Research progress toward the influence of mosquito salivary proteins on the transmission of mosquito-borne viruses

Abstract

Mosquito-borne viruses (MBVs) are a large class of viruses transmitted mainly through mosquito bites, including dengue virus, Zika virus, Japanese encephalitis virus, West Nile virus, and chikungunya virus, which pose a major threat to the health of people around the world. With global warming and extended human activities, the incidence of many MBVs has increased significantly. Mosquito saliva contains a variety of bioactive protein components. These not only enable blood feeding but also play a crucial role in regulating local infection at the bite site and the remote dissemination of MBVs as well as in remodeling the innate and adaptive immune responses of host vertebrates. Here, we review the physiological functions of mosquito salivary proteins (MSPs) in detail, the influence and the underlying mechanism of MSPs on the transmission of MBVs, and the current progress and issues that urgently need to be addressed in the research and development of MSP-based MBV transmission blocking vaccines.

Keywords

immune response / mosquito-borne virus / mosquito salivary protein / saliva vaccine / transmission

References

[1] Abraham,S.N. & St John, A.L. (2010) Mast cell-orchestrated immunity to pathogens. Nature Reviews Immunology, 10, 440–452.

[2] Ader,D.B., Celluzzi, C., Bisbing,J., Gilmore,L., Gunther, V., Peachman,K.K. et al. (2004) Modulation of dengue virus infection of dendritic cells by Aedes aegypti saliva. Viral immunology, 17, 252–265.

[3] Agarwal,A., Joshi,G., Nagar,D.P., Sharma, A.K., Sukumaran,D., Pant,S.C. et al. (2016) Mosquito saliva induced cutaneous events augment chikungunya virus replication and disease progression. Infection, Genetics and Evolution, 40, 126–135.

[4] Almeras,L., Fontaine, A., Belghazi,M., Bourdon,S., Boucomont-Chapeaublanc, E., Orlandi-Pradines,E. et al. (2010) Salivary gland protein repertoire from Aedes aegypti mosquitoes. Vector Borne Zoonotic Diseases, 10, 391–402.

[5] Almeras,L., Orlandi-Pradines, E., Fontaine,A., Villard,C. & De Senneville, L.D. (2009) Sialome individuality between Aedes aegypti colonies. Vector Borne Zoonotic Diseases, 9, 531–541.

[6] Briant,L., Despres, P., Choumet,V. & Misse,D. (2014) Role of skin immune cells on the host susceptibility to mosquito-borne viruses. Virology, 464–465, 26–32.

[7] Buezo Montero,S., Gabrieli, P., Montarsi,F., Borean,A., Capelli, S., De Silvestro,G. et al. (2020) IgG antibody responses to the Aedes albopictus 34k2 salivary protein as novel candidate marker of human exposure to the tiger mosquito. Frontiers in Cellular and Infection Microbiology, 10, 377.

[8] Cao-Lormeau,V.M. (2009) Dengue viruses binding proteins from Aedes aegypti and Aedes polynesiensis salivary glands. Virology Journal, 6, 35.

[9] Cerny,T., Schwarz, M., Schwarz,U., Lemant,J. & Keller, E. (2017) The range of neurological complications in chikungunya fever. Neurocritical Care, 27, 447–457.

[10] Chagas,A.C., Ramirez, J.L., Jasinskiene,N., James,A.A., Ribeiro, J.M., Marinotti,O. et al. (2014) Collagen-binding protein, Aegyptin, regulates probing time and blood feeding success in the dengue vector mosquito, Aedes aegypti. Proceedings of the National Academy of Sciences USA, 111, 6946–6951.

[11] Chisenhall,D.M., Londono, B.L., Christofferson,R.C., Mccracken,M.K. & Mores, C.N. (2014) Effect of dengue-2 virus infection on protein expression in the salivary glands of Aedes aegypti mosquitoes. The American Journal of Tropical Medicine and Hygiene, 90, 431–437.

[12] Chowdhury,A., Modahl, C.M., Misse,D., Kini,R.M. & Pompon, J. (2021) High resolution proteomics of Aedes aegypti salivary glands infected with either dengue, Zika or chikungunya viruses identify new virus specific and broad antiviral factors. Scientific Reports, 11, 23696.

