanosoma spp., or Schistosoma spp., the antigen switch takes place at the parasite-host interface, which - in the case of ticks - is between the blood and tick saliva. Both simultaneous and sequential expression of several antigenically different family members can result in a silent antigen phenomenon. E1-E5 – Epitope 1-5, M1-M5 – member of one hypothetical multigenic family 1-5.
Figure 3
Figure 3. A perplexed network of actions in the vertebrate host is mediated by tick salivary proteins
Pluripotency and redundancy in the action of tick salivary effectors drive the formation of a complex network of molecular interactions between ticks and the hosts they parasitize. Host anti-tick defenses can be schematically divided into four branches – hemostasis (HEM), inflammation (INF), complement (COM) and antigen specific acquired immune response (AI). Tick saliva contains multigenic protein families with known or unknown function that can together target all host’s defense mechanisms (the effect on host defense mechanisms is shown as a 'tentacle' in the figure). There is redundancy in their actions both in the frame of a single family or among the members of different families. The individual members of single family can exert the same effect on the host, while expressing different antigenic epitopes (as shown on the example of cystatin family), which leads to immune system evasion. Some pluripotent proteins (e.g. Iris, Sialo L or Salp15 in the figure and other -not yet characterized- proteins) could be considered as key factors, because they can target more than one branch of immune reaction. We hypothesize that by targeting these proteins with vaccines, the functional network of tick salivary immunomodulators could be disrupted, leading to stronger host resistance to ticks and the pathogens that ticks transmit. RGD – proteins containing integrin binding motif (Arg-Gly-Asp); ADAMTS – a disintegrin and metalloprotease with thrombospondin motifs; IRS – Ixodes ricinus serpin; Iris – Ixodes ricinus immunosuppressor; Salp – Salivary protein; Sialo – Sialostatin; IxAC – Ixodes anti-complement.

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