BACKGROUND: Salivary hyaluronidases have been described in a few bloodsucking arthropods. However, very little is known about the presence of this enzyme in various bloodsucking insects and no data are available on its effect on transmitted microorganisms. Here, we studied hyaluronidase activity in thirteen bloodsucking insects belonging to four different orders. In addition, we assessed the effect of hyaluronidase coinoculation on the outcome of Leishmania major infection in BALB/c mice. PRINCIPAL FINDINGS: High hyaluronidase activity was detected in several Diptera tested, namely deer fly Chrysops viduatus, blackflies Odagmia ornata and Eusimilium latipes, mosquito Culex quinquefasciatus, biting midge Culicoides kibunensis and sand fly Phlebotomus papatasi. Lower activity was detected in cat flea Ctenocephalides felis. No activity was found in kissing bug Rhodnius prolixus, mosquitoes Anopheles stephensi and Aedes aegypti, tse-tse fly Glossina fuscipes, stable fly Stomoxys calcitrans and human louse Pediculus humanus. Hyaluronidases of different insects vary substantially in their molecular weight, the structure of the molecule and the sensitivity to reducing conditions or sodium dodecyl sulphate. Hyaluronidase exacerbates skin lesions caused by Leishmania major; more severe lesions developed in mice where L. major promastigotes were coinjected with hyaluronidase. CONCLUSIONS: High hyaluronidase activities seem to be essential for insects with pool-feeding mode, where they facilitate the enlargement of the feeding lesion and serve as a spreading factor for other pharmacologically active compounds present in saliva. As this enzyme is present in all Phlebotomus and Lutzomyia species studied to date, it seems to be one of the factors responsible for enhancing activity present in sand fly saliva. We propose that salivary hyaluronidase may facilitate the spread of other vector-borne microorganisms, especially those transmitted by insects with high hyaluronidase activity, namely blackflies (Simuliidae), biting midges (Ceratopogonidae) and horse flies (Tabanidae).

Department of Parasitology Faculty of Science Charles University Prague Czech Republic

Zobrazit více v PubMed

Stern R, Jedrzejas MJ. Hyaluronidases: Their genomics, structures, and mechanisms of action. Chem Rev. 2006;106:818–839. PubMed PMC

Markovic-Housley Z, Miglierini G, Soldatova L, Rizkallah PJ, Muller U, et al. Crystal structure of hyaluronidase, a major allergen of bee venom. Structure. 2000;8:1025–1035. PubMed

Bilo BM, Rueff F, Mosbech H, Bonifazi F, Oude-Elberink JNG. Diagnosis of Hymenoptera venom allergy. Allergy. 2005;60:1339–1349. PubMed

King TP, Lu G, Gonzalez M, Qian NF, Soldatova L. Yellow jacket venom allergens, hyaluronidase and phospholipase: Sequence similarity and antigenic cross-reactivity with their hornet and wasp homologs and possible implications for clinical allergy. J Allergy Clin Immun. 1996;98:588–600. PubMed

Charlab R, Valenzuela JG, Rowton ED, Ribeiro JMC. Toward an understanding of the biochemical and pharmacological complexity of the saliva of a hematophagous sand fly Lutzomyia longipalpis. Proc Natl Acad Sci U S A. 1999;96:15155–15160. PubMed PMC

Ribeiro JMC, Charlab R, Pham VM, Garfield M, Valenzuela JG. An insight into the salivary transcriptome and proteome of the adult female mosquito Culex pipiens quinquefasciatus. Insect Biochem Molec. 2004;34:543–563. PubMed

Campbell CL, Vandyke KA, Letchworth GJ, Drolet BS, Hanekamp T, et al. Midgut and salivary gland transcriptomes of the arbovirus vector Culicoides sonorensis (Diptera: Ceratopogonidae). Insect Mol Biol. 2005;14:121–136. PubMed

Xu X, Yang H, Ma D, Wu J, Wang Y, et al. Toward an understanding of the molecular mechanism for successfully blood-feeding by proteomics analysis coupling with pharmacological testing of horse fly salivary glands. Mol Cell Proteomics. 2008;7:582–590. PubMed

