蚊媒黄病毒传播机制及疫苗与药物研发进展

doi:10.12211/2096-8280.2022-069

摘要/Abstract

摘要：

蚊媒病毒可通过蚊虫叮咬在宿主和蚊虫媒介之间传播循环。由蚊媒传播的病毒达数百种之多，每年可造成数亿人感染，这些病毒感染可引起严重的人类疾病，如出血热、关节炎、脑炎和脑膜炎等，严重者可导致死亡。蚊媒病毒大部分为RNA病毒，其中黄病毒科的蚊媒病毒流行最为广泛，包括登革病毒、寨卡病毒、黄热病毒、乙型脑炎病毒和西尼罗病毒等。目前虽然已有针对少数蚊媒黄病毒的有效疫苗，例如预防黄热病病毒和乙型脑炎病毒的疫苗，但仍然没有针对大多数蚊媒黄病毒的有效预防性疫苗和抗病毒疗法。因此，全面了解蚊媒黄病毒在脊椎动物宿主与蚊虫之间的感染与传播的机制，可能为抗蚊媒黄病毒的疫苗与药物研发提供新的思路与目标，从而使我们能够更有效地预测和控制蚊媒黄病毒在自然界传播和流行，为应对蚊媒黄病毒造成的公共卫生威胁提供新的解决方案。本文首先描述了蚊媒黄病毒的生物学特性和流行病学特性，接下来介绍了蚊媒黄病毒的传播途径与媒介模型，并进一步全面总结了目前对蚊媒黄病毒在宿主和媒介之间传播机制及病毒在蚊虫媒介中的感染机制的研究，同时针对蚊媒黄病毒的新型疫苗研发和药物筛选策略，对未来针对蚊媒黄病毒的机制研究与抗病毒策略开发进行了展望。

关键词: 蚊媒黄病毒, 蚊虫媒介, 感染与传播, 致病机制, 疫苗与药物

Abstract:

Mosquito-borne viruses transmit between hosts and mosquito carriers through mosquito biting, which cause hundreds of millions of infections each year. These viral infections result in serious human diseases such as hemorrhagic fever, biphasic fever, arthritis, encephalitis and meningitis, which can lead to death if proper treatment is not available. Most mosquito-borne viruses are RNA viruses, with the flavivirus family as the most prevalent ones, including dengue virus, Zika virus, yellow fever virus, Japanese encephalitis virus and West Nile virus. Although there are effective vaccines for a few mosquito-borne flaviviruses, such as those for yellow fever virus and Japanese encephalitis virus, there are still no effective preventive vaccines and antiviral therapies for most mosquito-borne flaviviruses. Therefore, a comprehensive understanding of the mechanisms underlying the infection and transmission of mosquito-borne flaviviruses between vertebrate hosts and mosquitoes would provide insights for vaccine and drug development, enabling us to more effectively predict and control the transmission of mosquito-borne flavivirus and occurrence of the epidemics in the future, and providing solutions for addressing the public health threats posed by arboviruses. In this article, we firstly describe the biological and epidemiological characteristics of mosquito-borne flaviviruses, introduce the transmission routes and carrier models of mosquito-borne flaviviruses, and summarize the current research on the transmission and infection mechanisms of mosquito-borne flaviviruses between hosts and carriers. Furthermore, we highlight the development of novel vaccines and strategies for screening drugs to fight against mosquito-borne flaviviruses, providing an outlook for future research and development of vaccines and antiviral drugs.

Key words: mosquito-borne flavivirus, mosquito vector, infection and transmission, pathogenesis, vaccine and drug

中图分类号:

Q939.93

余茜, 刘建英, 程功. 蚊媒黄病毒传播机制及疫苗与药物研发进展[J]. 合成生物学, 2023, 4(2): 347-372.

Xi YU, Jianying LIU, Gong CHENG. Research progress in mosquito-borne flaviviruses transmission and the development of vaccines and drugs[J]. Synthetic Biology Journal, 2023, 4(2): 347-372.

