Targeting Haemaphysalis longicornis serpin to prevent tick feeding and pathogen transmission

Abstract

Serine proteinase inhibitors (serpins), identified from the hard tick Haemaphysalis longicornis of China, play significant roles in various animal physiological processes. In this study, we showed that H. longicornis serpins (Hlserpin-a and Hlserpin-b) were induced during blood-feeding in nymph ticks and exhibited anticoagulation activity in vitro. Silencing Hlserpins through RNA interference (RNAi) significantly impaired tick feeding. Immunization of mice with recombinant Hlserpins or passive transfer of Hlserpin antiserum significantly curtails the efficacy of tick feeding. Concurrently, the transmission of the Langat virus (LGTV) from ticks to mice witnessed a substantial decrease when Hlserpins were silenced. Our findings suggest that inhibiting Hlserpins can hamper tick engorgement and pathogen transmission, indicating the potential of Hlserpins as a vaccine to counter tick-borne diseases.

Keywords

feeding / LGTV / serpin / TBEV / tick

References

[1] Abbas,M.N., Chlastakova, A., Jmel,M.A., Iliaki-Giannakoudaki,E., Chmelar,J. and Kotsyfakis, M. (2022) Serpins in tick physiology and tick-host interaction. Frontiers in Cellular and Infection Microbiology, 12, 892770.

[2] Abbas,M.N., Jmel,M.A., Mekki,I., Dijkgraaf, I. and Kotsyfakis,M. (2023) Recent advances in tick antigen discovery and anti-tick vaccine development. International Journal of Molecular Sciences, 24, 4969.

[3] Ali,A., Parizi, L.F., Guizzo,M.G., Tirloni,L., Seixas, A., Vaz Ida,S. et al. (2015) Immunoprotective potential of a Rhipicephalus (Boophilus) microplus metalloprotease. Veterinary Parasitology, 207, 107–114.

[4] Balbus,J.M., Boxall, A.B., Fenske,R.A., Mckone,T.E. and Zeise, L. (2013) Implications of global climate change for the assessment and management of human health risks of chemicals in the natural environment. Environmental Toxicology and Chemistry, 32, 62–78.

[5] Bensaci,M., Bhattacharya, D., Clark,R. and Hu,L.T. (2012) Oral vaccination with vaccinia virus expressing the tick antigen subolesin inhibits tick feeding and transmission of Borrelia burgdorferi. Vaccine, 30, 6040–6046.

[6] Bowman,A.S., Alan,S. and Nuttall,P.A. (2004) Ticks: biology, disease and control - Preface. Parasitology, 129 (S1),

[7] Brown,S.J. (1985) Immunology of acquired resistance to ticks. Parasitology Today, 1, 166–171.

[8] Calvo,E., Mizurini, D.M., Sa-Nunes,A., Ribeiro,J.M., Andersen, J.F., Mans,B.J. et al. (2011) Alboserpin, a factor Xa inhibitor from the mosquito vector of yellow fever, binds heparin and membrane phospholipids and exhibits antithrombotic activity. Journal of Biological Chemistry, 286, 27998–28010.

[9] Chmelar,J., Kotal,J., Kopecky,J., Pedra, J.H.F. and Kotsyfakis,M. (2016) All for one and one for all on the tick-host battlefield. Trends in Parasitology, 32, 368–377.

[10] Cornelius,A.D.A., Hosseini, S., Schreier,S., Fritzsch,D., Weichert, L., Michaelsen-Preusse,K. et al. (2020) Langat virus infection affects hippocampal neuron morphology and function in mice without disease signs. Journal of Neuroinflammation, 17, 278.

[11] Dai,J.F., Narasimhan, S., Zhang,L.L., Liu,L., Wang,P.H. and Fikrig,E. (2010) Tick histamine release factor is critical for Ixodes scapularis engorgement and transmission of the Lyme Disease agent. PLoS Pathogens, 6, e1001205.

[12] Das,S., Freier, A., Boussoffara,T., Das,S., Oswald, D., Losch,F.O. et al. (2014) Modular multiantigen T cell epitope-enriched DNA vaccine against human leishmaniasis. Science Translational Medicine, 6, 234ra56.

[13] De La Fuente,J., Almazan, C., Canales,M., Pérez de la Lastra,J.M., Kocan,K.M. and Willadsen, P. (2007) A ten-year review of commercial vaccine performance for control of tick infestations on cattle. Animal Health Research Reviews, 8, 23–28.

[14] De La Fuente,J. and Contreras, M. (2015) Tick vaccines: current status and future directions. Expert Review of Vaccines, 14, 1367–1376.

