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Mosquito–capsid interactions contribute to flavivirus vector specificity

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Abstract

Multiple mosquito species serve as competent vectors to carry and transmit numerous flaviviruses1,2. Several long-standing scientific questions remain to be answered, including identification of the fundamental factors that facilitate flavivirus infectivity in mosquitoes and the genetic basis that contributes to the naturally occurring interspecies specificity of mosquitoes to flaviviruses3,4,5,6,7,8, such as Aedes aegypti mosquitoes to dengue virus (DENV). Here we report that circulating mature virions are inactivated by the acidity of mosquito haemolymph; thus, extracellular vesicles carrying replication-competent viral nucleocapsids serve as the predominant means of intercellular viral dissemination. Mechanistically, mosquito valosin-containing protein (VCP) binds to the viral capsid, thereby allowing the incorporation of nucleocapsids into extracellular vesicles. The capsid of a flavivirus (such as DENV) selectively binds to the VCP of its natural vector (Ae. aegypti), but not to that of an incompetent vector (for example, Culex quinquefasciatus). Replacing the DENV capsid with that of Japanese encephalitis virus (JEV) renders DENV infectious in the haemolymph of the natural JEV vector, Cx. quinquefasciatus. Furthermore, two amino residues in Aedes (D723/N728) and Culex (E723/E728) VCP determine its binding specificity for viral capsid, thus contributing to interspecies specificity of mosquitoes to flaviviruses. In vivo ectopic expression of the Cx. quinquefasciatus VCP mutant E723D/E728N renders Cx. quinquefasciatus susceptible to DENV2 via intrathoracic microinjection. Our study provides a major molecular mechanism contributing to the selectivity and compatibility between mosquito vectors and flavivirus species, enabling systemic virus dissemination after the virus reaches the haemocoel. Upstream mechanisms that determine specificity at the midgut level remain to be determined.

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Fig. 1: Flaviviruses disseminate in the mosquito haemolymph in an envelope-independent manner.
Fig. 2: Mosquito VCPs facilitate EV-mediated flavivirus infection in mosquitoes.
Fig. 3: Mosquito VCP governs the incorporation of flavivirus nucleocapsids into EVs.
Fig. 4: The interaction between mosquito VCPs and viral capsids governs the specificity of the infectivity of flaviviruses in mosquitoes.
Fig. 5: VCP substitutions govern the VCP–C interaction and enable DENV2 infection in Culex.

Data availability

All data supporting this study are available within the Article and its Supplementary Information. The following sequences used in this study are available at NCBI GenBank: flavivirus genome sequences (U87411, KU501215 and U14163.1) and open reading frames encoding mosquito VCP (XP_001654680.1, XP_038116693.1 and XP_035913609.1). The sequences of the open reading frames encoding flavivirus C protein, the two chimeric viruses, and the DENV2 replicon are provided in Supplementary Data 1. The structure of CDENV2 is available in the PDB database (PDB: 1R6R) and the predicted AaVCP structure is available from the Alphafold Database (https://alphafold.com/entry/AF-Q16SH1-F1). MS raw data are available from iProX (www.iprox.cn) under accession number IPX0013860000. All biological materials are available upon request from the corresponding author. Source data are provided with this paper.

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Acknowledgements

We thank the core facilities of the Center for Life Sciences and Center of Biomedical Analysis for technical assistance (Tsinghua University); the Cell Biology Facility in Tsinghua University; the Core Facility for Biomolecule Preparation and Characterization of Tsinghua University; L. Zhang for the neutralizing antibodies; Q. Liu for the Ae. albopictus (Jiangsu strain); J. Wang for the An. stephensi (Hor strain) and MSQ43 cells; and F. Cui for providing the Cxq-1 cells. This study was supported by grants from the Shenzhen Medical Research Fund (B2404002), the National Natural Science Foundation of China (32188101, 82422049 and 32200772), the Yunnan Major Scientific and Technological Projects (202502AU100001), National Key Research and Development Plan of China (2023YFC2305900, 2021YFC2300200, 2022YFC2303200, 2021YFC2302405, 2022YFC2303400, and 2023YFC2305902), Shenzhen San-Ming Project for Prevention and Research on Vector-borne Diseases (SZSM202211023), Yunnan Provincial Science and Technology Project at Southwest United Graduate School (202302AO370010). This study was supported by the New Cornerstone Science Foundation through the New Cornerstone Investigator Program and the XPLORER PRIZE.

