An insight into the sialotranscriptome of the brown dog tick, Rhipicephalus sanguineus
- Elen Anatriello†1,
- José MC Ribeiro†3,
- Isabel KF de Miranda-Santos1, 4,
- Lucinda G Brandão1, 5,
- Jennifer M Anderson3,
- Jesus G Valenzuela3,
- Sandra R Maruyama1,
- João S Silva1 and
- Beatriz R Ferreira2Email author
© Anatriello et al; licensee BioMed Central Ltd. 2010
Received: 15 December 2009
Accepted: 22 July 2010
Published: 22 July 2010
Rhipicephalus sanguineus, known as the brown dog tick, is a common ectoparasite of domestic dogs and can be found worldwide. R. sanguineus is recognized as the primary vector of the etiological agent of canine monocytic ehrlichiosis and canine babesiosis. Here we present the first description of a R. sanguineus salivary gland transcriptome by the production and analysis of 2,034 expressed sequence tags (EST) from two cDNA libraries, one consctructed using mRNA from dissected salivary glands from female ticks fed for 3-5 days (early to mid library, RsSGL1) and the another from ticks fed for 5 days (mid library, RsSGL2), identifying 1,024 clusters of related sequences.
Based on sequence similarities to nine different databases, we identified transcripts of genes that were further categorized according to function. The category of putative housekeeping genes contained ~56% of the sequences and had on average 2.49 ESTs per cluster, the secreted protein category contained 26.6% of the ESTs and had 2.47 EST's/clusters, while 15.3% of the ESTs, mostly singletons, were not classifiable, and were annotated as "unknown function". The secreted category included genes that coded for lipocalins, proteases inhibitors, disintegrins, metalloproteases, immunomodulatory and antiinflammatory proteins, as Evasins and Da-p36, as well as basic-tail and 18.3 kDa proteins, cement proteins, mucins, defensins and antimicrobial peptides. Comparison of the abundance of ESTs from similar contigs of the two salivary gland cDNA libraries allowed the identification of differentially expressed genes, such as genes coding for Evasins and a thrombin inhibitor, which were over expressed in the RsSGL1 (early to mid library) versus RsSGL2 (mid library), indicating their role in inhibition of inflammation at the tick feeding site from the very beginning of the blood meal. Conversely, sequences related to cement (64P), which function has been correlated with tick attachment, was largely expressed in the mid library.
Our survey provided an insight into the R. sanguineus sialotranscriptome, which can assist the discovery of new targets for anti-tick vaccines, as well as help to identify pharmacologically active proteins.
The brown dog tick, Rhipicephalus sanguineus, is a cosmopolitan species from the Ixodidae family  found on all continents . Although dogs are the most common host for this tick, it has also been found on other animals, such as cats, rabbits, camels, bovines, goats, horses, sheep, bats, reptiles, and ground feeding birds , as well as from humans . It transmits two of the most important arthropod borne pathogens of dogs, namely, Ehrlichia canis and Babesia canis[4, 5].
The saliva of R. sanguineus mediates parasitism through components that modulate the innate and acquired immune response of the host [6, 7]. Accordingly, these compounds are of major importance for tick survival, helping it feed and evade host defenses, including hemostatic factors and the inflammatory responses . In order to identify protein families relevant for the tick-host interface, salivary transcriptomes (sialotranscriptomes) and microarray analysis of several Ixodid tick species have been done [9–18]. In addition, this strategy can help the identification of proteins from tick saliva that can induce anti-tick resistance and impair or block transmission of tick-borne pathogens [19–22].
Female adult ticks go through a notable succession of changes during feeding and mating. Their body sizes and weights increase gradually as the blood-feeding progresses. During the feeding period their salivary glands undergo a set of qualitative and quantitative alterations in the content of mRNA and protein [17, 18]. For R. sanguineus female ticks, at days 1-3 (i.e., the early phase of feeding) the change of weight and size is very small, while by the 5th day these parameters are 2 to 3 times greater. After this stage the rapid phase of engorgement (also called late phase) is initiated; the salivary glands start to degenerate and the ticks can reach 50 to100 times the size they were when unfed. The time taken by females of R. sanguineus to complete their engorgement is 7-10 days .
