editorial: exploring the messages of the salivary glands of ixodes ricinus

16 downloads 0 Views 32KB Size Report
Ixodes ricinus, a common tick of great medical and veteri- nary importance in Europe, belongs to the family of hard ticks. This obligate blood feeder is the vector ...
Am. J. Trop. Med. Hyg., 66(3), 2002, pp. 223–224 Copyright © 2002 by The American Society of Tropical Medicine and Hygiene

EDITORIAL: EXPLORING THE MESSAGES OF THE SALIVARY GLANDS OF IXODES RICINUS JESUS G. VALENZUELA Medical Entomology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland

The identification and isolation of tick salivary molecules with either pharmacologic or immunomodulatory activities has been a difficult task; only a few molecules have been reported in the literature16–19 Recently Das and others20 reported the identification of 14 immunodominant antigens using an I. scapularis salivary gland cDNA expression library. In a report in this issue, Leboulle and others21 used a different approach to isolate salivary cDNAs from ticks. Their objective was the isolation of genes induced during the feeding process, genes whose products may be immunogenic molecules injected during feeding or molecules that may affect the host hemostatic or immune system. This group constructed full-length and subtracted (5 days engorged I. ricinus mRNA minus unfed tick mRNA) cDNA libraries from the salivary glands of I. ricinus. They isolated 27 partial sequences (subtracted) and four full-length sequences, a number that surpasses all sequences together deposited in GenBank for an ixodid tick. Many of the sequences reported here are novel sequences (no matches in searched databanks), and some are similar to anti-hemostatic or immunomodulatory proteins. The putative anti-coagulant, as well as a putative metalloprotease and a putative elastase inhibitor, were produced as recombinant proteins, although no activity was tested or reported. The group also reported that 13 of the 14 mRNAs tested were upregulated upon feeding, suggesting that the products of these messages may be of importance in bloodfeeding, and also, potentially immunogenic. These findings presented represent an alternative methodology in identifying tick salivary molecules in a more “highthroughput” fashion. The proteins encoded by the identified genes may affect the host hemostatic and immune system, or pathogen transmission directly. These functions remain to be tested. It is important to point out that although Leboulle and others isolated 9,600 subtracted clones, only 96 sequences were analyzed. This accounted for only 1% of the randomly collected subtracted products. Further investigation of the rest of the library will provide additional information on what other molecules are present in the salivary gland of I. ricinus ticks and the complexity of the system. The challenge now is how to use this information in a more practical way. It is critical to associate the newly discovered cDNAs with pharmacologic and immunomodulatory activities. Expression of active recombinant proteins in heterologous systems and proteomic analyses are just two of the current technologies that can be used for these purposes. Since Leboulle and others found that the molecules whose genes they identified may be secreted, and that the expression of these genes was upregulated in the salivary glands, they could be potential targets in developing transmission-blocking strategies. The large number of candidates necessitates a highthroughput functional genomics approach to test these candidates as immunogens and protective agents. The concept of tick immunity was reported more than 60

Ixodes ricinus, a common tick of great medical and veterinary importance in Europe, belongs to the family of hard ticks. This obligate blood feeder is the vector of diverse pathogens such as Borrelia burgdorferi, Ehrlichia spp., Babesia spp., and tick-borne encephalitis virus. Transmission of these pathogens present in the saliva of the tick occurs when the vertebrate host is bitten. These salivary secretions, besides delivering pathogens to the host, contain components that affect the vertebrate host’s hemostatic, inflammatory, and immune systems that help the tick to start and finish a blood meal.1,2 Arthropod saliva can affect the infectivity of pathogens delivered during blood feeding and consequently the outcome of the disease in the vertebrate host.3,4 There is evidence that tick arthropod salivary proteins can be used as immunogens to control pathogen transmission. Early work by Bell and others5 showed that rabbits sensitized to the bites of the tick Dermacentor variabilis were protected against tick-borne Francisella tularensis. Later work by Wikel and others6 showed that mice previously exposed to bites of uninfected nymphs were later protected against transmission of B. burgdorferi during subsequent infestation with Borreliainfected Ixodes scapularis. Similar results were obtained by Nazario and others,7 who demonstrated that guinea pigs exposed to uninfected I. scapularis were protected against subsequent challenge by Borrelia-infected ticks. Animals exposed to I. ricinus were also protected against Borreliainfected ticks.8 Recent work with a different vector-parasite pair (the sand fly Phlebotomus papatasi and Leishmania major) has shown that animals pre-exposed to salivary gland homogenate,9 to sand fly bites,10 or to a salivary protein11 were protected against subsequent parasite challenge. The protection was suggested to be the result of a delayed-type hypersensitivity reaction mounted by the host to the previously exposed salivary protein; this cellular response killed the parasite indirectly and antibodies produced against salivary proteins were not necessary for the protection.11 Similar immune reactions to salivary proteins and consequently protection against the pathogen may occur in other vector-host pairs, including ticks and other arthropod vectors of disease. Tick saliva has immunomodulatory properties that help the tick attach to its host for a long period of time and to obtain a blood meal.12 Tick saliva may also help the pathogen it carries to become established.1,2,4,12 It is also known that tick bites (or injection of tick salivary proteins) can produce a strong immune response leading to tick rejection or anti-tick immunity.13–15 Therefore, as previously proposed,11 there are two potential vaccination strategies for tick-borne diseases using vector salivary proteins as targets. The first strategy is the identification and neutralization of salivary immunomodulators or immunosuppressors that affect the establishment of the parasite. The second strategy is to search for salivary proteins that may induce a strong cellular response, which may kill the pathogen indirectly.