Author information

Author notes

  1. These authors contributed equally: Jichen Niu, Jun Ma, Yibin Zhu

Authors and Affiliations

  1. New Cornerstone Science Laboratory, Tsinghua University–Peking University Joint Center for Life Sciences, School of Basic Medical Sciences, Tsinghua University, Beijing, China

    Jichen Niu, Yibin Zhu, Gang Wang, Xiang Xu, Mao Wang, Zhaoyang Wang, Xinhui Bao, Enhao Ma, Ye Xiang & Gong Cheng

  2. Institute of Infectious Diseases, Shenzhen Bay Laboratory, Shenzhen, China

    Jun Ma, Jianying Liu, Xianwen Zhang & Gong Cheng

  3. Institute of Pathogenic Organisms, Shenzhen Center for Disease Control and Prevention, Shenzhen, China

    Yibin Zhu & Gong Cheng

  4. Institute of Virology, Shiyan Key Laboratory of Virology, Hubei University of Medicine, Shiyan, China

    Long Liu

  5. School of Pharmaceutical Sciences, Tsinghua University, Beijing, China

    Ying Zhang & Hang Yin

  6. National Key Laboratory of Intelligent Tracking and Forecasting for Infectious Diseases, National Institute for Communicable Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China

    Qiyong Liu

  7. State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing, China

    Chunxiao Li

  8. Department of Immunology, School of Medicine, University of Connecticut Health Center, Farmington, CT, USA

    Penghua Wang

  9. Southwest United Graduate School, Kunming, China

    Gong Cheng

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  1. Jichen Niu
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  2. Jun Ma
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Contributions

G.C. conceived and designed the study. J.N. performed the majority of the experiments and analysed the data. J.M. purified the recombinant mosquito VCP and viral capsid proteins. Y. Zhu provided the pUb vector and contributed to data analysis. G.W. and X.Z. provided the chimeric viruses. X.X. and Y.X. assisted with protein structure prediction and docking analysis. M.W., Z.W., X.B., J.L., E.M. and L.L. assisted with the mice immunization. Y. Zhang and H.Y. provided technical guidance for the nanoparticle tracking analysis experiments. Q.L. and C.L. provided the mosquitoes. G.C. wrote and edited the manuscript. P.W. and Y. Zhu provided experimental suggestions and improved the manuscript. All of the authors revised and approved the manuscript before submission.

Corresponding author

Correspondence to Gong Cheng.

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Extended data figures and tables

Extended Data Fig. 1 Systemic dissemination of flaviviruses in mosquitoes and infectivity of the acellular haemolymph fraction.

a-c, A mixture containing fresh human blood (50% v/v) and supernatant from (a) DENV2- or (b) ZIKV-infected Vero cells (50% v/v) was used to feed Ae. aegypti via an in vitro blood feeding system. For Cx. quinquefasciatus, the supernatant from (c) JEV-infected Vero cells were used for oral infection. A total of 3 × 106 FFU/ml DENV2, ZIKV or JEV were used for oral infection. d-g, Evaluating the infectivity of the acellular fraction of haemolymph isolated from infected mosquitoes. d, Schematic representation of the study design. Created in BioRender. Chen, J. (2025) https://BioRender.com/im0oaf9. Ae. aegypti mosquitoes were intrathoracically inoculated with 10 MID50 DENV2 or ZIKV, and Cx. quinquefasciatus mosquitoes were inoculated with 10 MID50 JEV. The acellular fraction of perfused haemolymph from virus-infected mosquitoes was collected at 4 days postinoculation by low-speed centrifugation. The acellular fraction isolated from the haemolymph of (e) DENV2-, (f) ZIKV-, or (g) JEV-infected mosquitoes was microinjected into naïve mosquitoes. a-c, e-g Mosquito infectivity was determined by RT-qPCR at 3, 5, and 9 days after a blood meal (a-c) or at 2, 4, 6, and 8 days after inoculation (e-g). The number at the top of each column represents the number of infected mosquitoes (or tissues)/total number of mosquitoes (or tissues). The data were pooled from 2 independent biological replicates. Each dot represents data from an individual mosquito or tissue sample. a-c, The P values were analysed statistically with a two-tailed Mann–Whitney test. The horizontal line represents the median and the limit of detection is illustrated by black dotted lines.