Ribeiro JMC, Charlab R, Rowton ED, Cupp EW. Simulium vittatum (Diptera: Simuliidae) and Lutzomyia longipalpis (Diptera: Psychodidae) salivary gland hyaluronidase activity. J Med Entomol. 2000;37:743–747. PubMed

Cerna P, Mikes L, Volf P. Salivary gland hyaluronidase in various species of phlebotomine sand flies (Diptera: Psychodidae). Insect Biochem Mol Biol. 2002;32:1691–1697. PubMed

Kreil G. Hyaluronidases – a group of neglected enzymes. Protein Sci. 1995;4:1666–1669. PubMed PMC

Mummert ME. Immunologic roles of hyaluronan. Immunol Res. 2005;31:189–205. PubMed

Titus RG, Ribeiro JMC. Salivary-gland lysates from the sand fly Lutzomyia longipalpis enhance Leishmania infectivity. Science. 1988;239:1306–1308. PubMed

Sacks D, Kamhawi S. Molecular aspects of parasite-vector and vector-host interactions in leishmaniasis. Annu Rev Microbiol. 2001;55:453–483. PubMed

Rohousova I, Volf P. Sand fly saliva: effects on host immune response and Leishmania transmission. Folia Parasitol (Praha) 2006;53:161–171. PubMed

Morris RV, Shoemaker CB, David JR, Lanzaro GC, Titus RG. Sandfly maxadilan exacerbates infection with Leishmania major and vaccinating against it protects against L. major infection. J Immunol. 2001;167:5226–5230. PubMed

Qureshi AA, Asahina A, Ohnuma M, Tajima M, Granstein RD, et al. Immunomodulatory properties of maxadilan, the vasodilator peptide from sand fly salivary gland extracts. Am J Trop Med Hyg. 1996;54:665–671. PubMed

Rogers KA, Titus RG. Immunomodulatory effects of maxadilan and Phlebotomus papatasi sand fly salivary gland lysates on human primary in vitro immune responses. Parasite Immunol. 2003;25:127–134. PubMed

Belkaid Y, Kamhawi S, Modi G, Valenzuela J, Noben-Trauth N, et al. Development of a natural model of cutaneous leishmaniasis: Powerful effects of vector saliva and saliva preexposure on the long-term outcome of Leishmania major infection in the mouse ear dermis. J Exp Med. 1998;188:1941–1953. PubMed PMC

Kamhawi S, Belkaid Y, Modi G, Rowton E, Sacks D. Protection against cutaneous leishmaniasis resulting from bites of uninfected sand flies. Science. 2000;290:1351–1354. PubMed

Ribeiro JMC, Katz O, Pannell LK, Waitumbi J, Warburg A. Salivary glands of the sand fly Phlebotomus papatasi contain pharmacologically active amounts of adenosine and 5 ′-AMP. J Exp Biol. 1999;202:1551–1559. PubMed

StatSoft I. STATISTICA (data analysis software system), version 7.1. 2006. www.statsoft.com.

Svobodova M, Votypka J, Nicolas L, Volf P. Leishmania tropica in the black rat (Rattus rattus): persistence and transmission from asymptomatic host to sand fly vector Phlebotomus sergenti. Microbes Infect. 2003;5:361–364. PubMed

Mary C, Faraut F, Lascombe L, Dumon H. Quantification of Leishmania infantum DNA by a real-time PCR assay with high sensitivity. J Clin Microbiol. 2004;42:5249–5255. PubMed PMC

Stern R. Devising a pathway for hyaluronan catabolism: are we there yet? Glycobiology. 2003;13:105R–115R. PubMed

Calvo E, Andersen J, Francischetti IM, deL Capurro M, deBianchi AG, et al. The transcriptome of adult female Anopheles darlingi salivary glands. Insect Mol Biol. 2004;13:73–88. PubMed