图/表 4

参考文献 250

1	WEAVER S C, REISEN W K. Present and future arboviral threats[J]. Antiviral Research, 2010, 85(2): 328-345.
2	WEAVER S C, BARRETT A D T. Transmission cycles, host range, evolution and emergence of arboviral disease[J]. Nature Reviews Microbiology, 2004, 2(10): 789-801.
3	BHATT S, GETHING P W, BRADY O J, et al. The global distribution and burden of dengue[J]. Nature, 2013, 496(7446): 504-507.
4	GAO G F. From "A"IV to "Z"IKV: attacks from emerging and re-emerging pathogens[J]. Cell, 2018, 172(6): 1157-1159.
5	PIERSON T C, DIAMOND M S. The emergence of Zika virus and its new clinical syndromes[J]. Nature, 2018, 560(7720): 573-581.
6	GOULD E A, SOLOMON T. Pathogenic flaviviruses[J]. Lancet, 2008, 371(9611): 500-509.
7	HEGDE N R, GORE M M. Japanese encephalitis vaccines: immunogenicity, protective efficacy, effectiveness, and impact on the burden of disease[J]. Human Vaccines & Immunotherapeutics, 2017, 13(6): 1320-1337.
8	ROEHRIG J T. West Nile virus in the United States - a historical perspective[J]. Viruses, 2013, 5(12): 3088-3108.
9	COLLINS M H, METZ S W. Progress and works in progress: update on flavivirus vaccine development[J]. Clinical Therapeutics, 2017, 39(8): 1519-1536.
10	SCHERWITZL I, MONGKOLSAPAJA J, SCREATON G. Recent advances in human flavivirus vaccines[J]. Current Opinion in Virology, 2017, 23: 95-101.
11	SIMMONDS P, BECHER P, BUKH J, et al. ICTV virus taxonomy profile: Flaviviridae[J]. The Journal of General Virology, 2017, 98(1): 2-3.
12	BURKE D S, MONATH T P. Flavivirus[M]//KNIPE D M and HOWLEY P M. Field virology, 4th ed. Philadelphia: Lippincott Williams & Wilkins, 2001: 852-921.
13	KOSTYUCHENKO V A, LIM E X Y, ZHANG S J, et al. Structure of the thermally stable Zika virus[J]. Nature, 2016, 533(7603): 425-428.
14	BYK L A, GAMARNIK A V. Properties and functions of the dengue virus capsid protein[J]. Annual Review of Virology, 2016, 3(1): 263-281.
15	MUKHOPADHYAY S, KUHN R J, ROSSMANN M G. A structural perspective of the flavivirus life cycle[J]. Nature Reviews Microbiology, 2005, 3(1): 13-22.
16	FALGOUT B, PETHEL M, ZHANG Y M, et al. Both nonstructural proteins NS2B and NS3 are required for the proteolytic processing of dengue virus nonstructural proteins[J]. Journal of Virology, 1991, 65(5): 2467-2475.
17	PERERA R, KUHN R J. Structural proteomics of dengue virus[J]. Current Opinion in Microbiology, 2008, 11(4): 369-377.
18	WESTAWAY E G, MACKENZIE J M, KHROMYKH A A. Kunjin RNA replication and applications of Kunjin replicons[J]. Advances in Virus Research, 2003, 59: 99-140.
19	LORENZ I C, ALLISON S L, HEINZ F X, et al. Folding and dimerization of tick-borne encephalitis virus envelope proteins prM and E in the endoplasmic reticulum[J]. Journal of Virology, 2002, 76(11): 5480-5491.
20	KELLY E P, GREENE J J, KING A D, et al. Purified dengue 2 virus envelope glycoprotein aggregates produced by baculovirus are immunogenic in mice[J]. Vaccine, 2000, 18(23): 2549-2559.
21	ZHANG Y, CORVER J, CHIPMAN P R, et al. Structures of immature flavivirus particles[J]. The EMBO Journal, 2003, 22(11): 2604-2613.
22	YU I M, ZHANG W, HOLDAWAY H A, et al. Structure of the immature dengue virus at low pH primes proteolytic maturation[J]. Science, 2008, 319(5871): 1834-1837.
23	LORENZ I C, KARTENBECK J, MEZZACASA A, et al. Intracellular assembly and secretion of recombinant subviral particles from tick-borne encephalitis virus[J]. Journal of Virology, 2003, 77(7): 4370-4382.
24	FARIA N R, KRAEMER M G, HILL S C, et al. Genomic and epidemiological monitoring of yellow fever virus transmission potential[J]. Science, 2018, 361(6405): 894-899.
25	INGELBEEN B, WEREGEMERE N A, NOEL H, et al. Urban yellow fever outbreak-Democratic Republic of the Congo, 2016: towards more rapid case detection[J]. PLoS Neglected Tropical Diseases, 2018, 12(12): e0007029.
26	LING Y, CHEN J, HUANG Q, et al. Yellow fever in a worker returning to China from Angola, March 2016[J]. Emerging Infectious Diseases, 2016, 22(7): 1317-1318.
27	YOUNG P. Arboviruses: a family on the move[M]// HILGENFELD R, VASUDEVAN S G. Dengue and Zika: control and antiviral treatment strategies. Singapore: Springer, 2018: 1-10.
28	TABACHNICK W J. Climate change and the arboviruses: lessons from the evolution of the dengue and yellow fever viruses[J]. Annual Review of Virology, 2016, 3(1): 125-145.
29	MANSFIELD K L, HERNÁNDEZ-TRIANA L M, BANYARD A C, et al. Japanese encephalitis virus infection, diagnosis and control in domestic animals[J]. Veterinary Microbiology, 2017, 201: 85-92.
30	MCLEAN R G, UBICO S R, BOURNE D, et al. West Nile virus in livestock and wildlife[M]//MACKENZIE J, BARRETT A, DEUBEL V eds. Japanese encephalitis and West Nile viruses. 2002, 267:271-308.
31	VENTER M. Assessing the zoonotic potential of arboviruses of African origin[J]. Current Opinion in Virology, 2018, 28: 74-84.
32	ZHANG W, CHEN S, MAHALINGAM S, et al. An updated review of avian-origin Tembusu virus: a newly emerging avian Flavivirus[J]. The Journal of General Virology, 2017, 98(10): 2413-2420.
33	PANDIT P S, DOYLE M M, SMART K M, et al. Predicting wildlife reservoirs and global vulnerability to zoonotic Flaviviruses[J]. Nature Communications, 2018, 9: 5425.
34	WHO. Global strategy for dengue prevention and control 2012-2020[EB/OL].[2022-12-01]. .
35	GUO C C, ZHOU Z X, WEN Z H, et al. Global epidemiology of dengue outbreaks in 1990—2015: a systematic review and meta-analysis[J]. Frontiers in Cellular and Infection Microbiology, 2017, 7: 317.
36	STRUCHINER C J, ROCKLÖV J, WILDER-SMITH A, et al. Increasing dengue incidence in Singapore over the past 40 years: population growth, climate and mobility[J]. PLoS One, 2015, 10(8): e0136286.
37	BRATHWAITE DICK O, MARTÍN J L SAN, MONTOYA R H, et al. The history of dengue outbreaks in the americas[J]. The American Journal of Tropical Medicine and Hygiene, 2012, 87(4): 584-593.
38	DHIMAL M, GAUTAM I, JOSHI H D, et al. Risk factors for the presence of chikungunya and dengue vectors (Aedes aegypti and Aedes albopictus), their altitudinal distribution and climatic determinants of their abundance in central Nepal[J]. PLoS Neglected Tropical Diseases, 2015, 9(3): e0003545.
39	PANDEY B D, RAI S K, MORITA K, et al. First case of Dengue virus infection in Nepal[J]. Nepal Medical College Journal: NMCJ, 2004, 6(2): 157-159.
40	MALLA S, THAKUR G D, SHRESTHA S K, et al. Identification of all dengue serotypes in Nepal[J]. Emerging Infectious Diseases, 2008, 14(10): 1669-1670.
41	YANG L, CHEN Y, YAN H C, et al. A survey of the 2014 dengue fever epidemic in Guangzhou, China[J]. Emerging Microbes & Infections, 2015, 4(9): e57.
42	KOBAYASHI D, MUROTA K, FUJITA R, et al. Dengue virus infection in Aedes albopictus during the 2014 autochthonous dengue outbreak in Tokyo metropolis, Japan[J]. The American Journal of Tropical Medicine and Hygiene, 2018, 98(5): 1460-1468.
43	関なおみ, 岩下裕子, 本涼子, ほか. 東京都におけるデング熱国内感染事例の発生について[J/OL]. 日本公衆衛生雑誌, 2015, 62(5): 238-250[2022-12-01]. .
	SEKI N, IWASHITA Y, MOTO R, et al. An autochthonous outbreak of dengue type 1 in Tokyo, Japan 2014[J/OL]. Japanese Journal of Public Health, 2015, 62(5): 238-250[2022-12-01]. .
44	DUCHEYNE E, TRAN MINH N N, HADDAD N, et al. Current and future distribution of Aedes aegypti and Aedes albopictus (Diptera: Culicidae) in WHO Eastern Mediterranean Region[J]. International Journal of Health Geographics, 2018, 17(1): 4.
45	SUCCO T, LEPARC-GOFFART I, FERRÉ J B, et al. Autochthonous dengue outbreak in Nîmes, south of France, July to September 2015[J]. Eurosurveillance, 2016, 21(21): pii=30240.
46	DUFFY M R, CHEN T H, HANCOCK W T, et al. Zika virus outbreak on Yap Island, Federated States of Micronesia[J]. The New England Journal of Medicine, 2009, 360(24): 2536-2543.
47	FOY B D, KOBYLINSKI K C, FOY J L C, et al. Probable non-vector-borne transmission of Zika virus, Colorado, USA[J]. Emerging Infectious Diseases, 2011, 17(5): 880-882.
48	KURSCHEIDT F A, MESQUITA C S S, DAMKE G M Z F, et al. Persistence and clinical relevance of Zika virus in the male genital tract[J]. Nature Reviews Urology, 2019, 16(4): 211-230.
49	OEHLER E, WATRIN L, LARRE P, et al. Zika virus infection complicated by Guillain-Barre syndrome — case report, French Polynesia, December 2013[J]. Euro Surveillance, 2014, 19(9): 20720.
50	HALSTEAD S B. Chapter 3-Chikungunya and Zika Disease[M/OL]// Chikungunya and Zika Viruses. HIGGS S, VANLANDINGHAM D L, POWERS A M, ed. Pittsburgh: Academic Press, 2018: 69-85 [2022-12-01]. .
51	VALIANT W G, LALANI T, YUN H C, et al. Human serum with high neutralizing antibody titers against both Zika and dengue virus shows delayed in vitro antibody-dependent enhancement of dengue virus infection[J]. Open Forum Infectious Diseases, 2018, 5(7): ofy151.
52	BRYANT J E, HOLMES E C, BARRETT A D T. Out of Africa: a molecular perspective on the introduction of yellow fever virus into the Americas[J]. PLoS Pathogens, 2007, 3(5): e75.
53	VAN DER STUYFT P, GIANELLA A, PIRARD M, et al. Urbanisation of yellow fever in Santa Cruz, Bolivia[J]. Lancet, 1999, 353(9164): 1558-1562.
54	BARRETT A D T. Yellow fever live attenuated vaccine: a very successful live attenuated vaccine but still we have problems controlling the disease[J]. Vaccine, 2017, 35(44): 5951-5955.
55	SHEARER F M, MOYES C L, PIGOTT D M, et al. Global yellow fever vaccination coverage from 1970 to 2016: an adjusted retrospective analysis[J]. The Lancet Infectious Diseases, 2017, 17(11): 1209-1217.
56	GARSKE T, VAN KERKHOVE M D, YACTAYO S, et al. Yellow fever in Africa: estimating the burden of disease and impact of mass vaccination from outbreak and serological data[J]. PLoS Medicine, 2014, 11(5): e1001638.
57	MONATH T P, VASCONCELOS P F C. Yellow fever[J]. Journal of Clinical Virology, 2015, 64: 160-173.
58	BARRETT A D T. Yellow fever in Angola and beyond — the problem of vaccine supply and demand[J]. The New England Journal of Medicine, 2016, 375(4): 301-303.
59	CASEY R M, HARRIS J B, AHUKA-MUNDEKE S, et al. Immunogenicity of fractional-dose vaccine during a yellow fever outbreak - final report[J]. The New England Journal of Medicine, 2019, 381(5): 444-454.
60	ZHENG Y Y, LI M H, WANG H Y, et al. Japanese encephalitis and Japanese encephalitis virus in mainland China[J]. Reviews in Medical Virology, 2012, 22(5): 301-322.
61	DE WISPELAERE M, DESPRÈS P, CHOUMET V. European Aedes albopictus and culex pipiens are competent vectors for Japanese encephalitis virus[J]. PLoS Neglected Tropical Diseases, 2017, 11(1): e0005294.
62	HUANG Y J S, HETTENBACH S M, PARK S L, et al. Differential infectivities among different Japanese encephalitis virus genotypes in Culex quinquefasciatus mosquitoes[J]. PLoS Neglected Tropical Diseases, 2016, 10(10): e0005038.
63	SCHUH A J, WARD M J, LEIGH BROWN A J, et al. Dynamics of the emergence and establishment of a newly dominant genotype of Japanese encephalitis virus throughout Asia[J]. Journal of Virology, 2014, 88(8): 4522-4532.
64	FAN Y C, LIN J W, LIAO S Y, et al. Virulence of Japanese encephalitis virus genotypesⅠandⅢ, Taiwan[J/OL]. Emerging Infectious Diseases, 2017, 23(11): 1883-1886[2022-12-01]. .
65	PARK S L, HUANG Y J S, LYONS A C, et al. North American domestic pigs are susceptible to experimental infection with Japanese encephalitis virus[J]. Scientific Reports, 2018, 8: 7951.
66	RICKLIN M E, GARCÌA-NICOLÀS O, BRECHBÜHL D, et al. Japanese encephalitis virus tropism in experimentally infected pigs[J]. Veterinary Research, 2016, 47: 34.
67	SUNWOO J S, JUNG K H, LEE S T, et al. Reemergence of Japanese encephalitis in South Korea, 2010-2015[J]. Emerging Infectious Diseases, 2016, 22(10): 1841-1843.
68	HEFFELFINGER J D, LI X, BATMUNKH N, et al. Japanese encephalitis surveillance and immunization-Asia and Western Pacific regions, 2016[J]. MMWR Morbidity and Mortality Weekly Report, 2017, 66(22): 579-583.
69	NEMETH N, BOSCO-LAUTH A, OESTERLE P, et al. North American birds as potential amplifying hosts of Japanese encephalitis virus[J]. The American Journal of Tropical Medicine and Hygiene, 2012, 87(4): 760-767.
70	LYONS A C, HUANG Y J S, PARK S L, et al. Shedding of Japanese encephalitis virus in oral fluid of infected swine[J]. Vector Borne and Zoonotic Diseases, 2018, 18(9): 469-474.
71	RICKLIN M E, GARCÍA-NICOLÁS O, BRECHBÜHL D, et al. Vector-free transmission and persistence of Japanese encephalitis virus in pigs[J]. Nature Communications, 2016, 7: 10832.
72	CDC. West Nile virus final cumulative maps & data for 1999-2021 [EB/OL].[2023-01-10]. .
73	PETERSEN L R, BRAULT A C, NASCI R S. West Nile virus: review of the literature[J]. JAMA, 2013, 310(3): 308-315.
74	DAVIS C T, EBEL G D, LANCIOTTI R S, et al. Phylogenetic analysis of North American West Nile virus isolates, 2001-2004: evidence for the emergence of a dominant genotype[J]. Virology, 2005, 342(2): 252-265.
75	MAY F J, DAVIS C T, TESH R B, et al. Phylogeography of West Nile virus: from the cradle of evolution in Africa to Eurasia, Australia, and the Americas[J]. Journal of Virology, 2011, 85(6): 2964-2974.
76	REITER P. West Nile virus in Europe: understanding the present to gauge the future[J]. Euro Surveillance, 2010, 15(10): 19508.
77	GUBLER D J, TRENT D W. Emergence of epidemic dengue/dengue hemorrhagic fever as a public health problem in the Americas[J]. Infectious Agents and Disease, 1993, 2(6): 383-393.
78	GUBLER D J, NALIM S, TAN R, et al. Variation in susceptibility to oral infection with dengue viruses among geographic strains of Aedes aegypti [J]. The American Journal of Tropical Medicine and Hygiene, 1979, 28(6): 1045-1052.
79	GUBLER D J, ROSEN L. Variation among geographic strains of Aedes albopictus in susceptibility to infection with dengue viruses[J]. The American Journal of Tropical Medicine and Hygiene, 1976, 25(2): 318-325.
80	RICO-HESSE R. Molecular evolution and distribution of dengue viruses type 1 and 2 in nature[J]. Virology, 1990, 174(2): 479-493.
81	RUDNICK A. Studies of the ecology of dengue in Malaysia: a preliminary report[J]. Journal of Medical Entomology, 1965, 2(2): 203-208.
82	RUDNICK A, MARCHETTE N J, GARCIA R. Possible jungle dengue — recent studies and hypotheses[J]. Japanese Journal of Medical Science & Biology, 1967, 20 Suppl: 69-74.
83	ZHU Y B, ZHANG R D, ZHANG B, et al. Blood meal acquisition enhances arbovirus replication in mosquitoes through activation of the GABAergic system[J]. Nature Communications, 2017, 8: 1262.
84	SOUZA-NETO J A, POWELL J R, BONIZZONI M. Aedes aegypti vector competence studies: a review[J]. Infection, Genetics and Evolution, 2019, 67: 191-209.
85	ROUNDY C M, AZAR S R, ROSSI S L, et al. Variation in Aedes aegypti mosquito competence for Zika virus transmission[J]. Emerging Infectious Diseases, 2017, 23(4): 625-632.
86	CHENG G, LIU Y, WANG P H, et al. Mosquito defense strategies against viral infection[J]. Trends in Parasitology, 2016, 32(3): 177-186.
87	FRANZ A W E, KANTOR A M, PASSARELLI A L, et al. Tissue barriers to arbovirus infection in mosquitoes[J]. Viruses, 2015, 7(7): 3741-3767.
88	STYER L M, KENT K A, ALBRIGHT R G, et al. Mosquitoes inoculate high doses of West Nile virus as they probe and feed on live hosts[J]. PLoS Pathogens, 2007, 3(9): 1262-1270.