In the present work, we analyzed the sialotranscriptome of two R. sanguineus cDNA libraries, that included transcripts from salivary glands from female ticks fed for 3-5 or 5 days on dogs. A total of 2,034 high quality expressed sequence tags (ESTs) were analyzed producing 1,024 contigs, of which 910 were derived from only one EST. For functional annotation of the unique transcripts we used the BLASTx, comparing them against nine different databases. The comparison of the abundance of ESTs from each contig of the two libraries allowed identification of some genes that were significantly differentially represented. To our knowledge, this work is the first transcriptome analysis of salivary glands of R. sanguineus tick species. Moreover, the characterization of components from tick saliva is likely to be of value in future when designing novel methods for the control of ticks and tick-borne diseases, as well as searching for proteins that may have potential use in medical and veterinary pathologies".
Ticks and salivary gland collection
Ticks were obtained from two laboratory colonies, one from the Ribeirão Preto School of Medicine, University of São Paulo, Ribeirão Preto, SP (FMRP-USP), and the other from the School of Agronomical and Veterinary Sciences, São Paulo State University, Jaboticabal, SP (FCAV-UNESP), both were maintained at 29°C in a biochemical oxygen-demand incubator with 85% relative humidity. Adult ticks (25 females and 25 males) were allowed to feed in plastic feeding chambers glued (Britania Adhesives P4104 Latex, Brentwood, UK) to the back of 1-3 years old female mongrel dogs for either libraries. These dogs were not naïve to ticks, however had no ticks when were tick-infested. Tick infestations were performed at both locations (FCAV-UNESP and FMRP-USP) using four dogs (2 per group). After five days, 25 female ticks were collected and used to construct the RsSGL2 library (FCAV-UNESP), while 10 female ticks fed for 3, 4 and 5 days (summing 30 ticks) were pooled and used to make up the RsSGL1 library (FMRP-USP). Salivary glands (25-30 pairs) were dissected from female ticks and washed in ice-cold phosphate-buffered saline (PBS), pH 7.4 and then incubated in RNAlater solution (Ambion, Austin, USA) for 24 h at 4°C and then stored at -80°C until used.
cDNA library construction and sequencing
Total mRNA was isolated from R. sanguineus salivary glands using the micro Fast Track™ 2.0 RNA extraction kit (Invitrogen, Carlsbad, USA) according to the manufacturer's protocol. A long distance PCR based cDNA library was constructed in a λ TripleEx2 vector following the procedures from the SMART™ cDNA Library Construction Kit (Clontech, Palo Alto, USA). This system utilizes oligoribonucleotide (SMART IV) to attach an identical sequence at the 5' end of each reverse-transcribed cDNA strand. The sequence was then employed in subsequent PCR reactions and then digested with restriction enzymes. First-strand synthesis was carried out using PowerScript reverse transcriptase at 42°C for 1 h in the presence of the SMART IV and CDS III (3') primers. Second-strand synthesis was performed by a long-distance (LD) PCR-based protocol using Advantage™ Taq Polymerase (Clontech) mix in the presence of the 5' PCR primer and the CDS III (3') primer. The cDNA synthesis procedure resulted in the creation of Sfi I A and B restriction enzyme sites at the ends of the PCR products that are used for cloning into the phage vector.
A small portion of the cDNA obtained by PCR was analyzed on a 1.1% agarose gel with ethidium bromide (1.5 μg/mL). The optimal number of cycles with visible and equally represented products was used. Double-stranded cDNA was immediately treated with proteinase K at 45°C for 20 min, and the enzyme was removed by ultrafiltration though a Microcon (Amicon Inc., Beverly, USA) YM-100 centrifugal filter device. The cleaned, double-stranded cDNA was then digested with Sfi I at 50°C for 2 h, followed by size fractionation on a ChromaSpin-1000 column (Clontech).
The cDNA mixture was ligated into the λ TriplEx2 vector (Clontech) and the resulting ligation mixture was packaged using the GigaPack® III Plus packaging extract (Stratagene, La Jolla, CA) according to the manufacturer's instructions. The packaged library was plated by infecting log-phase XL1-Blue Escherichia coli cells (Clontech). The percentage of recombinant clones was determined by performing a blue-white selection screening on LB/MgSO4 plates containing X-gal/IPTG. Recombinants were also determined by PCR, using vector primers from the SMART™ cDNA Library Construction Kit (Clontech) and visualizing the products on a 1.1% agarose gel with ethidium bromide. Random clones were sequenced from the 5' direction only, because successful sequencing from the 3' end was usually lower than 40%. Full length sequences were obtained in selected cases by performing primer-based extension protocols. For details see Francischetti et al. and Valenzuela et al. [23, 24].