[15] De La Fuente,J., Kocan,K.M., Almazan,C. and Blouin, E.F. (2008) Targeting the tick-pathogen interface for novel control strategies. Fronters in Bioscience, 13, 6947–6956.

[16] Garcia-Garcia,J.C., Montero, C., Redondo,M., Vargas,M., Canales, M., Boue,O. et al. (2000) Control of ticks resistant to immunization with Bm86 in cattle vaccinated with the recombinant antigen Bm95 isolated from the cattle tick, Boophilus microplus. Vaccine, 18, 2275–2287.

[17] Githaka,N.W., Konnai, S., Isezaki,M., Goto,S., Xavier, M.A., Fujisawa,S. et al. (2020) Identification and functional analysis of ferritin 2 from the Taiga tick Ixodes persulcatus Schulze. Ticks and Tick Borne Diseases, 11, 101547.

[18] Gulley,M.M., Zhang,X. and Michel,K. (2013) The roles of serpins in mosquito immunology and physiology. Journal of Insect Physiology, 59, 138–147.

[19] Huercha, Song,R.Q., Li,M., Fan, X.L., Hu,Z.X., Wu,L.J. et al. (2020) Caracterization of glutathione S-transferase of Dermacantor marginatus and effect of the recombinant antigen as a potential anti-tick vaccine. Veterinary Parasitology, 279, 109043.

[20] Hussein,H.E., Scoles, G.A., Ueti,M.W., Suarez,C.E., Adham,F.K., Guerrero,F.D. et al. (2015) Targeted silencing of the Aquaporin 2 gene of Rhipicephalus (Boophilus) microplus reduces tick fitness. Parasit Vectors, 8, 618.

[21] Imamura,S., Konnai, S., Junior,I.D.V., Yamada,S., Nakajima, C., Ito,Y. et al. (2008) Effects of anti-tick cocktail vaccine against Rhipicephalus appendiculatus. Japanese Journal of Veterinary Research, 56, 85–98.

[22] Imamura,S., Namangala, B., Tajima,T., Tembo,M.E., Yasuda, J., Ohashi,K. et al. (2006) Two serine protease inhibitors (serpins) that induce a bovine protective immune response against Rhipicephalus appendiculatus ticks. Vaccine, 24, 2230–2237.

[23] Imamura,S., Vaz,I.D., Sugino,M., Ohashi, K. and Onuma,M. (2005) A serine protease inhibitor (serpin) from Haemaphysalis longicornis as an anti-tick vaccine. Vaccine, 23, 1301–1311.

[24] Kasaija,P.D., Contreras, M., Kabi,F., Mugerwa,S. and De La Fuente, J. (2020) Vaccination with recombinant subolesin antigens provides cross-tick species protection in Bos indicus and crossbred cattle in Uganda. Vaccines (Basel), 8, 319.

[25] Kim,T.K., Tirloni, L., Berger,M., Diedrich,J.K., Yates,J.R., 3rd, Termignoni,C. et al. (2020) Amblyomma americanum serpin 41 (AAS41) inhibits inflammation by targeting chymase and chymotrypsin. International Journal of Biological Macromolecules, 156, 1007–1021.

[26] Kung,F., Kaur,S., Smith,A.A., Yang, X., Wilder,C.N., Sharma,K. et al. (2016) A Borrelia burgdorferi surface-exposed transmembrane protein lacking detectable immune responses supports pathogen persistence and constitutes a vaccine target. Journal of Infectious Diseases, 213, 1786–1795.

[27] Matias,J., Kurokawa, C., Sajid,A., Narasimhan,S., Arora,G., Diktas,H. et al. (2021) Tick immunity using mRNA, DNA and protein-based Salp14 delivery strategies. Vaccine, 39, 7661–7668.

[28] Narasimhan,S., Kurokawa, C., Diktas,H., Strank,N.O., Cerny,J., Murfin,K. et al. (2020) Ixodes scapularis saliva components that elicit responses associated with acquired tick-resistance. Ticks and Tick Borne Diseases, 11, 101369.

[29] Overby,A.K., Popov,V.L., Niedrig,M. and Weber, F. (2010) Tick-borne encephalitis virus delays interferon induction and hides its double-stranded RNA in intracellular membrane vesicles. Journal of Virology, 84, 8470–8483.

[30] Pardi,N., Hogan,M.J. and Weissman,D. (2020) Recent advances in mRNA vaccine technology. Current in Opinion Immunology, 65, 14–20.

[31] Parizi,L.F., Rangel, C.K., Sabadin,G.A., Saggin,B.F., Kiio,I., Xavier,M.A. et al. (2020) Rhipicephalus microplus cystatin as a potential cross-protective tick vaccine against Rhipicephalus appendiculatus. Ticks and Tick-Borne Diseases, 11, 101378.