223

224

VALENZUELA

years ago.14 More than 20 years ago, tick salivary proteins were demonstrated to alter the vertebrate host hemostatic and immune systems.12 However, there is currently no clear candidate vaccine from tick saliva that can control pathogen transmission. In the last three years, the emergence of high throughput molecular biology tools and bioinformatic analysis is helping to close this gap. The work of Leboulle and others reported in this issue is a novel approach to the identification of salivary molecules that may eventually lead to pathogen transmission–blocking vaccines for tick-borne diseases. Author’s address: Jesus G. Valenzuela, Medical Entomology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, 4 Center Drive, Building 4, Room B2–12, Bethesda, MD 20892, Telephone: 301-4022748, Fax: 301-402-4941, E-mail: [email protected].

10. 11.

12. 13.

14.

REFERENCES 1. Ribeiro JMC, 1995. Blood-feeding arthropods: live syringes or invertebrate pharmacologists? Infect Agents Dis 4: 143–152. 2. Wikel SK, 1999. Tick modulation of host immunity: an important factor in pathogen transmission. Int J Parasitol 29: 851–859. 3. Kamhawi S, 2000. The biological and immunomodulatory properties of sand fly saliva and its role in the establishment of Leishmania infections. Microbes Infect 2: 1765–1773. 4. Nuttall PA, Paesen GC, Lawrie CH, Wang H, 2000. Vector-host interactions in disease transmission. J Mol Microbiol Biotechnol 2: 381–386. 5. Bell JF, Stewart SJ, Wikel SK, 1979. Resistance to tick-borne Francisella tularensis by tick-sensitized rabbits: allergic klendusity. Am J Trop Med Hyg 28: 876–880. 6. Wikel SK, Ramachandra RN, Bergman DK, Burkot TR, Piesman J, 1997. Infestation with pathogen-free nymphs of the tick Ixodes scapularis induces host resistance to transmission of Borrelia burgdorferi by ticks. Infect Immun 65: 335–338. 7. Nazario S, Das S, de Silva AM, Deponte K, Marcantonio N, Anderson JF, Fish D, Fikrig E, Kantor FS, 1998. Prevention of Borrelia burgdorferi transmission in guinea pigs by tick immunity. Am J Trop Med Hyg 58: 780–785. 8. Dizij A, Arndt S, Seitz HM, Kurtenbach K, 1994. Clethrionomys glareolus acquires resistance to Ixodes ricinus: a mechanism to prevent spirochete inoculation? Cevenini R, Sambri V, la Placa M, eds. Advances in Lyme Borreliosis Research. Bologna, Italy: 228–232. 9. Belkaid Y, Kamhawi S, Modi G, Valenzuela J, Noben-Trauth N,

15. 16.

17.

18.

19.

20.

21.

Rowton E, Ribeiro J, Sacks DL, 1998. Development of a natural model of cutaneous leishmaniasis: powerful effects of vector saliva and saliva pre-exposure on the long-term outcome of Leishmania major infection in the mouse ear dermis. J Exp Med 188: 1941–1953. Kamhawi S, Belkaid Y, Modi G, Rowton E, Sacks D, 2000. Protection against cutaneous leishmaniasis resulting from bites of uninfected sand flies. Science 290: 1351–1354. Valenzuela JG, Belkaid Y, Garfield MK, Mendez S, Kamhawi S, Rowton ED, Sacks DL, Ribeiro JMC, 2001. Toward a defined anti-Leishmania vaccine targeting vector antigens: characterization of a protective salivary protein. J Exp Med 194: 331– 342. Ribeiro JM, 1989. Role of saliva in tick/host interactions. Exp Appl Acarol 7: 15–20. Brown SJ, 1988. Characterization of tick antigens inducing host immune resistance. II. Description of rabbit-acquired immunity to Amblyomma americanum ticks and identification of potential tick antigens by Western blot analysis. Vet Parasitol 28: 245–259. Trager W, 1939. Acquired immunity to ticks. J Parasitol 25: 57– 78. Wikel SK, 1981. The induction of host resistance to tick infestation with a salivary gland antigen. Am J Trop Med Hyg 30: 284–288. Bergman DK, Palmer MJ, Caimano MJ, Radolf JD, Wikel SK, 2000. Isolation and molecular cloning of a secreted immunosuppressant protein from Dermacentor andersoni salivary gland. J Parasitol 86: 516–525. Jaworski DC, Jasinskas A, Metz CN, Bucala R, Barbour AG, 2001. Identification and characterization of a homologue of the pro-inflammatory cytokine macrophage migration inhibitory factor in the tick, Amblyomma americanum. Insect Mol Biol 10: 323–331. Das S, Marcantonio N, Deponte K, Telford SR III, Anderson JF, Kantor FS, Fikrig E, 2000. SALP16, a gene induced in Ixodes scapularis salivary glands during tick feeding. Am J Trop Med Hyg 62: 99–105. Valenzuela JG, Charlab R, Mather TN, Ribeiro JM, 2000. Purification, cloning, and expression of a novel salivary anticomplement protein from the tick, Ixodes scapularis. J Biol Chem 275: 18717–18723. Das S, Banerjee G, DePonte K, Marcantonio N, Kantor FS, Fikrig E, 2001. Salp25D, an Ixodes scapularis antioxidant, is 1 of 14 immunodominant antigens in engorged tick salivary glands. J Infect Dis 184: 1056–1064. Leboulle G, Rochez C, Louahed J, Rutti B, Brossard M, Bollen A, Godfroid E, 2002. Isolation of Ixodes ricinus salivary gland mRNA encoding factors induced during blood feeding. Am J Trop Med Hyg 66: 225–233.