Bioinformatic tools and statistical tests used
ESTs were trimmed of primer and vector sequences. The BLASTn , CAP3 assembler  and ClustalW software  were used to compare, assemble, and align high quality ESTs, respectively. For functional annotation of the transcripts we used BLASTx  to compare the nucleotide sequences with the non-redundant (NR) protein database of the National Center of Biological Information (NCBI) and to the Gene Ontology (GO) database . The program reverse position-specific BLAST (RPS-BLAST)  was used to search for conserved protein domains in the Pfam , SMART , Kog , and conserved domains databases (CDD) . We have also compared the transcripts with a subset of mitochondrial/plastid and rRNA nucleotide sequences downloaded from NCBI and to several organism proteomes downloaded from NCBI, ENSEMBL, or VectorBase. For all comparisons please consult Additional file 1. Segments of the three-frame translations of the EST (as the libraries were unidirectional, six-frame translations were not used) starting with a methionine found in the first 30 predicted amino acids, or the predicted protein translation in the case of complete coding sequences, were submitted to the SignalP server  to help identify translation products that could be secreted. O-glycosylation sites on the proteins were predicted with the program NetOGlyc .
All sequences reported in this paper are available publicly under the accession numbers GT030184-GT032391 and EZ406035-EZ406256 (EST's from adult female salivary gland cDNA library) at GenBank and are accessible in Additional file 1.
For sequence comparisons and phylogenetic analysis, we retrieved tick sequences from GenBank, as well as deduced protein sequences from ESTs deposited in dbEST, as described and made accessible in a previous review article . Phylogenetic analysis and statistical neighbour-joining (NJ) bootstrap tests of the phylogenies were done using the Mega package  after sequence alignment was performed using ClustalX .
The individual cDNA libraries were directly compared with each other using a customized program (Count Libraries) that assesses the individual contribution of each library to the combined contig. This analysis is interesting to suggest putative proteins that may be over- or under-represented at a given time point. A Chi-square analysis was used to evaluate the significance level at p < 0.05 between the number of transcripts in the same contig originating from the two libraries used.
Results and Discussion
Overview of the assembled salivary EST set
A total of 2,034 ESTs were used to produce a R. sanguineus salivary gland specific transcriptome database (Additional file 1), 875 ESTs from 5 days fed ticks (RsSGL2) and 1,159 from 3 to 5 days fed ticks (RsSGL1), which were assembled yielding 1,024 unique transcripts ("clusters" of related sequences), 910 of which were derived from only one EST (singleton). This large number of singletons contrasts with previous sialotranscriptomes of hematophagous insects and Ixodid ticks, giving an appearance of a "normalized" library.
Classification and abundance of salivary transcripts.
Classification of transcripts associated with housekeeping function.
Protein synthesis machinery
Protein modification machinery
Metabolism, amino acid
Metabolism, free radicals
Extracellular matrix, adhesion
Putatively secreted class of expressed genes
Classification of transcripts that are associated with a secretory function.
Other putative secreted
Glycine rich polypeptides
Protease inhibitor domains
Similar to mammal skin proteins
Possible cuticle or cement
Similar to Grillus accessory gland peptide
Detailed analysis of the sialome of R. sanguineus
Putative secreted proteins with presumed or experimentally validated function
The analysis of the R. sanguineus sialotranscriptome revealed several protein sequences containing domains associated with protease inhibitors, such as Kunitz , thyropin [57, 58] and cystatins , as well as unique tick protease inhibitor domains, such as a tick carboxypeptidase inhibitor , and a tick anti-thrombin of the madanin/hirudin like family .
Cystatins are cysteine proteinase inhibitors  and have been described in the sialotranscriptome of I. scapularis, two members of which have been characterized as inhibitors of cathepsins L and S, which play roles in inflammation and immunity [70–72]. These proteins also have been regularly found in sialotranscriptomes of other hard and soft tick species . The R. sanguineus sialotranscriptome contained 3 members of this protein family (Additional file 1). Their role as a cysteine proteinase inhibitor remains to be determined.