89	SANCHEZ-VARGAS I, HARRINGTON L C, W C Ⅳ BLACK, et al. Analysis of salivary glands and saliva from Aedes albopictus and Aedes aegypti infected with chikungunya viruses[J]. Insects, 2019, 10(2): 39.
90	DU S Y, LIU Y, LIU J Y, et al. Aedes mosquitoes acquire and transmit Zika virus by breeding in contaminated aquatic environments[J]. Nature Communications, 2019, 10: 1324.
91	MACIEL-DE-FREITAS R, CODEÇO C T, LOURENÇO-DE-OLIVEIRA R. Daily survival rates and dispersal of Aedes aegypti females in Rio de Janeiro, Brazil[J]. The American Journal of Tropical Medicine and Hygiene, 2007, 76(4): 659-665.
92	WHITEHORN J, KIEN D T H, NGUYEN N M, et al. Comparative susceptibility of Aedes albopictus and Aedes aegypti to dengue virus infection after feeding on blood of viremic humans: implications for public health[J]. The Journal of Infectious Diseases, 2015, 212(8): 1182-1190.
93	BARROWS N J, CAMPOS R K, LIAO K C, et al. Biochemistry and molecular biology of flaviviruses[J]. Chemical Reviews, 2018, 118(8): 4448-4482.
94	CHENG G, COX J, WANG P H, et al. A C-type lectin collaborates with a CD45 phosphatase homolog to facilitate West Nile virus infection of mosquitoes[J]. Cell, 2010, 142(5): 714-725.
95	LIU Y, ZHANG F C, LIU J Y, et al. Transmission-blocking antibodies against mosquito C-type lectins for dengue prevention[J]. PLoS Pathogens, 2014, 10(2): e1003931.
96	KUADKITKAN A, WIKAN N, FONGSARAN C, et al. Identification and characterization of prohibitin as a receptor protein mediating DENV-2 entry into insect cells[J]. Virology, 2010, 406(1): 149-161.
97	SALAS-BENITO J, REYES-DEL VALLE J, SALAS-BENITO M, et al. Evidence that the 45 kD glycoprotein, part of a putative dengue virus receptor complex in the mosquito cell line C6/36, is a heat-shock related protein[J]. The American Journal of Tropical Medicine and Hygiene, 2007, 77(2): 283-290.
98	SAKOONWATANYOO P, BOONSANAY V, SMITH D R. Growth and production of the dengue virus in C6/36 cells and identification of a laminin-binding protein as a candidate serotype 3 and 4 receptor protein[J]. Intervirology, 2006, 49(3): 161-172.
99	LONDONO-RENTERIA B, TROUPIN A, CONWAY M J, et al. Dengue virus infection of Aedes aegypti requires a putative cysteine rich venom protein[J]. PLoS Pathogens, 2015, 11(10): e1005202.
100	KAKUMANI P K, PONIA S S, S R K, et al. Role of RNA interference (RNAi) in dengue virus replication and identification of NS4B as an RNAi suppressor[J]. Journal of Virology, 2013, 87(16): 8870-8883.
101	GÖERTZ G P, FROS J J, MIESEN P, et al. Noncoding subgenomic flavivirus RNA is processed by the mosquito RNA interference machinery and determines West Nile virus transmission by culex pipiens mosquitoes[J]. Journal of Virology, 2016, 90(22): 10145-10159.
102	MOON S L, DODD B J T, BRACKNEY D E, et al. Flavivirus sfRNA suppresses antiviral RNA interference in cultured cells and mosquitoes and directly interacts with the RNAi machinery[J]. Virology, 2015, 485: 322-329.
103	POMPON J, MANUEL M, NG G K, et al. Dengue subgenomic flaviviral RNA disrupts immunity in mosquito salivary glands to increase virus transmission[J]. PLoS Pathogens, 2017, 13(7): e1006535.
104	PARIKH G R, OLIVER J D, BARTHOLOMAY L C. A haemocyte tropism for an arbovirus[J]. The Journal of General Virology, 2009, 90(Pt 2): 292-296.
105	GOIC B, STAPLEFORD K A, FRANGEUL L, et al. Virus-derived DNA drives mosquito vector tolerance to arboviral infection[J]. Nature Communications, 2016, 7: 12410.
106	XIAO X P, ZHANG R D, PANG X J, et al. A neuron-specific antiviral mechanism prevents lethal flaviviral infection of mosquitoes[J]. PLoS Pathogens, 2015, 11(4): e1004848.
107	XIAO X P, LIU Y, ZHANG X Y, et al. Complement-related proteins control the flavivirus infection of Aedes aegypti by inducing antimicrobial peptides[J]. PLoS Pathogens, 2014, 10(4): e1004027.
108	BLANDIN S, SHIAO S H, MOITA L F, et al. Complement-like protein TEP1 is a determinant of vectorial capacity in the malaria vector Anopheles gambiae [J]. Cell, 2004, 116(5): 661-670.
109	SHOKAL U, ELEFTHERIANOS I. Evolution and function of thioester-containing proteins and the complement system in the innate immune response[J]. Frontiers in Immunology, 2017, 8: 759.
110	KINGSOLVER M B, HUANG Z J, HARDY R W. Insect antiviral innate immunity: pathways, effectors, and connections[J]. Journal of Molecular Biology, 2013, 425(24): 4921-4936.
111	TASSETTO M, KUNITOMI M, ANDINO R. Circulating immune cells mediate a systemic RNAi-based adaptive antiviral response in Drosophila [J]. Cell, 2017, 169(2): 314-325.e13.
112	GOIC B, VODOVAR N, MONDOTTE J A, et al. RNA-mediated interference and reverse transcription control the persistence of RNA viruses in the insect model Drosophila [J]. Nature Immunology, 2013, 14(4): 396-403.
113	WU P, YU X, WANG P, et al. Arbovirus lifecycle in mosquito: acquisition, propagation and transmission[J]. Expert Reviews in Molecular Medicine, 2019, 21: e1.
114	RAMIREZ J L, SHORT S M, BAHIA A C, et al. Chromobacterium Csp_P reduces malaria and dengue infection in vector mosquitoes and has entomopathogenic and in vitro anti-pathogen activities[J]. PLoS Pathogens, 2014, 10(10): e1004398.
115	SARAIVA R G, FANG J R, KANG S, et al. Aminopeptidase secreted by Chromobacterium sp. Panama inhibits dengue virus infection by degrading the E protein[J]. PLoS Neglected Tropical Diseases, 2018, 12(4): e0006443.
116	YU X, TONG L Q, ZHANG L M, et al. Lipases secreted by a gut bacterium inhibit arbovirus transmission in mosquitoes[J]. PLoS Pathogens, 2022, 18(6): e1010552.
117	RAMIREZ J L, SOUZA-NETO J, TORRES COSME R, et al. Reciprocal tripartite interactions between the Aedes aegypti midgut microbiota, innate immune system and dengue virus influences vector competence[J]. PLoS Neglected Tropical Diseases, 2012, 6(3): e1561.
118	APTE-DESHPANDE A, PAINGANKAR M, GOKHALE M D, et al. Serratia odorifera a midgut inhabitant of Aedes aegypti mosquito enhances its susceptibility to dengue-2 virus[J]. PLoS One, 2012, 7(7): e40401.
119	ANGLERÓ-RODRÍGUEZ Y I, TALYULI O A, BLUMBERG B J, et al. An Aedes aegypti-associated fungus increases susceptibility to dengue virus by modulating gut trypsin activity[J]. eLife, 2017, 6: e28844.
120	DONG Y M, MORTON J C Jr, RAMIREZ J L, et al. The entomopathogenic fungus Beauveria bassiana activate toll and JAK-STAT pathway-controlled effector genes and anti-dengue activity in Aedes aegypti [J]. Insect Biochemistry and Molecular Biology, 2012, 42(2): 126-132.
121	GARZA-HERNÁNDEZ J A, RODRÍGUEZ-PÉREZ M A, SALAZAR M I, et al. Vectorial capacity of Aedes aegypti for dengue virus type 2 is reduced with co-infection of Metarhizium anisopliae [J]. PLoS Neglected Tropical Diseases, 2013, 7(3): e2013.
122	NGUYEN N M, KIEN D THI HUE, TUAN T V, et al. Host and viral features of human dengue cases shape the population of infected and infectious Aedes aegypti mosquitoes[J]. Proceedings of the National Academy of Sciences of the United States of America, 2013, 110(22): 9072-9077.
123	WAGAR Z L, TREE M O, MPOY M C, et al. Low density lipopolyprotein inhibits flavivirus acquisition in Aedes aegypti [J]. Insect Molecular Biology, 2017, 26(6): 734-742.
124	BOTTINO-ROJAS V, TALYULI O A, JUPATANAKUL N, et al. Heme signaling impacts global gene expression, immunity and dengue virus infectivity in Aedes aegypti [J]. PLoS One, 2015, 10(8): e0135985.
125	LIU J Y, LIU Y, NIE K X, et al. Flavivirus NS1 protein in infected host sera enhances viral acquisition by mosquitoes[J]. Nature Microbiology, 2016, 1: 16087.
126	LIU Y, LIU J Y, DU S Y, et al. Evolutionary enhancement of Zika virus infectivity in Aedes aegypti mosquitoes[J]. Nature, 2017, 545(7655): 482-486.
127	WU P, YU X, WANG P H, et al. Arbovirus lifecycle in mosquito: acquisition, propagation and transmission[J]. Expert Reviews in Molecular Medicine, 2019, 21: e1.
128	WICHIT S, DIOP F, HAMEL R, et al. Aedes aegypti saliva enhances chikungunya virus replication in human skin fibroblasts via inhibition of the typeⅠinterferon signaling pathway[J]. Infection, Genetics and Evolution, 2017, 55: 68-70.
129	CERNY D, HANIFFA M, SHIN A, et al. Selective susceptibility of human skin antigen presenting cells to productive dengue virus infection[J]. PLoS Pathogens, 2014, 10(12): e1004548.
130	SCHMID M A, HARRIS E. Monocyte recruitment to the dermis and differentiation to dendritic cells increases the targets for dengue virus replication[J]. PLoS Pathogens, 2014, 10(12): e1004541.
131	HAMEL R, DEJARNAC O, WICHIT S, et al. Biology of Zika virus infection in human skin cells[J]. Journal of Virology, 2015, 89(17): 8880-8896.
132	SCHAEFFER E, FLACHER V, PAPAGEORGIOU V, et al. Dermal CD14⁺ dendritic cell and macrophage infection by dengue virus is stimulated by interleukin-4[J]. The Journal of Investigative Dermatology, 2015, 135(7): 1743-1751.
133	MACDONALD G H, JOHNSTON R E. Role of dendritic cell targeting in Venezuelan equine encephalitis virus pathogenesis[J]. Journal of Virology, 2000, 74(2): 914-922.
134	GARDNER C L, BURKE C W, TESFAY M Z, et al. Eastern and Venezuelan equine encephalitis viruses differ in their ability to infect dendritic cells and macrophages: impact of altered cell tropism on pathogenesis[J]. Journal of Virology, 2008, 82(21): 10634-10646.
135	DAVISON A M, KING N J C. Accelerated dendritic cell differentiation from migrating Ly6C(lo) bone marrow monocytes in early dermal West Nile virus infection[J]. Journal of Immunology, 2011, 186(4): 2382-2396.
136	WU S J L, GROUARD-VOGEL G, SUN W, et al. Human skin Langerhans cells are targets of dengue virus infection[J]. Nature Medicine, 2000, 6(7): 816-820.
137	DIAMOND M S, SHRESTHA B, MEHLHOP E, et al. Innate and adaptive immune responses determine protection against disseminated infection by West Nile encephalitis virus[J]. Viral Immunology, 2003, 16(3): 259-278.
138	STYER L M, LIM P Y, LOUIE K L, et al. Mosquito saliva causes enhancement of West Nile virus infection in mice[J]. Journal of Virology, 2011, 85(4): 1517-1527.
139	SCHNEIDER B S, SOONG L, GIRARD Y A, et al. Potentiation of West Nile encephalitis by mosquito feeding[J]. Viral Immunology, 2006, 19(1): 74-82.
140	COX J, MOTA J, SUKUPOLVI-PETTY S, et al. Mosquito bite delivery of dengue virus enhances immunogenicity and pathogenesis in humanized mice[J]. Journal of Virology, 2012, 86(14): 7637-7649.
141	SCHNEIDER B S, HIGGS S. The enhancement of arbovirus transmission and disease by mosquito saliva is associated with modulation of the host immune response[J]. Transactions of the Royal Society of Tropical Medicine and Hygiene, 2008, 102(5): 400-408.
142	PINGEN M, SCHMID M A, HARRIS E, et al. Mosquito biting modulates skin response to virus infection[J]. Trends in Parasitology, 2017, 33(8): 645-657.
143	URAKI R, HASTINGS A K, MARIN-LOPEZ A, et al. Aedes aegypti AgBR1 antibodies modulate early Zika virus infection of mice[J]. Nature Microbiology, 2019, 4(6): 948-955.
144	URAKI R, HASTINGS A K, BRACKNEY D E, et al. AgBR1 antibodies delay lethal Aedes aegypti-borne West Nile virus infection in mice[J]. Npj Vaccines, 2019, 4: 23.
145	SURASOMBATPATTANA P, EKCHARIYAWAT P, HAMEL R, et al. Aedes aegypti saliva contains a prominent 34 kDa protein that strongly enhances dengue virus replication in human keratinocytes[J]. The Journal of Investigative Dermatology, 2014, 134(1): 281-284.
146	MCCRACKEN M K, CHRISTOFFERSON R C, CHISENHALL D M, et al. Analysis of early dengue virus infection in mice as modulated by Aedes aegypti probing[J]. Journal of Virology, 2014, 88(4): 1881-1889.
147	JIN L, GUO X M, SHEN C B, et al. Salivary factor LTRIN from Aedes aegypti facilitates the transmission of Zika virus by interfering with the lymphotoxin-β receptor[J]. Nature Immunology, 2018, 19(4): 342-353.
148	CONWAY M J, WATSON A M, COLPITTS T M, et al. Mosquito saliva serine protease enhances dissemination of dengue virus into the mammalian host[J]. Journal of Virology, 2014, 88(1): 164-175.
149	SCHMID M A, GLASNER D R, SHAH S, et al. Mosquito saliva increases endothelial permeability in the skin, immune cell migration, and dengue pathogenesis during antibody-dependent enhancement[J]. PLoS Pathogens, 2016, 12(6): e1005676.
150	MOYA A, HOLMES E C, GONZÁLEZ-CANDELAS F. The population genetics and evolutionary epidemiology of RNA viruses[J]. Nature Reviews Microbiology, 2004, 2(4): 279-288.
151	DOLAN P T, WHITFIELD Z J, ANDINO R. Mechanisms and concepts in RNA virus population dynamics and evolution[J]. Annual Review of Virology, 2018, 5(1): 69-92.
152	MUSTAFA M S, RASOTGI V, JAIN S, et al. Discovery of fifth serotype of dengue virus (DENV-5): a new public health dilemma in dengue control[J]. Medical Journal Armed Forces India, 2015, 71(1): 67-70.
153	DÍAZ F J, BLACK W C IV, FARFÁN-ALE J A, et al. Dengue virus circulation and evolution in Mexico: a phylogenetic perspective[J]. Archives of Medical Research, 2006, 37(6): 760-773.
154	ZHANG C L, MAMMEN M P Jr, CHINNAWIROTPISAN P, et al. Clade replacements in dengue virus serotypes 1 and 3 are associated with changing serotype prevalence[J]. Journal of Virology, 2005, 79(24): 15123-15130.
155	LEWIS J A, CHANG G J, LANCIOTTI R S, et al. Phylogenetic relationships of dengue-2 viruses[J]. Virology, 1993, 197(1): 216-224.
156	RICO-HESSE R, HARRISON L M, NISALAK A, et al. Molecular evolution of dengue type 2 virus in Thailand[J]. The American Journal of Tropical Medicine and Hygiene, 1998, 58(1): 96-101.
157	MESSER W B, GUBLER D J, HARRIS E, et al. Emergence and global spread of a dengue serotype 3, subtype Ⅲvirus[J]. Emerging Infectious Diseases, 2003, 9(7): 800-809.
158	LANCIOTTI R S, LEWIS J G, GUBLER D J, et al. Molecular evolution and epidemiology of dengue-3 viruses[J]. The Journal of General Virology, 1994, 75 ( Pt 1): 65-75.
159	WANG E, NI H, XU R, et al. Evolutionary relationships of endemic/epidemic and sylvatic dengue viruses[J]. Journal of Virology, 2000, 74(7): 3227-3234.
160	LANCIOTTI R S, GUBLER D J, TRENT D W. Molecular evolution and phylogeny of dengue-4 viruses[J]. The Journal of General Virology, 1997, 78 ( Pt 9): 2279-2284.
161	BALMASEDA A, HAMMOND S N, PÉREZ L, et al. Serotype-specific differences in clinical manifestations of dengue[J]. The American Journal of Tropical Medicine and Hygiene, 2006, 74(3): 449-456.
162	BURKE D S, NISALAK A, JOHNSON D E, et al. A prospective study of dengue infections in Bangkok[J]. The American Journal of Tropical Medicine and Hygiene, 1988, 38(1): 172-180.
163	GUZMÁN M G, KOURÍ G, VALDÉS L, et al. Enhanced severity of secondary dengue-2 infections: death rates in 1981 and 1997 Cuban outbreaks[J]. Revista Panamericana De Salud Publica=Pan American Journal of Public Health, 2002, 11(4): 223-227.
164	NISALAK A, ENDY T P, NIMMANNITYA S, et al. Serotype-specific dengue virus circulation and dengue disease in Bangkok, Thailand from 1973 to 1999[J]. The American Journal of Tropical Medicine and Hygiene, 2003, 68(2): 191-202.
165	SANGKAWIBHA N, ROJANASUPHOT S, AHANDRIK S, et al. Risk factors in dengue shock syndrome: a prospective epidemiologic study in rayong, Thailand:Ⅰ. the 1980 outbreak[J]. American Journal of Epidemiology, 1984, 120(5): 653-669.
166	THEIN S, AUNG M M, SHWE T N, et al. Risk factors in dengue shock syndrome[J]. The American Journal of Tropical Medicine and Hygiene, 1997, 56(5): 566-572.