[13] Conway,M.J. (2021) Type I hypersensitivity promotes Aedes aegypti blood feeding. Scientific Reports, 11, 14891.

[14] Conway,M.J., Londono-Renteria, B., Troupin,A., Watson,A.M., Klimstra, W.B., Fikrig,E. et al. (2016) Aedes aegypti D7 saliva protein inhibits dengue virus infection. PLoS Neglected Tropical Diseases, 10, e0004941.

[15] Conway,M.J., Watson, A.M., Colpitts,T.M., Dragovic,S.M., Li,Z., Wang,P. et al. (2014) Mosquito saliva serine protease enhances dissemination of dengue virus into the mammalian host. Journal of Virology, 88, 164–175.

[16] Demeure,C.E., Brahimi, K., Hacini,F., Marchand,F., Peronet, R., Huerre,M. et al. (2005) Anopheles mosquito bites activate cutaneous mast cells leading to a local inflammatory response and lymph node hyperplasia. Journal of Immunology, 174, 3932–3940.

[17] Dhawan,R., Kumar,M., Mohanty,A.K., Dey,G., Advani, J., Prasad,T.S. et al. (2017) Mosquito-borne diseases and omics: salivary gland proteome of the female Aedes aegypti mosquito. Omics, 21, 45–54.

[18] Doucoure,S., Mouchet, F., Cornelie,S., Dehecq,J.S., Rutee,A.H., Roca,Y. et al. (2012) Evaluation of the human IgG antibody response to Aedes albopictus saliva as a new specific biomarker of exposure to vector bites. PLoS Neglected Tropical Diseases, 6, e1487.

[19] Driskell,R.R., Lichtenberger, B.M., Hoste,E., Kretzschmar,K., Simons, B.D., Charalambous,M. et al. (2013) Distinct fibroblast lineages determine dermal architecture in skin development and repair. Nature, 504, 277–281.

[20] Duvall,L.B. (2019) Mosquito host-seeking regulation: targets for behavioral control. Trends in Parasitology, 35, 704–714.

[21] Elanga Ndille,E., Doucoure, S., Poinsignon,A., Mouchet,F., Cornelie, S., D'Ortenzio,E. et al. (2016) Human IgG antibody response to Aedes Nterm-34kDa salivary peptide, an Epidemiological tool to assess vector control in chikungunya and dengue transmission area. PLoS Neglected Tropical Diseases, 10, e0005109.

[22] Fong,S.W., Kini,R.M. & Ng,L.F.P. (2018) Mosquito saliva reshapes alphavirus infection and immunopathogenesis. Journal of Virology, 92, e01004-17.

[23] Friedman-Klabanoff,D.J., Birkhold,M., Short,M.T., Wilson,T.R., Meneses, C.R., Lacsina,J.R. et al. (2022) Safety and immunogenicity of AGS-v PLUS, a mosquito saliva peptide vaccine against arboviral diseases: a randomized, double-blind, placebo-controlled Phase 1 trial. EBioMedicine, 86, 104375.

[24] Furie,B. & Furie, B.C. (1988) The molecular basis of blood coagulation. Cell, 53, 505–518.

[25] Garcia,M., Alout,H., Diop,F., Damour, A., Bengue,M., Weill,M. et al. (2018) Innate immune response of primary human keratinocytes to West Nile virus infection and its modulation by mosquito saliva. Frontiers in Cellular and Infection Microbiology, 8, 387.

[26] Guerrero,D., Vo,H.T.M., Lon,C., Bohl, J.A., Nhik,S., Chea,S. et al. (2022) Evaluation of cutaneous immune response in a controlled human in vivo model of mosquito bites. Nature Communications, 13, 7036.

[27] Hastings,A.K., Uraki,R., Gaitsch,H., Dhaliwal, K., Stanley,S., Sproch,H. et al. (2019) Aedes aegypti NeSt1 protein enhances Zika virus pathogenesis by activating neutrophils. Journal of Virology, 93, e00395–19.

[28] Heath,W.R. & Carbone, F.R. (2013) The skin-resident and migratory immune system in steady state and memory: innate lymphocytes, dendritic cells and T cells. Nature Immunology, 14, 978–985.

[29] Hemme,R.R., Poole-Smith, B.K., Hunsperger,E.A., Felix,G.E., Horiuchi, K., Biggerstaff,B.J. et al. (2016) Non-human primate antibody response to mosquito salivary proteins: implications for dengue virus transmission in Puerto Rico. Acta Tropica, 164, 369–374.