Source Data

Extended Data Fig. 2 Evaluating the neutralizing activity of antibodies against flaviviruses in vitro and in vivo, and their stability in mosquito haemolymph.

a, Neutralizing activity of GTX29202, 4E11, 4G2, and 21F2 antibodies against the DENV2 NGC strain. b, Neutralizing activity of the Z20 antibody against the ZIKV PRVABC59 strain. c, Neutralizing activity of anti-JEV serum against the JEV SA14 strain. a-c, Viruses were preincubated with the corresponding antibody at 37 °C for 30 min and then transferred to Vero cell monolayers. FFU, focus-forming units. d-f, The stabilities of anti-DENV (d) and anti-ZIKV (e) antibodies and anti-JEV serum (f) were assessed by ELISA. Each anti-flavivirus E neutralizing antibody (0.2 μg/μl) was microinjected into the thorax of Ae. aegypti mosquitoes. Anti-JEV serum (1:10 dilution) was injected thoracically into Cx. quinquefasciatus. Mosquitoes were homogenized in sterile PBS at the indicated time points of postinoculation. The supernatant was filtered (0.22 μm) and examined by ELISA. For all ELISAs, the results of dilution at 1:2000 are presented. a-f, Representatives results from 2 independent experiments and the data are presented as the mean ± s.e.m. g-i, Determination of the neutralizing activity of antibodies against flaviviruses in vivo. Ten MID50 DENV2 or ZIKV was premixed with 0.2 μg/μl of anti-E neutralizing antibodies for 30 mins. The mixture was intrathoracically microinjected into the Ae. aegypti mosquitoes. The Cx. quinquefasciatus mosquitoes were intrathoracically inoculated with the mixture of 10 MID50 JEV and anti-JEV serum (1:10 dilution) with the same experimental settings. j-l, Intrathoracic inoculation of neutralizing antibodies into the infected mosquitoes (3 days after oral infection) did not interrupt the flavivirus propagation in the mosquitoes. A mixture containing fresh human blood (50% v/v) and supernatant from (j) DENV2- or (k) ZIKV-infected Vero cells (50% v/v) was used to feed Ae. aegypti via an in vitro blood feeding system. For Cx. quinquefasciatus, the supernatant from (l) JEV-infected Vero cells were used for oral infection. At 3 days post infection, 0.2 μg/μl anti-flavivirus E neutralizing antibody or anti-JEV serum (1:10 dilution) was microinjected into the thorax of fed mosquitoes, with mouse isotype control IgG or pre-immune serum serving as controls. A total of 3 × 106 FFU/ml of either DENV2 or ZIKV, or JEV was used for oral infection. g-l, Mosquito infectivity was determined by RT-qPCR at 4 days after virus inoculation (g-i) or 8 days after oral infection (j-l). Each dot represents data from an individual mosquito. The P values were analysed statistically with a two-tailed Mann–Whitney test. The data were pooled from 2 independent biological replicates. The horizontal line represents the median and the limit of detection is illustrated by black dotted lines. Bonferroni correction was used to account for multiple comparisons (g,j). (a,b,d,e,g,h,j,k) Mouse isotype IgG served as a negative control. (c,f,i,l) Pre-immune serum served as a negative control.

Source Data

Extended Data Fig. 3 Neutralizing antibody treatment abolished the per os infection of flaviviruses, rather than affecting dissemination of flaviviruses in mosquitoes.

a-j, Sequential microinjection of flaviviruses and neutralizing antibodies at 1-day intervals did not influence the propagation of flaviviruses. a, Schematic representation of the study design. Created in BioRender. Chen, J. (2025) https://BioRender.com/5dx1vtp. (b-j) Ae. aegypti were microinjected thoracically with 10 MID50 DENV2 (b-d) or ZIKV (e-g). Cx. quinquefasciatus were microinjected thoracically with 10 MID50 JEV (h-j). One day postinoculation, 0.2 μg/μl of each anti-flavivirus E neutralizing antibody or anti-JEV serum (1:10 dilution) was thoracically microinjected into the infected mosquitoes. k-m, The neutralizing antibodies abolished the per os infection of flaviviruses in mosquitoes. The supernatant from (k) DENV2-, (l) ZIKV-, or (m) JEV-infected Vero cells (50% v/v) was premixed with fresh human blood (50% v/v). Neutralizing antibodies against flavivirus E protein at a final concentration of 100 μg/ml was individually incubated with the infectious blood for 30 mins. The mixture was then used to feed either Ae. aegypti or Cx. quinquefasciatus mosquitoes. A total of 3 × 106 FFU/ml DENV2, ZIKV or JEV were used for oral infection. b-m, Mosquito infectivity was determined by RT-qPCR at 8 days (k-m) after a blood meal or at 4 days (b-j) post virus microinjection. The number at the top of each column represents the number of infected mosquitoes/total number of mosquitoes. Each dot represents data from an individual mosquito or a mosquito tissue sample. The horizontal line represents the median and the limit of detection is illustrated by black dotted lines. Statistical significance was evaluated with a two-tailed Mann–Whitney test. The data were pooled from 2 independent biological replicates. Mouse isotype IgG (b-g,k,l) or pre-immune serum (h-j,m) served as a negative control. Bonferroni correction was used for multiple comparisons (b-d,k).