167	GRAHAM R R, JUFFRIE M, TAN R, et al. A prospective seroepidemiologic study on dengue in children four to nine years of age in Yogyakarta, IndonesiaⅠ. studies in 1995—1996[J]. The American Journal of Tropical Medicine and Hygiene, 1999, 61(3): 412-419.
168	HARRIS E, VIDEA E, PÉREZ L, et al. Clinical, epidemiologic, and virologic features of dengue in the 1998 epidemic in Nicaragua[J]. The American Journal of Tropical Medicine and Hygiene, 2000, 63(1/2): 5-11.
169	MESSER W B, VITARANA U T, SIVANANTHAN K, et al. Epidemiology of dengue in Sri Lanka before and after the emergence of epidemic dengue hemorrhagic fever[J]. The American Journal of Tropical Medicine and Hygiene, 2002, 66(6): 765-773.
170	LEITMEYER K C, VAUGHN D W, WATTS D M, et al. Dengue virus structural differences that correlate with pathogenesis[J]. Journal of Virology, 1999, 73(6): 4738-4747.
171	COLOGNA R, RICO-HESSE R. American genotype structures decrease dengue virus output from human monocytes and dendritic cells[J]. Journal of Virology, 2003, 77(7): 3929-3938.
172	PRYOR M J, CARR J M, HOCKING H, et al. Replication of dengue virus type 2 in human monocyte-derived macrophages: comparisons of isolates and recombinant viruses with substitutions at amino acid 390 in the envelope glycoprotein[J]. The American Journal of Tropical Medicine and Hygiene, 2001, 65(5): 427-434.
173	OHAINLE M, BALMASEDA A, MACALALAD A R, et al. Dynamics of dengue disease severity determined by the interplay between viral genetics and serotype-specific immunity[J]. Science Translational Medicine, 2011, 3(114): 114-128.
174	CHEN H L, LIN S R, LIU H F, et al. Evolution of dengue virus type 2 during two consecutive outbreaks with an increase in severity in southern Taiwan in 2001—2002[J]. The American Journal of Tropical Medicine and Hygiene, 2008, 79(4): 495-505.
175	MUSSO D, GUBLER D J. Zika virus[J]. Clinical Microbiology Reviews, 2016, 29(3): 487-524.
176	ENFISSI A, CODRINGTON J, ROOSBLAD J, et al. Zika virus genome from the americas[J]. Lancet, 2016, 387(10015): 227-228.
177	WINKLER G, RANDOLPH V B, CLEAVES G R, et al. Evidence that the mature form of the flavivirus nonstructural protein NS1 is a dimer[J]. Virology, 1988, 162(1): 187-196.
178	ALCON S, TALARMIN A, DEBRUYNE M, et al. Enzyme-linked immunosorbent assay specific to Dengue virus type 1 nonstructural protein NS1 reveals circulation of the antigen in the blood during the acute phase of disease in patients experiencing primary or secondary infections[J]. Journal of Clinical Microbiology, 2002, 40(2): 376-381.
179	GUO M J, HUI L X, NIE Y W, et al. ZIKV viral proteins and their roles in virus-host interactions[J]. Science China Life Sciences, 2021, 64(5): 709-719.
180	YU X, SHAN C, ZHU Y B, et al. A mutation-mediated evolutionary adaptation of Zika virus in mosquito and mammalian host[J]. Proceedings of the National Academy of Sciences of the United States of America, 2021, 118(42): e2113015118.
181	ZHU Z, CHAN J F W, TEE K M, et al. Comparative genomic analysis of pre-epidemic and epidemic Zika virus strains for virological factors potentially associated with the rapidly expanding epidemic[J]. Emerging Microbes & Infections, 2016, 5(1): 1-12.
182	YUAN L, HUANG X Y, LIU Z Y, et al. A single mutation in the prM protein of Zika virus contributes to fetal microcephaly[J]. Science, 2017, 358(6365): 933-936.
183	SHAN C, XIA H J, HALLER S L, et al. A Zika virus envelope mutation preceding the 2015 epidemic enhances virulence and fitness for transmission[J]. Proceedings of the National Academy of Sciences of the United States of America, 2020, 117(33): 20190-20197.
184	GEERLING E, STEFFEN T L, BRIEN J D, et al. Current flavivirus research important for vaccine development[J]. Vaccines, 2020, 8(3): 477.
185	THEILER M, SMITH H H. The use of yellow fever virus modified by in vitro cultivation for human immunization[J]. The Journal of Experimental Medicine, 1937, 65(6): 787-800.
186	BOIGARD H, ALIMOVA A, MARTIN G R, et al. Zika virus-like particle (VLP) based vaccine[J]. PLoS Neglected Tropical Diseases, 2017, 11(5): e0005608.
187	URAKAMI A, NGWE TUN M M, MOI M L, et al. An envelope-modified tetravalent dengue virus-like-particle vaccine has implications for flavivirus vaccine design[J]. Journal of Virology, 2017, 91(23): e01181-e01117.
188	RICHNER J M, HIMANSU S, DOWD K A, et al. Modified mRNA vaccines protect against Zika virus infection[J]. Cell, 2017, 168(6): 1114-1125.e10.
189	COLLINS N D, BARRETT A D T. Live attenuated yellow fever 17D vaccine: a legacy vaccine still controlling outbreaks in modern day[J]. Current Infectious Disease Reports, 2017, 19(3): 14.
190	SATCHIDANANDAM V. Japanese encephalitis vaccines[J]. Current Treatment Options in Infectious Diseases, 2020, 12(4): 375-386.
191	GUY B, BARRERE B, MALINOWSKI C, et al. From research to phaseⅢ: preclinical, industrial and clinical development of the Sanofi Pasteur tetravalent dengue vaccine[J]. Vaccine, 2011, 29(42): 7229-7241.
192	THOMAS R E. Yellow fever vaccine-associated viscerotropic disease: current perspectives[J]. Drug Design, Development and Therapy, 2016, 10: 3345-3353.
193	DEM MARTINS R, PAVÃO A L B, DE OLIVEIRA P M N, et al. Adverse events following yellow fever immunization: report and analysis of 67 neurological cases in Brazil[J]. Vaccine, 2014, 32(49): 6676-6682.
194	BREUGELMANS J G, LEWIS R F, AGBENU E, et al. Adverse events following yellow fever preventive vaccination campaigns in eight African countries from 2007 to 2010[J]. Vaccine, 2013, 31(14): 1819-1829.
195	MCMAHON A W, EIDEX R B, MARFIN A A, et al. Neurologic disease associated with 17D-204 yellow fever vaccination: a report of 15 cases[J]. Vaccine, 2007, 25(10): 1727-1734.
196	BURCHARD G D, CAUMES E, CONNOR B A, et al. Expert opinion on vaccination of travelers against Japanese encephalitis[J]. Journal of Travel Medicine, 2009, 16(3): 204-216.
197	HADINEGORO S R, ARREDONDO-GARCÍA J L, CAPEDING M R, et al. Efficacy and long-term safety of a dengue vaccine in regions of endemic disease[J]. The New England Journal of Medicine, 2015, 373(13): 1195-1206.
198	SRIDHAR S, LUEDTKE A, LANGEVIN E, et al. Effect of dengue serostatus on dengue vaccine safety and efficacy[J]. The New England Journal of Medicine, 2018, 379(4): 327-340.
199	GEORGE J, VALIANT W G, MATTAPALLIL M J, et al. Prior exposure to Zika virus significantly enhances peak dengue-2 viremia in rhesus macaques[J]. Scientific Reports, 2017, 7: 10498.
200	DEJNIRATTISAI W, SUPASA P, WONGWIWAT W, et al. Dengue virus sero-cross-reactivity drives antibody-dependent enhancement of infection with Zika virus[J]. Nature Immunology, 2016, 17(9): 1102-1108.
201	BARDINA S V, BUNDUC P, TRIPATHI S, et al. Enhancement of Zika virus pathogenesis by preexisting antiflavivirus immunity[J]. Science, 2017, 356(6334): 175-180.
202	FOWLER A M, TANG W W, YOUNG M P, et al. Maternally acquired Zika antibodies enhance dengue disease severity in mice[J]. Cell Host & Microbe, 2018, 24(5): 743-750.
203	KATZELNICK L C, GRESH L, HALLORAN M E, et al. Antibody-dependent enhancement of severe dengue disease in humans[J]. Science, 2017, 358(6365): 929-932.
204	KATZELNICK L C, NARVAEZ C, ARGUELLO S, et al. Zika virus infection enhances future risk of severe dengue disease[J]. Science, 2020, 369(6507): 1123-1128.
205	RAVIPRAKASH K, PORTER K R, KOCHEL T J, et al. Dengue virus type 1 DNA vaccine induces protective immune responses in rhesus macaques[J]. The Journal of General Virology, 2000, 81(Pt 7): 1659-1667.
206	KHETARPAL N, KHANNA I. Dengue fever: causes, complications, and vaccine strategies[J]. Journal of Immunology Research, 2016, 2016: 6803098.
207	WONG G, GAO G F. An mRNA-based vaccine strategy against Zika[J]. Cell Research, 2017, 27(9): 1077-1078.
208	JIMÉNEZ DE OYA N, ESCRIBANO-ROMERO E, BLÁZQUEZ A B, et al. Current progress of avian vaccines against west Nile virus[J]. Vaccines, 2019, 7(4): 126.
209	KHOU C, PARDIGON N. Identifying attenuating mutations: tools for a new vaccine design against flaviviruses[J]. Intervirology, 2017, 60(1/2): 8-18.
210	LONDONO-RENTERIA B, TROUPIN A, COLPITTS T M. Arbovirosis and potential transmission blocking vaccines[J]. Parasites & Vectors, 2016, 9(1): 516.
211	WU S F, LEE C J, LIAO C L, et al. Antiviral effects of an iminosugar derivative on flavivirus infections[J]. Journal of Virology, 2002, 76(8): 3596-3604.
212	TCHANKOUO-NGUETCHEU S, KHUN H, PINCET L, et al. Differential protein modulation in midguts of Aedes aegypti infected with chikungunya and dengue 2 viruses[J]. PLoS One, 2010, 5(10): e13149.
213	THAM H W, BALASUBRAMANIAM V R M T, TEJO B A, et al. CPB₁ of Aedes aegypti interacts with DENV2 E protein and regulates intracellular viral accumulation and release from midgut cells[J]. Viruses, 2014, 6(12): 5028-5046.
214	DINGLASAN R R, VALENZUELA J G, AZAD A F. Sugar epitopes as potential universal disease transmission blocking targets[J]. Insect Biochemistry and Molecular Biology, 2005, 35(1): 1-10.
215	LIU K, QIAN Y J, JUNG Y S, et al. mosGCTL-7, a C-type lectin protein, mediates Japanese encephalitis virus infection in mosquitoes[J]. Journal of Virology, 2017, 91(10): e01348-e01316.
216	PERERA-LECOIN M, MEERTENS L, CARNEC X, et al. Flavivirus entry receptors: an update[J]. Viruses, 2014, 6(1): 69-88.
217	PERERA R, KHALIQ M, KUHN R J. Closing the door on flaviviruses: entry as a target for antiviral drug design[J]. Antiviral Research, 2008, 80(1): 11-22.
218	LI P C, JANG J, HSIA C Y, et al. Small molecules targeting the flavivirus E protein with broad-spectrum activity and antiviral efficacy in vivo [J]. ACS Infectious Diseases, 2019, 5(3): 460-472.
219	KAMPMANN T, YENNAMALLI R, CAMPBELL P, et al. In silico screening of small molecule libraries using the dengue virus envelope E protein has identified compounds with antiviral activity against multiple flaviviruses[J]. Antiviral Research, 2009, 84(3): 234-241.
220	ZHANG W, CHIPMAN P R, CORVER J, et al. Visualization of membrane protein domains by cryo-electron microscopy of dengue virus[J]. Nature Structural & Molecular Biology, 2003, 10(11): 907-912.
221	COSTIN J M, JENWITHEESUK E, LOK S M, et al. Structural optimization and de novo design of dengue virus entry inhibitory peptides[J]. PLoS Neglected Tropical Diseases, 2010, 4(6): e721.
222	ALTMEYER R. Virus attachment and entry offer numerous targets for antiviral therapy[J]. Current Pharmaceutical Design, 2004, 10(30): 3701-3712.
223	DIGHE S N, EKWUDU O, DUA K, et al. Recent update on anti-dengue drug discovery[J]. European Journal of Medicinal Chemistry, 2019, 176: 431-455.
224	KANG C B, KELLER T H, LUO D H. Zika virus protease: an antiviral drug target[J]. Trends in Microbiology, 2017, 25(10): 797-808.
225	NITSCHE C. Proteases from dengue, West Nile and Zika viruses as drug targets[J]. Biophysical Reviews, 2019, 11(2): 157-165.
226	KOK W M. New developments in flavivirus drug discovery[J]. Expert Opinion on Drug Discovery, 2016, 11(5): 433-445.
227	RAY D, SHI P Y. Recent advances in flavivirus antiviral drug discovery and vaccine development[J]. Recent Patents on Anti-Infective Drug Discovery, 2006, 1(1): 45-55.
228	MASTRANGELO E, PEZZULLO M, DE BURGHGRAEVE T, et al. Ivermectin is a potent inhibitor of flavivirus replication specifically targeting NS3 helicase activity: new prospects for an old drug[J]. Journal of Antimicrobial Chemotherapy, 2012, 67(8): 1884-1894.
229	BOLLATI M, ALVAREZ K, ASSENBERG R, et al. Structure and functionality in flavivirus NS-proteins: perspectives for drug design[J]. Antiviral Research, 2010, 87(2): 125-148.
230	CHATRIN C, TALAPATRA S K, CANARD B, et al. The structure of the binary methyltransferase-SAH complex from Zika virus reveals a novel conformation for the mechanism of mRNA capping[J]. Oncotarget, 2018, 9(3): 3160-3171.
231	ZHOU Y S, RAY D, ZHAO Y W, et al. Structure and function of flavivirus NS5 methyltransferase[J]. Journal of Virology, 2007, 81(8): 3891-3903.
232	AFAQ S, ATIYA A, MALIK A, et al. Analysis of methyltransferase (MTase) domain from Zika virus (ZIKV)[J]. Bioinformation, 2020, 16(3): 229-235.
233	BRECHER M, CHEN H, LI Z, et al. Identification and characterization of novel broad-spectrum inhibitors of the flavivirus methyltransferase[J]. ACS Infectious Diseases, 2015, 1(8): 340-349.
234	NOBLE C G, LI S H, DONG H P, et al. Crystal structure of dengue virus methyltransferase without S-adenosyl-L-methionine[J]. Antiviral Research, 2014, 111: 78-81.
235	WANG B X, THURMOND S, HAI R, et al. Structure and function of Zika virus NS5 protein: perspectives for drug design[J]. Cellular and Molecular Life Sciences, 2018, 75(10): 1723-1736.
236	JAIN R, BUTLER K V, COLOMA J, et al. Development of a S-adenosylmethionine analog that intrudes the RNA-cap binding site of Zika methyltransferase[J]. Scientific Reports, 2017, 7: 1632.
237	LIM S V, RAHMAN M B A, TEJO B A. Structure-based and ligand-based virtual screening of novel methyltransferase inhibitors of the dengue virus[J]. BMC Bioinformatics, 2011, 12(): S24.
238	BRECHER M, CHEN H, LIU B B, et al. Novel broad spectrum inhibitors targeting the flavivirus methyltransferase[J]. PLoS One, 2015, 10(6): e0130062.
239	SIQUEIRA-BATISTA R, DE SOUZA BAYÃO T, CARMO CUPERTINO M DO, et al. Sofosbuvir use for yellow fever: a new perspective treatment[J]. Pathogens and Global Health, 2019, 113(5): 207-208.
240	BULLARD-FEIBELMAN K M, GOVERO J, ZHU Z, et al. The FDA-approved drug sofosbuvir inhibits Zika virus infection[J]. Antiviral Research, 2017, 137: 134-140.
241	FERREIRA A C, ZAVERUCHA-DO-VALLE C, REIS P A, et al. Sofosbuvir protects Zika virus-infected mice from mortality, preventing short- and long-term sequelae[J]. Scientific Reports, 2017, 7: 9409.
242	JACOBS S, DELANG L E, VERBEKEN E, et al. A viral polymerase inhibitor reduces Zika virus replication in the reproductive organs of male mice[J]. International Journal of Molecular Sciences, 2019, 20(9): 2122.
243	IVANOVA T, HARDES K, KALLIS S, et al. Optimization of substrate-analogue furin inhibitors[J]. ChemMedChem, 2017, 12(23): 1953-1968.
244	SKRZYPEK R, CALLAGHAN R. The "pushmi-pullyu" of resistance to chloroquine in malaria[J]. Essays in Biochemistry, 2017, 61(1): 167-175.
245	BYRD C M, DAI D C, GROSENBACH D W, et al. A novel inhibitor of dengue virus replication that targets the capsid protein[J]. Antimicrobial Agents and Chemotherapy, 2013, 57(1): 15-25.
246	QIN C F, QIN E D. Capsid-targeted viral inactivation can destroy dengue 2 virus from within in vitro [J]. Archives of Virology, 2006, 151(2): 379-385.
247	STOERMER K A, MORRISON T E. Complement and viral pathogenesis[J]. Virology, 2011, 411(2): 362-373.
248	AKEY D L, BROWN W C, JOSE J, et al. Structure-guided insights on the role of NS1 in flavivirus infection[J]. BioEssays: News and Reviews in Molecular, Cellular and Developmental Biology, 2015, 37(5): 489-494.
249	SOMNUKE P, HAUHART R E, ATKINSON J P, et al. N-linked glycosylation of dengue virus NS1 protein modulates secretion, cell-surface expression, hexamer stability, and interactions with human complement[J]. Virology, 2011, 413(2): 253-264.
250	WATTERSON D, MODHIRAN N, YOUNG P R. The many faces of the flavivirus NS1 protein offer a multitude of options for inhibitor design[J]. Antiviral Research, 2016, 130: 7-18.