Calvo E, Dao A, Pham VM, Ribeiro JMC. An insight into the sialome of Anopheles funestus reveals an emerging pattern in anopheline salivary protein families. Insect Biochem Mol Biol. 2007;37:164–175. PubMed PMC

Arca B, Lombardo F, Valenzuela JG, Francischetti IMB, Marinotti O, et al. An updated catalogue of salivary gland transcripts in the adult female mosquito, Anopheles gambiae. J Exp Biol. 2005;208:3971–3986. PubMed

Ribeiro JMC, Arca B, Lombardo F, Calvo E, Pham VM, et al. An annotated catalogue of salivary gland transcripts in the adult female mosquito, Aedes aegypti. BMC Genomics. 2007;8:6. PubMed PMC

Arca B, Lombardo F, Francischetti IMB, Pham VM, Mestres-Simon M, et al. An insight into the sialome of the adult female mosquito Aedes albopictus. Insect Biochem Mol Biol. 2007;37:107–127. PubMed

Holt RA, Subramanian GM, Halpern A, Sutton GG, Charlab R, et al. The genome sequence of the malaria mosquito Anopheles gambiae. Science. 2002;298:129–149. PubMed

Nene V, Wortman JR, Lawson D, Haas B, Kodira C, et al. Genome sequence of Aedes aegypti, a major arbovirus vector. Science. 2007;316:1718–1723. PubMed PMC

Freye HB, Litwin C. Coexistent anaphylaxis to diptera and hymenoptera. Ann Allergy Asthma Immunol. 1996;76:270–272. PubMed

Sabbah A, Hassoun S, Drouet M, Lauret MG, Doucet M. Le syndrome guepe/moustique. Allerg Immunol (Paris) 1999;31:175–184. PubMed

Sabbah A, Hassoun S, Drouet M, Lauret MG, Doucet M. Le syndrome guepe/moustique: extension de l'allergénicité croisée au taon. Allerg Immunol (Paris) 2000;32:16–19. PubMed

McKee CM, Penno MB, Cowman M, Burdick MD, Strieter RM, et al. Hyaluronan (HA) fragments induce chemokine gene expression in alveolar macrophages – The role of HA size and CD44. J Clin Invest. 1996;98:2403–2413. PubMed PMC

Uchiyama H, Dobashi Y, Ohkouchi K, Nagasawa K. Chemical-change involved in the oxidative reductive depolymerization of hyaluronic-acid. J Biol Chem. 1990;265:7753–7759. PubMed

Taylor KR, Trowbridge JM, Rudisill JA, Termeer CC, Simon JC, et al. Hyaluronan fragments stimulate endothelial recognition of injury through TLR4. J Biol Chem. 2004;279:17079–17084. PubMed

Taylor KR, Gallo RL. Glycosaminoglycans and their proteoglycans: host-associated molecular patterns for initiation and modulation of inflammation. Faseb J. 2006;20:9–22. PubMed

Matzinger P. The danger model: A renewed sense of self. Science. 2002;296:301–305. PubMed

Laskay T, van Zandbergen G, Solbach W. Neutrophil granulocytes – Trojan horses for Leishmania major and other intracellular microbes? Trends Microbiol. 2003;11:210–214. PubMed

Human immune response against salivary antigens of Simulium damnosum s.l.: A new epidemiological marker for exposure to blackfly bites in onchocerciasis endemic areas

Promastigote secretory gel from natural and unnatural sand fly vectors exacerbate Leishmania major and Leishmania tropica cutaneous leishmaniasis in mice

Insights into the sand fly saliva: Blood-feeding and immune interactions between sand flies, hosts, and Leishmania

Hyaluronidase Activity in Saliva of European Culicoides (Diptera: Ceratopogonidae)

Comparative analysis of salivary gland transcriptomes of Phlebotomus orientalis sand flies from endemic and non-endemic foci of visceral leishmaniasis

Salivary gland transcriptomes and proteomes of Phlebotomus tobbi and Phlebotomus sergenti, vectors of leishmaniasis

Analysis of salivary transcripts and antigens of the sand fly Phlebotomus arabicus