Source Data

Extended Data Fig. 4 Treatment with EV inhibitors reduced the number of EVs in mosquito haemolymph without affecting mosquito fitness, and a mouse anti-AaAlix polyclonal antibody was generated.

a,b, The concentration and size distribution of EVs isolated from the haemolymph of Ae. aegypti treated with GW4869 (a) or Imipramine (b) were measured by nanoparticle tracking analysis (NTA). The graph (left) shows the fold change in the number of EVs isolated from mosquito haemolymph. The results are representative of 3 independent experiments. Serial concentrations of GW4869 or Imipramine were microinjected thoracically into Ae. aegypti. EVs from mosquito haemolymph were purified at 3 days postinjection by differential ultracentrifugation and analysed by NTA. The results are representative of 3 independent biological replicates. c-h, Assessment of Ae. aegypti fitness after GW4869 and Imipramine treatment. Mosquitoes were intrathoracically inoculated with a series of concentrations of GW4869 or Imipramine. c,d, Survival rates of mosquitoes inoculated with GW4869 (c) or Imipramine (d). Mosquitoes were offered a bloodmeal at 3 days after inoculation, and then the number of laid eggs (e,f) and the hatching rate (g,h) of mosquitoes were measured. The data were pooled from 2 independent biological replicates. i, Generation of a mouse anti-AaAlix polyclonal antibody by immunizing mice with purified recombinant AaAlix protein expressed in E. coli. The antibody was validated by probing mosquito EVs purified from the Aag2 or Cxq-1 cell culture supernatant. Samples probed with mouse pre-immune serum served as a negative control. The representative images from 3 independent biological replicates are shown. j, Detection of the E and prM protein in EVs isolated from DENV2-infected mosquitoes haemolymph by immunogold stanning. EVs were stained with AaAlix (6 nm) and anti-E (18 nm) or anti-prM (18 nm) antibody. The black arrowheads indicate mosquito Alix. Scale bar, 50 nm. The results are representative images of 2 independent biological replicates. a-h, P values were analysed with a two-tailed t test (a,b,g,h), the two-tailed log-rank (Mantel–Cox) test (c,d), or a two-tailed Mann–Whitney test (e,f). n.s., not significant (c-h). a,b,e-h, Bonferroni correction was used to account for multiple comparisons. a,b, Each dot represents data from a pool of EVs collected from the haemolymph of 60 mosquitoes. These data are presented as the mean ± s.e.m. Each dot represents the number of laid eggs per mosquito (e-f). The dots represent the data from 2 independent biological replicates: 277 ~ 337 eggs per dot (g-h). These data are presented as the mean ± s.e.m.

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Extended Data Fig. 5 Detection of flaviviral genomes in EVs from infected mosquitoes and propagation of the DENV2 sub-viral repliconΔprM-E in Ae. aegypti.

a-c, Flaviviral genome in EVs was detected by reverse transcription-polymerase chain reaction (RT-PCR). The EVs were isolated from haemolymph of (a) DENV2- or (b) ZIKV-infected Ae. aegypti, or (c) JEV-infected Cx. quinquefasciatus. Total RNA was extracted. The cDNA derived from total RNA was used as template. The viral genome was detected by RT-PCR with specific primers (Supplementary Table 3). Five fragments generated by PCR demonstrated the amplification of the viral genome. The regions of each fragment in viral genome are shown: DENV2 fragment 1 (1-2228), DENV2 fragment 2 (2130-4456), DENV2 fragment 3 (4323-6635), DENV2 fragment 4 (6505-8839), and DENV2 fragment 5 (8736-10723); ZIKV fragment 1 (1-2243), ZIKV fragment 2 (2184-4436), ZIKV fragment 3 (4348-6560), ZIKV fragment 4 (6502-8816), and ZIKV fragment 5 (8744-10675); JEV fragment 1 (1-2282), JEV fragment 2 (2215-4495), JEV fragment 3 (4426-6650), JEV fragment 4 (6579-8822), and JEV fragment 5 (8760-10976). NC, uninfected groups; I, infected groups; Mock, ultrapure water; M, marker. The results are representative images of 2 independent biological replicates. d, Propagation of the DENV2 sub-viral repliconΔprM-E in Ae. aegypti. Mosquito Aag2 cells were transfected with DENV2 repliconΔprM-E RNA, and the supernatant was collected at 72 h post transfection. EVs were collected by ultracentrifugation and then intrathoracically microinjected into Ae. aegypti mosquitoes. Mosquito infectivity was determined by RT-qPCR at indicated time points. Each dot represents data from a mosquito sample. The horizontal line represents the median. The number at the top of each column represents the number of infected mosquito/total number of mosquitoes. The limit of detection is illustrated by black dotted lines. Statistical significance was evaluated with a two-tailed Mann–Whitney test. The data were pooled from 2 independent biological replicates.