疫苗名称	疫苗种类	抗原	针对病毒种类	疫苗开发阶段	开发者
17D	减毒活疫苗	E蛋白	YFV	已获得许可	[185]
SA14-14-2	减毒活疫苗	E蛋白	JEV	已获得许可	CDIBP
TV003	减毒活疫苗	prM-E	DENV 1～4	临床三期	NIAID
DENVax	减毒活疫苗	prM-E	DENV 1～4	临床三期	Takeda
TDENV-PIV	灭活疫苗	C-prM-E-NS1/3/5	DENV 1～4	临床一期	GSK, Fiocruz & WRAIR
ZPIV	灭活疫苗	E蛋白	ZIKV	临床一期	WRAIR/NIAID
CYD-TDV(Dengvaxia)	重组疫苗	prM-E	DENV 1～4	已获得许可	Sanofi Pasteur
ChimeriVax-WN02	重组疫苗	prM-E	WNV	临床二期	Sanofi Pasteur
V180	重组疫苗	E蛋白	DENV 1～4	临床一期	Merck
ZIKV-VLP	VLPs	C-prM-E-NS2B/NS3	ZIKV	动物实验	[186]
DENV-VLP	VLPs	prM-E	DENV 1～4	临床前	[187]
GLS-5700	DNA疫苗	prM-E/NS1	ZIKV	临床一期	Inovio GeneOne
IgEsig-prM-E-LNP	mRNA疫苗	prM-E	ZIKV	动物实验	[188]

