Implication of haematophagous arthropod salivary proteins in host-vector interactions

Abstract

The saliva of haematophagous arthropods contains an array of anti-haemostatic, anti-inflammatory and immunomodulatory molecules that contribute to the success of the blood meal. The saliva of haematophagous arthropods is also involved in the transmission and the establishment of pathogens in the host and in allergic responses. This survey provides a comprehensive overview of the pharmacological activity and immunogenic properties of the main salivary proteins characterised in various haematophagous arthropod species. The potential biological and epidemiological applications of these immunogenic salivary molecules will be discussed with an emphasis on their use as biomarkers of exposure to haematophagous arthropod bites or vaccine candidates that are liable to improve host protection against vector-borne diseases.

Figure 1

Schematic representation of arthropod salivary proteins acting on primary and secondary haemostasis. Haematophagous arthropods (HA) induce injuries to vascular endothelium when probing for a blood meal. The initial event of this vascular damage is vasoconstriction (1), which retards extravascular blood loss and enhances the adhesion of platelets to exposed subendothelial collagen. This adhesion activates platelets (2) and causes the release of platelet activation agonists (Adenosine diphosphate (ADP), Thrombin, Thromboxane A₂ (TXA₂), serotonin (5-HT)) as well as platelet membrane integrin receptor αIIbβ3. Fibrinogen binds to this receptor and crosslinks platelets to form a platelet plug. The blood coagulation cascade (3) is then initiated to strengthen the platelet plug with fibrin at the site of injury. The coagulation cascade is separated into two pathways converging into a common pathway. The contact activation pathway (intrinsic) involves high-molecular weight kininogen (HMWK), prekallikrein (PK), factor XII, factor XI and factor IX (3a), and the tissue factor pathway (extrinsic) involves the tissue factor and factor VII complex (3b). Both pathways lead to the activation of factor X. The common pathway leads to the generation of thrombin from prothrombin and the ultimate production of insoluble fibrin from fibrinogen. HA have evolved anti-haemostatic salivary proteins that inhibit specific agonists and factors of platelet aggregation and the blood coagulation cascade. The known actions of some HA salivary proteins listed in Additional file 1 are indicated. (Salivary protein affiliation to HA families is indicated by colour as represented on the bottom right corner legend).

Figure 2

Schematic representation of arthropod salivary proteins involved in the modulation of innate and adaptive immunity. Protective immunity against haematophagous arthropods (HA) involves both innate and adaptive immunity. Cells involved in the innate response (e.g., neutrophils, natural killers cells (NK), mast cells and macrophages (MΦ)) represent the first line of defence. Once activated, these cells release molecules (e.g., macrophage inflammatory proteins -1 α (MIP-1α), tumour necrosis factor- α (TNF- α) or leukotrienes (LB₄, LTC₄) that initiate the inflammation process. This local inflammation can further be triggered by the activation of complement, which has chemotactic and inflammatory properties. Endothelial cells and platelets can be activated by the binding of factors of the coagulation cascade to PAR receptors, leading to an over-expression of surface adhesive molecules (ICAMs, E-selectin, P-selectin) that participate in neutrophil migration. Antigen presenting cells, such as dendritic cells (DC) migrate to the lymph nodes where they interact with naïve CD4+ helper T lymphocytes (Th0 cells) via the interplay of their T cell receptors (TCR) and major histocompatibility complex (MHC) class II proteins. Th0 cells have the potential to proliferate and to differentiate into two distinct lineages of effectors cells: Th1 and Th2 cells. Memory T helper (Th M) cells, which can improve the quality of the response to a subsequent exposure by developing more efficient memory capacity over time, are also produced. In a general pattern, HA saliva down-regulates the expression of Th1 cytokines (such as IL-2) modulating the adaptive immune response to an antibody mediated Th2 response. The action of saliva or salivary proteins is indicated in the figure as well as their corresponding organism's family. (Salivary protein affiliation to HA families is indicated by colour as represented on the bottom right corner legend).

Figure 3

Protein sequence diversity of haematophagous arthropods salivary proteins. Sequences of 13 salivary proteins of haematophagous arthropods described in the present review were submitted to BLAST analysis on the non-redundant protein database (NCBInr, NIH, Bethesda). The blastp program was used with default parameters excepting the following: search was done on the Arthropoda taxonomic level (taxid: 6656, Nov 15^th, 2010, 12,289,957 sequences), the E-value threshold was changed to a setting of 1 in order to recover only hits with highest significance on the overall protein sequence and the hit-list size was set to 5000 proteins. The number of homologous proteins with a score above 40 and their respective percentage of coverage and identity were recovered for all query proteins and sorted according to their increasing percentage of coverage. The number of homologous proteins is indicated in brackets (this includes the query sequence) and the distributions of both the percentage of coverage (bar graph with a coloured scale) and the percentage of identity (line profile above each bar graph) are represented. Proteins are grouped according to the taxonomic level of the last common taxon regrouping their corresponding homologous proteins. For graphical convenience, subclass, class and infraclass as well as superfamily, family and subfamily taxonomic levels were grouped into class and family, respectively. Salivary proteins reported to be targeted by an immune response are indicated by an asterisk (*).