Thyropin is a domain found as a repeat in the amino terminal region of human thyroglobulin that is proposed to be an inhibitor of cysteine proteases and binding partners of heparin [73, 74]. Proteins containing these domains have been reported from other tick sialotranscriptomes . RS-899 is a R. sanguineus protein containing 2 thyropin domains, as indicated by its comparison to the Pfam database. No tick thyropins have been functionally characterized to date.
A carboxypeptidase inhibitor, a protein that is rich in cysteins, has been previously reported in R. bursa, and postulated to affect fibrinolysis [60, 75]. Analysis of our data showed a protein RS-334 that presented match with a carboxypeptidase inhibitor (Additional file 1).
Thrombin inhibitors named madanins were isolated from the tick Haemaphysalis longicornis. A related protein named chimadanin is also a thrombin inhibitor . They have no similarities to other proteins found in the NR database. The R. sanguineus sialotranscriptome revealed 4 proteins of this family, one of which has a weak similarity to chimadanin, the others being similar to uncharacterized Amblyomma variegatum proteins annotated as hirudin-like , purported to be a thrombin inhibitor, shown by the ability to inhibit human platelet aggregation stimulated by thrombin. Members of this family were also found in deduced proteins of previously published sialotranscriptomes from metastriate, but not prostriate, ticks .
The Kazal motif characterizes many serine protease inhibitors that affects several target proteins, such as thrombin and trypsin . Three related putative peptide sequences from the R. sanguineus sialotranscriptome (RS-132, RS-359 and RS-827) matched proteins annotated as Kazal-domain, despite the fact that the R. sanguineus proteins themselves lack Kazal domain signature, as searched by rpsBLAST against the conserved domains database.
The basic tail and 18.3 kDa superfamily
The disintegrins contain an Arg-Gly-Asp (RGD) or Arg-Thr-Ser (RTS) triad flanked by cysteines. These peptides, originally discovered in snake venom, bind to platelet integrins that normally attach to fibrinogen and promote platelet aggregation [82, 83]. The R. sanguineus sialotranscriptome reveals two members (RS-325 and RS-609) related to this family. RS-325 codes for a 4.7 kDa peptide that has a typical RGD domain, but no similarity to any other known protein. Acquisition of the RGD motif by proteins of other families has been described in antigen-5 salivary proteins from tabanids , and in Kunitz peptides of ticks . In addition to its affect on host platelet aggregation, disintegrins may also act on several other inflammatory/immune cell features [85, 86], which could decrease host cell migration to the tick-feeding lesion. The transcriptome presented herein also displayed a lipocalin (RS-926) that contains a typical RTS domain of the disintegrin family , which was not found in any other member of the lipocalin family, suggesting a possible additional function. Similarly, the Kunitz containing proteins RS-316 and RS-589 also each have a RTS and a KTS motif surrounded by cysteines.
Cys-rich peptides associated with metalloproteases
Metalloproteases often have extra domains that may interact with matrix proteins . Tick sialotranscriptomes revealed Cys rich proteins that are similar to these extra domains of metalloproteases, including the expanded ixostatin family in I. scapularis and I. pacificus[11, 13]. RS-707 codes for a 14.8 kDa mature protein of that is similar to other Cys rich metastriate proteins. Their function has not been characterized.
Immunomodullatory and antiinflammatory proteins
Tick saliva has been known to have immunomodulatory activity for decades now [89–91]. More recently, unique proteins have been characterized that act directly on immune cells, or in complexing and annihilating the effect of cytokines [92, 93].