[30] Ho,L.J., Wang,J.J., Shaio,M.F., Kao, C.L., Chang,D.M., Han,S.W. et al. (2001) Infection of human dendritic cells by dengue virus causes cell maturation and cytokine production. Journal of Immunology, 166, 1499–1506.

[31] Huang,Y.S., Higgs,S. & Vanlandingham,D.L. (2019) Emergence and re-emergence of mosquito-borne arboviruses. Current Opinion in Virology, 34, 104–109.

[32] James,A.A., Blackmer, K. & Racioppi,J.V. (1989) A salivary gland-specific, maltase-like gene of the vector mosquito, Aedes aegypti. Gene, 75, 73–83.

[33] James,A.A. & Rossignol, P.A. (1991) Mosquito salivary glands: parasitological and molecular aspects. Parasitology Today, 7, 267–271.

[34] Jaques,L.B., Mahadoo, J. & Riley,J.F. (1977) The mast cell/heparin paradox. Lancet, 1, 411–413.

[35] Jin,L., Guo,X., Shen,C., Hao, X., Sun,P., Li,P. et al. (2018) Salivary factor LTRIN from Aedes aegypti facilitates the transmission of Zika virus by interfering with the lymphotoxin-beta receptor. Nature Immunology, 19, 342–353.

[36] Kyle,J.L. & Harris, E. (2008) Global spread and persistence of dengue. Annual Review of Microbiology, 62, 71–92.

[37] Lefteri,D.A., Bryden, S.R., Pingen,M., Terry,S., Mccafferty, A., Beswick,E.F. et al. (2022) Mosquito saliva enhances virus infection through sialokinin-dependent vascular leakage. Proceedings of the National Academy of Sciences USA, 119, e2114309119.

[38] Li,X.P., Lin,D., Zhang,Y., Chen, S.Q., Bai,H.Q., Zhang,S.N. et al. (2020) Expression and characterization of anticoagulant activity of salivary protein alALP from Asian tiger mosquito Aedes albopictus. Tropical Biomedicine, 37, 116–126.

[39] Luplertlop,N., Surasombatpattana, P., Patramool,S., Dumas,E., Wasinpiyamongkol, L., Saune,L. et al. (2011) Induction of a peptide with activity against a broad spectrum of pathogens in the Aedes aegypti salivary gland, following infection with Dengue virus. PLoS Pathogens, 7, e1001252.

[40] Manning,J.E., Oliveira, F., Coutinho-Abreu,I.V., Herbert,S., Meneses, C., Kamhawi,S. et al. (2020) Safety and immunogenicity of a mosquito saliva peptide-based vaccine: a randomised, placebo-controlled, double-blind, phase 1 trial. Lancet, 395, 1998–2007.

[41] Marin-Lopez,A., Wang,Y., Jiang,J., Ledizet, M. & Fikrig,E. (2021) AgBR1 and NeSt1 antisera protect mice from Aedes aegypti-borne Zika infection. Vaccine, 39, 1675–1679.

[42] Martin-Martin,I., Valenzuela Leon,P.C., Amo,L., Shrivastava,G., Iniguez,E., Aryan,A. et al. (2022) Aedes aegypti sialokinin facilitates mosquito blood feeding and modulates host immunity and vascular biology. Cell Reports, 39, 110648.

[43] Peng,Z. & Simons, F.E. (2007) Advances in mosquito allergy. Current Opinion in Allergy and Clinical Immunology, 7, 350–354.

[44] Pingen,M., Bryden, S.R., Pondeville,E., Schnettler,E., Kohl,A., Merits,A. et al. (2016) Host inflammatory response to mosquito bites enhances the severity of arbovirus infection. Immunity, 44, 1455–1469.

[45] Pingen,M., Schmid, M.A., Harris,E. & Mckimmie,C.S. (2017) Mosquito biting modulates skin response to virus infection. Trends in Parasitology, 33, 645–657.

[46] Reagan,K.L., Machain-Williams, C., Wang,T. & Blair,C.D. (2012) Immunization of mice with recombinant mosquito salivary protein D7 enhances mortality from subsequent West Nile virus infection via mosquito bite. PLoS Neglected Tropical Diseases, 6, e1935.