疫苗名称	疫苗种类	抗原	针对病毒种类	疫苗开发阶段	开发者
17D	减毒活疫苗	E蛋白	YFV	已获得许可	[185]
SA14-14-2	减毒活疫苗	E蛋白	JEV	已获得许可	CDIBP
TV003	减毒活疫苗	prM-E	DENV 1～4	临床三期	NIAID
DENVax	减毒活疫苗	prM-E	DENV 1～4	临床三期	Takeda
TDENV-PIV	灭活疫苗	C-prM-E-NS1/3/5	DENV 1～4	临床一期	GSK, Fiocruz & WRAIR
ZPIV	灭活疫苗	E蛋白	ZIKV	临床一期	WRAIR/NIAID
CYD-TDV(Dengvaxia)	重组疫苗	prM-E	DENV 1～4	已获得许可	Sanofi Pasteur
ChimeriVax-WN02	重组疫苗	prM-E	WNV	临床二期	Sanofi Pasteur
V180	重组疫苗	E蛋白	DENV 1～4	临床一期	Merck
ZIKV-VLP	VLPs	C-prM-E-NS2B/NS3	ZIKV	动物实验	[186]
DENV-VLP	VLPs	prM-E	DENV 1～4	临床前	[187]
GLS-5700	DNA疫苗	prM-E/NS1	ZIKV	临床一期	Inovio GeneOne
IgEsig-prM-E-LNP	mRNA疫苗	prM-E	ZIKV	动物实验	[188]