Dendritic cells pre-exposed to R. sanguineus tick saliva showed reduced migration towards chemokines CCL3 and CCL4 . These results lead to the discovery of the family of Evasin proteins, which are chemokine binding molecules isolated from R. sanguineus tick saliva  that inhibit inflammation and dendritic cell migration [95, 96]. Evasin-1 (gi|215275254) binds to chemokines CCL3, CCL4 and CCL18 and corresponds to the contig RS-77 (Additional file 2). Evasin-3 (gi|215275255) binds to chemokines CXCL1 and CXCL8, corresponding to RS-60. Evasin-4 (gi|215275256) binds to chemokines CCL5 and CCL11 and corresponds to RS-909. The R. sanguineus sialotranscriptome revealed five additional Evasin sequences (RS-95, RS-119, RS-216, RS-391 and RS-505). These Evasins group into two families, family 1: contains Evasins-1 and -4 and present the conserved block C-x(14,16)-C-x(3)-C-x(9,18)-C-x(15,18)-Y-x-C-x(2)-G-x-C-x-N-x(2,3)-C-x(8)-C, while family 2: contains Evasin-3 and the conserved motif C-x(3)-C-x(2,5)-G-x(3,4)-C-P-x(1,2)-G-x(0,1)-C-x-C.
GY (Gly-Tyr) rich peptides
Salivary transcriptomes of haematophagous arthropods, including ticks have revealed the presence of 10 kDa secreted peptides containing multiple GY repeats . Similar peptides in Caenorhabditis elegans were shown to have antimicrobial activity . The R. sanguineus sialotranscriptome contained three transcripts coding for peptides containing GY repeats, two of which have less than 60 amino acids and are distantly related (RS-11 and RS-76). They present similarities to tick and worm peptides deposited in the NR database, as well as to several peptides deduced from ESTs present in other tick transcriptomes deposited in dbEST. RS-79 codes for a larger peptide homologous to other GY rich proteins of arthropods, including some annotated as egg-shell proteins. The abundance of Tyr residues may provide for cross linking of these peptides upon phenol oxidase activity. In arthropods, these enzymes participate in sclerotizing the proteins in the flexible exoskeleton after a molt [102, 103].
Ticks attach to their hosts with the help of specialized mouthparts and remain attached by the secretion of cement proteins that glues the mouthparts into the host's skin . Some of these proteins have been characterized and tested as anti-tick vaccines [105–108]. Tick salivary Gly rich proteins are derived from several gene families, some of which are similar to spider fibroin . The R. sanguineus sialotranscriptome contained seven full length proteins of this generic family, plus eight fragments (Additional file 1).
Mucins are proteins containing galactosylation of Ser or Thr residues, and are normally found associated with mucosal membranes where they may play a role in the immune response [109, 110]. Sialotranscriptomes of ticks and other blood feeding arthropods regularly display such proteins, often with a chitin binding domain that might coat the food canals with a mucous lubricant, in addition to functioning in extracellular matrix adhesion [13, 49]. RS-676, similar to arthropod proteins annotated as mucins and peritrophins, contains five putative glycosylation sites near the carboxy terminus and a chitin binding domain (Additional file 2). RS-843 and RS-588 are related proteins with 11 putative glycosylation sites each. These proteins only provide poor matches to other proteins when queried using the program BLASTp against the NR database.
Putative secreted proteins with uncharacterized function
8.9 kDa family
5.3 kDa family
This family of peptides was initially found in I. scapularis, where some members were up regulated in ticks infected with Borrelia burgdorferi, suggesting a role in immune responses to bacteria . Two sequences (RS-968 and RS-402) of the R. sanguineus sialotranscriptome matched with this family.
Metastriate one-of-each family
Metastriate acid tail family
RS-907 and RS-881 are similar to R. microplus and Amblyomma proteins that have an acidic tail. PsiBLAST of these proteins against the NR plus tick protein data sets recovers only tick proteins thus this appears to be a tick specific protein with unknown function.
Other putative secreted proteins
Additional file 2 describes 11 proteins annotated as putative secreted. Some of them match previously described tick proteins that have not been characterized as a protein family due to lack of members in different species. It is possible that they may be recognizable as members of protein families as more transcriptomes/genomes are annotated, or they may represent R. sanguineus proteins resulting from genes under accelerated divergent evolution. It should also be noted that some of these proteins may represent annotation artifacts of 3' UTR's, or may represent the truncated carboxyterminus of known proteins, because their membrane domains will often appear as a signal peptide. Additionally, four proteins with putative signal peptide were highly conserved, and accordingly, may represent housekeeping proteins with hormonal or extracellular matrix functions.