[47] Ribeiro,J.M., Arca,B., Lombardo,F., Calvo, E., Phan,V.M., Chandra,P.K. et al. (2007) An annotated catalogue of salivary gland transcripts in the adult female mosquito, Aedes aegypti. BMC Genomics, 8, 6.

[48] Ribeiro,J.M. & Francischetti, I.M. (2003) Role of arthropod saliva in blood feeding: sialome and post-sialome perspectives. Annual Review of Entomology, 48, 73–88.

[49] Schneider,B.S. & Higgs, S. (2008) The enhancement of arbovirus transmission and disease by mosquito saliva is associated with modulation of the host immune response. Transactions of the Royal Society of Tropical Medicine and Hygiene, 102, 400–408.

[50] Sierra,C., Moreno, M. & Garcia-Ruiz,J.C. (2022) The physiology of hemostasis. Blood Coagulation & Fibrinolysis, 33, S1–S2.

[51] Silva,L.A. & Dermody, T.S. (2017) Chikungunya virus: epidemiology, replication, disease mechanisms, and prospective intervention strategies. The Journal of Clinical Investigation, 127, 737–749.

[52] Sri-In,C., Weng,S.C., Chen,W.Y., Wu-Hsieh, B.A., Tu,W.C. & Shiao,S.H. (2019) A salivary protein of Aedes aegypti promotes dengue-2 virus replication and transmission. Insect Biochemistry and Molecular Biology, 111, 103181.

[53] Styer,L.M., Lim,P.Y., Louie,K.L., Albright, R.G., Kramer,L.D. & Bernard,K.A. (2011) Mosquito saliva causes enhancement of West Nile virus infection in mice. Journal of Virology, 85, 1517–1527.

[54] Sun,P., Nie,K., Zhu,Y., Liu, Y., Wu,P., Liu,Z. et al. (2020) A mosquito salivary protein promotes flavivirus transmission by activation of autophagy. Nature Communications, 11, 260.

[55] Surasombatpattana,P., Patramool, S., Luplertlop,N., Yssel,H. & Misse, D. (2012) Aedes aegypti saliva enhances dengue virus infection of human keratinocytes by suppressing innate immune responses. The Journal of Investigative Dermatology, 132, 2103–2105.

[56] Uraki,R., Hastings, A.K., Marin-Lopez,A., Sumida,T., Takahashi, T., Grover,J.R. et al. (2019) Aedes aegypti AgBR1 antibodies modulate early Zika virus infection of mice. Nature Microbiology, 4, 948–955.

[57] Valenzuela-Leon,P.C., Shrivastava, G., Martin-Martin,I., Cardenas,J.C. & Calvo, E. (2022) Multiple salivary proteins from Aedes aegypti mosquito bind to the Zika virus envelope protein. Viruses, 14, 221.

[58] Vogt,M.B., Lahon,A., Arya,R.P., Kneubehl, A.R., Spencer Clinton,J.L., Paust,S. et al. (2018) Mosquito saliva alone has profound effects on the human immune system. PLoS Neglected Tropical Diseases, 12, e0006439.

[59] Wang,F., Trier,A.M., Li,F., Kim, S., Chen,Z., Chai,J.N. et al. (2021) A basophil-neuronal axis promotes itch. Cell, 184, 422–440.

[60] Wasinpiyamongkol,L., Patramool, S., Thongrungkiat,S., Maneekan,P., Sangmukdanan, S., Misse,D. et al. (2012) Protein expression in the salivary glands of dengue-infected Aedes aegypti mosquitoes and blood-feeding success. The Southeast Asian Journal of Tropical Medicine and Public Health, 43, 1346–1357.

[61] Wasserman,H.A., Singh,S. & Champagne,D.E. (2004) Saliva of the Yellow Fever mosquito, Aedes aegypti, modulates murine lymphocyte function. Parasite Immunology, 26, 295–306.

[62] Weaver,S.C. & Barrett, A.D. (2004) Transmission cycles, host range, evolution and emergence of arboviral disease. Nature Reviews Microbiology, 2, 789–801.

[63] Wichit,S., Ferraris, P., Choumet,V. & Misse,D. (2016) The effects of mosquito saliva on dengue virus infectivity in humans. Current Opinion in Virology, 21, 139–145.

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