候选因子	蚊虫媒介	对病毒感染的影响	机制与功能
α-葡萄糖苷酶	埃及伊蚊	抑制DENV-2的复制和传播	α-葡萄糖苷酶抑制剂能够抑制内质网出芽病毒的复制^[211]；这种酶在蚊子中肠细胞被DENV-2的感染中起作用^[212]
羧肽酶B-1（CPB-1）	埃及伊蚊	抑制蚊子中的DENV-2感染	与沉积在内质网腔内膜上的E蛋白结合并抑制DENV-2的RNA封装，从而抑制病毒在内质网上的出芽，并可能干扰未成熟病毒向高尔基体网络的运输^[210,213]
富含半胱氨酸的毒液蛋白	埃及伊蚊	登革病毒感染蚊虫的过程中需要这种蛋白	与抑制素蛋白相互作用；登革病毒对埃及伊蚊的感染需要这种蛋白质^[99]
糖蛋白（Glycoproteins）	蚊虫	阻断目标病毒	潜在的普遍疾病传播阻断目标^[214]
热休克蛋白60（Hsp60）	埃及伊蚊	Hsp60 蛋白影响DENV-2对蚊虫的感染	感染了DENV-2的埃及伊蚊中Hsp60的水平上调^[212]
蚊子半乳糖特异性C型凝集素-1（mosGCTL-1）	埃及伊蚊、致倦库蚊	抑制蚊子中西尼罗病毒的感染	参与西尼罗病毒对细胞的附着过程，免疫沉淀实验表明，该蛋白与西尼罗病毒颗粒相互作用并结合^[94]
蚊子半乳糖特异性C型凝集素-3（mosGCTL-3）	埃及伊蚊	抑制蚊子中登革病毒的感染	通过与登革病毒E蛋白相互作用调节病毒进入细胞的过程^[95]
蚊子半乳糖特异性C型凝集素-7（mosGCTL-7）	埃及伊蚊	mosGCTL-7介导乙型脑炎病毒感染	mosGCTL-7在乙型脑炎病毒E蛋白的N154位点与N-聚糖结合。病毒感染需要mosGCTL-7能够识别病毒N-聚糖^[215]
蚊子半乳糖特异性C型凝集素-15, 19, 20, 22, 23, 24, 26, 32	埃及伊蚊	抑制蚊子中登革病毒的感染	通过与登革病毒E蛋白相互作用调节病毒进入细胞的过程^[95]
蚊子蛋白酪氨酸磷酸酶-1 （mosPTP-1）	伊蚊、库蚊	mosPTP-1参与西尼罗病毒和乙型脑炎病毒的内吞作用	分泌蛋白mosGCTL-1通过与病毒相互作用并将其桥接至mosPTP-1细胞受体来增强西尼罗病毒感染^[216]；mosPTP-1可促进埃及伊蚊中的乙型脑炎病毒感染^[215]
唾液蛋白	埃及伊蚊	抑制或增强登革病毒感染	参考2.3.2节