Differential expression among the two libraries
The EST abundance and assembly derived from two libraries, one made of mRNA from ticks feeding for 3-5 days (early to mid library, RsSGL1) and the other from ticks feeding for 5 days (mid library, RsSGL2) is depicted in Additional file 1. Comparison of the abundance of ESTs contributing to each contig in Count Libraries by chi square analysis allowed for the identification of some genes that are significantly differentially represented among the two libraries.
Differentially expressed transcripts between the RsSGL1 and RsSGL2 cDNA libraries.
Number of Contig
Best match of Over expressed Cluster to NR protein database Probable secreted class of protein
No of ESTs RsSGL1
No of ESTs RsSGL2
p value χ2test
Protease inhibitor domain-containing
gi67968373 chimadanin Thrombin inhibitor
gi82791912 putative serotonin and histamine binding protein [Rhipicephalus haemaphysaloides haemaphysaloides]
gi82791912 putative serotonin and histamine binding protein [Rhipicephalus haemaphysaloides haemaphysaloides]
gi68131541 hypothetical protein
Glycine rich proteins/other cement related sequences
gi20069012salivary gland-associated protein 64P
gi215275255EVA3_RHISA RecName: Full = Evasin-3
Other putative salivary peptides
gi215497897 secreted protein, putative
gi76786687 putative secreted protein
Analysis of the sialotranscriptome of two R. sanguineus cDNA libraries, from RsSGL1 and RsSGL2, identified many transcripts coding for different components that can favor the tick in detriment of the host. Some were common to both libraries, such as protein sequences associated with proteases inhibitors, disintegrins with RGD, RST and KTS motifs, immunomodullatory and antiinflammatory proteins, such as Evasins and Da-p36, as well as basic tail and 18.3 kDa proteins, mucins, defensins and antimicrobial peptides. An additional phylogenetic analysis indicated conservation between protein families, a phenomenon also found in other tick species, in particular expansion of the lipocalin and Kunitz superfamilies. The phylograms also indicated species specific expansions that probably result from recent gene duplication events, suggested as of important evolutionary adaptive value [13, 113]. Moreover, the phylogenetic trees depict that most of the R. sanguineus sequences are dispersed into different clades, which contain sequences from other tick species, suggesting an ancient origin for these genes. One of the phylogram also clearly demonstrates the evolutionary pathways of 18.3 kDa protein family are divergent among metastriate and prostriate ticks. Furthermore, we found that the transcript RS-255 codes for a sequence closely related to a recently identified transcript found in H. longicornis that codes for a protein that is similar to the immunosuppressant protein Da-p36.
Of interest, we observed that many genes were significantly differentially represented among the early to mid library (RsSGL1) and mid library (RsSGL2). Two transcripts related with lipocalin were over expressed, whereas one was down expressed in the mid library. Thrombin inhibitor and Evasins were over expressed in the early to mid library, while unexpectedly sequences related to cement (64P) were mostly expressed in the mid library. These differences possibly represent adaptations of the tick to the dynamics of the host's anti-homeostatic responses to tick feeding. However, mentioned differences require more detailed examination.
Taken together, these results improve our knowledge of the salivary components of the R. sanguineus that can lead to a better understanding of parasite-host interactions, and may originate innovative strategies to find candidate antigens for vaccines, as well as help to discover drugs that could give support to treat coagulopathies and, inflammatory and immunological disorders.
Note: All sequences reported in this paper are available publicly under the accession numbers GT030184-GT032391 and EZ406035-EZ406256 (EST's from adult female salivary gland cDNA libraries) at GenBank.
This work was supported by the Intramural Research Program of the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, by the Fundação de Amparo à Pesquisa do Estado de São Paulo - FAPESP (2004/09992-7) and by the Conselho Nacional de Desenvolvimento Científico e Tecnológico - CNPq. E.A. was supported by a scholarship from CNPq (130780/2005-7). The authors thank Dr. G.H. Bechara for the tick specimens used to generate the RsSGL2 library (FCAV-UNESP), and Dr. A.E. Proudfoot and Dr. A. Frauenschuh for some of the ESTs employed in the work. Because J.M.C. Ribeiro is a government employee and this is a government work, the work is in the public domain in the United States. Notwithstanding any other agreements, the NIH reserves the right to provide the work to PubMedCentral for display and use by the public, and PubMedCentral may tag or modify the work consistent with its customary practices. You can establish rights outside of the U.S. subject to a government use license.
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