[32] Parizi,L.F., Rech,H., Ferreira,C.A., Imamura,S., Ohashi, K., Onuma,M. et al. (2009) Comparative immunogenicity of Haemaphysalis longicornis and Rhipicephalus (Boophilus) microplus calreticulins. Veterinary Parasitology, 164, 282–290.

[33] Parizi,L.F., Utiumi, K.U., Imamura,S., Onuma,M., Ohashi, K., Masuda,A. et al. (2011) Cross immunity with Haemaphysalis longicornis glutathione S-transferase reduces an experimental Rhipicephalus (Boophilus) microplus infestation. Experimental Parasitology, 127, 113–118.

[34] Phipps,L.P. and Johnson, N. (2022) Tick-borne encephalitis virus. Journal Medical Microbiology, 71, 001492.

[35] Pilz,A., Erber,W. and Schmitt,H.J. (2023) Vaccine uptake in 20 countries in Europe 2020: focus on tick-borne encephalitis (TBE). Ticks and Tick Borne Diseases, 14, 102059.

[36] Pongprayoon,P., Kaewhom, P., Kaewmongkol,S., Suwan,E., Stich,R.W., Wiriya,B. et al. (2021) Structural dynamics of Rhipicephalus microplus serpin-3. Molecular Simulation, 47, 1209–1216.

[37] Prevot,P.P., Couvreur, B., Denis,V., Brossard,M., Vanhamme, L. and Godfroid,E. (2007) Protective immunity against Ixodes ricinus induced by a salivary serpin. Vaccine, 25, 3284–3292.

[38] Simo,L., Kazimirova, M., Richardson,J. and Bonnet,S.I. (2017) The essential role of tick salivary glands and saliva in tick feeding and pathogen transmission. Frontiers in Cellular and Infection Microbiology, 7, 281.

[39] Spence,M.A., Mortimer, M.D., Buckle,A.M., Minh,B.Q. and Jackson, C.J. (2021) A comprehensive phylogenetic analysis of the serpin superfamily. Molecular Biology and Evolution, 38, 2915–2929.

[40] Sugino,M., Imamura, S., Mulenga,A., Nakajima,M., Tsuda,A., Ohashi,K. et al. (2003) A serine proteinase inhibitor (serpin) from ixodid tick Haemaphysalis longicornis; cloning and preliminary assessment of its suitability as a candidate for a tick vaccine. Vaccine, 21, 2844–2851.

[41] Talactac,M.R., Yoshii, K., Hernandez,E.P., Kusakisako,K., Galay,R.L., Fujisaki,K. et al. (2017) Synchronous langat virus infection of Haemaphysalis longicornis using anal pore microinjection. Viruses, 9, 189.

[42] Valle,M.R., Mendez, L., Valdez,M., Redondo,M., Espinosa, C.M., Vargas,M. et al. (2004) Integrated control of Boophilus microplus ticks in Cuba based on vaccination with the anti-tick vaccine Gavac (TM). Experimental and Applied Acarology, 34, 375–382.

[43] Villar,M., Marina, A. and De La Fuente,J. (2017) Applying proteomics to tick vaccine development: where are we? Expert Review of Proteomics, 14, 211–221.

[44] Wang,F., Song,Z., Chen,J., Wu, Q., Zhou,X., Ni,X. et al. (2020) The immunosuppressive functions of two novel tick serpins, HlSerpin-a and HlSerpin-b, from Haemaphysalis longicornis. Immunology, 159, 109–120.

[45] Weber,E., Finsterbusch, K., Lindquist,R., Nair,S., Lienenklaus, S., Gekara,N.O. et al. (2014) Type I interferon protects mice from fatal neurotropic infection with Langat virus by systemic and local antiviral responses. Journal of Virology, 88, 12202–12212.

[46] Willadsen,P., Bird,P., Cobon,G.S. and Hungerford, J. (1995) Commercialisation of a recombinant vaccine against Boophilus microplus. Parasitology, 110, S43–S50.

[47] Willadsen,P., Smith,D., Cobon,G. and Mckenna, R.V. (1996) Comparative vaccination of cattle against Boophilus microplus with recombinant antigen Bm86 alone or in combination with recombinant Bm91. Parasite Immunology, 18, 241–246.

[48] Zhao,L., Li,J., Cui,X., Jia, N., Wei,J., Xia,L. et al. (2020) Distribution of Haemaphysalis longicornis and associated pathogens: analysis of pooled data from a China field survey and global published data. Lancet Planet Health, 4, e320–e329.

RIGHTS & PERMISSIONS

2023 2023 The Authors. Insect Science published by John Wiley & Sons Australia, Ltd on behalf of Institute of Zoology, Chinese Academy of Sciences.