候选因子	蚊虫媒介	对病毒感染的影响	机制与功能
α-葡萄糖苷酶	埃及伊蚊	抑制DENV-2的复制和传播	α-葡萄糖苷酶抑制剂能够抑制内质网出芽病毒的复制^[211]；这种酶在蚊子中肠细胞被DENV-2的感染中起作用^[212]
羧肽酶B-1（CPB-1）	埃及伊蚊	抑制蚊子中的DENV-2感染	与沉积在内质网腔内膜上的E蛋白结合并抑制DENV-2的RNA封装，从而抑制病毒在内质网上的出芽，并可能干扰未成熟病毒向高尔基体网络的运输^[210,213]
富含半胱氨酸的毒液蛋白	埃及伊蚊	登革病毒感染蚊虫的过程中需要这种蛋白	与抑制素蛋白相互作用；登革病毒对埃及伊蚊的感染需要这种蛋白质^[99]
糖蛋白（Glycoproteins）	蚊虫	阻断目标病毒	潜在的普遍疾病传播阻断目标^[214]
热休克蛋白60（Hsp60）	埃及伊蚊	Hsp60 蛋白影响DENV-2对蚊虫的感染	感染了DENV-2的埃及伊蚊中Hsp60的水平上调^[212]
蚊子半乳糖特异性C型凝集素-1（mosGCTL-1）	埃及伊蚊、致倦库蚊	抑制蚊子中西尼罗病毒的感染	参与西尼罗病毒对细胞的附着过程，免疫沉淀实验表明，该蛋白与西尼罗病毒颗粒相互作用并结合^[94]
蚊子半乳糖特异性C型凝集素-3（mosGCTL-3）	埃及伊蚊	抑制蚊子中登革病毒的感染	通过与登革病毒E蛋白相互作用调节病毒进入细胞的过程^[95]
蚊子半乳糖特异性C型凝集素-7（mosGCTL-7）	埃及伊蚊	mosGCTL-7介导乙型脑炎病毒感染	mosGCTL-7在乙型脑炎病毒E蛋白的N154位点与N-聚糖结合。病毒感染需要mosGCTL-7能够识别病毒N-聚糖^[215]
蚊子半乳糖特异性C型凝集素-15, 19, 20, 22, 23, 24, 26, 32	埃及伊蚊	抑制蚊子中登革病毒的感染	通过与登革病毒E蛋白相互作用调节病毒进入细胞的过程^[95]
蚊子蛋白酪氨酸磷酸酶-1 （mosPTP-1）	伊蚊、库蚊	mosPTP-1参与西尼罗病毒和乙型脑炎病毒的内吞作用	分泌蛋白mosGCTL-1通过与病毒相互作用并将其桥接至mosPTP-1细胞受体来增强西尼罗病毒感染^[216]；mosPTP-1可促进埃及伊蚊中的乙型脑炎病毒感染^[215]
唾液蛋白	埃及伊蚊	抑制或增强登革病毒感染	参考2.3.2节