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Extended Data Fig. 6 The role of AaVCP in EV biogenesis of Ae. aegypti and the knockdown of AaVCP abolished flavivirus infection under acidic conditions.

a, b, Knockdown efficiency of AaVCP in Ae. aegypti. Mosquitoes were microinjected with AaVCP dsRNA. GFP dsRNA served as a control. AaVCP abundance was assessed by RT-qPCR (a) and western blotting (b) at 3 days postinjection. a, Each dot represents data from an individual mosquito. The horizontal line represents the median. Statistical significance was evaluated by two-tailed Mann–Whitney test. c-e, Knockdown of AaVCP did not influence the number of EVs in the mosquito haemolymph. Mosquitoes were microinjected with AaVCP dsRNA. GFP dsRNA served as a control. A mixture containing fresh human blood (50% v/v) and supernatant from (c) uninfected Vero cells, (d) DENV2- or (e) ZIKV-infected Vero cells (50% v/v) was used for in vitro blood feeding. EVs were isolated from the haemolymph of Ae. aegypti mosquitoes at 4 days post bloodmeal. The concentration and size distribution of EVs were analysed by NTA. The graph (left) shows the fold change in the number of EVs isolated from mosquito haemolymph. Each dot represents data from a pool of EVs collected from the haemolymph of at least 60 mosquitoes. Statistical significance was evaluated by two-tailed t test. n.s., not significant. Data are presented as the mean ± s.e.m. Representative results from 3 independent experiments are shown. f, Generation of a mouse anti-AaVCP polyclonal antibody by immunizing mice with purified recombinant AaVCP protein expressed in E. coli. The antibody was validated by probing mosquito EVs purified from the Aag2 or Cxq-1 cell culture supernatants. The samples probed with mouse pre-immune serum served as a negative control. Representative results from 2 independent experiments are shown. g-i, Silencing mosquito VCP abolished flavivirus infection under acidic conditions. Growth curves of DENV2 (g) and ZIKV (h) in Aag2 cells transfected with GFP or AaVCP dsRNA under either normal or acidic conditions (pH=6.1). Growth curve of JEV in Cxq-1 cells transfected with GFP or CqVCP dsRNA under either normal or acidic conditions (pH=6.1) (i). The cells were transfected with the indicated dsRNA and then infected with DENV2 or ZIKV at an MOI of 0.1 or JEV at an MOI of 0.01 at 48 h post-transfection. The cell lysates were collected at 24, 48, 72, and 96 h postinfection. Total RNA was extracted, and infectivity was detected by RT-qPCR. The viral load was normalized to that of Ae. aegypti actin (AAEL011197) or Cx. quinquefasciatus actin (CPIJ012570). Statistical significance was evaluated by two-tailed t test. n.s., not significant. Data are presented as the mean ± s.e.m. Representative results from 2 independent experiments are shown.

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Extended Data Fig. 7 Culex VCP governs the incorporation of JEV nucleocapsids into EVs.

a,b, Knockdown of CqVCP expression in Cx. quinquefasciatus. Mosquitoes were microinjected with CqVCP dsRNA. GFP dsRNA served as a control. CqVCP abundance was assessed by RT-qPCR (a) and western blotting (b) at 3 days postinjection. CqVCP mRNA level was normalized to that of Cx. quinquefasciatus actin (CPIJ012570). The results are representative of 3 independent biological replicates. c, Silencing CqVCP inhibited JEV infection in Cx. quinquefasciatus. A mixture containing fresh human blood (50% v/v) and supernatant from JEV-infected Vero cells (50% v/v) was used for in vitro blood feeding. Mosquito infectivity was determined by RT-qPCR at 8 days after oral infection. The data were pooled from 2 independent biological replicates. d, The interaction between CqVCP and CJEV was detected by coimmunoprecipitation assay. Aag2 cells were cotransfected with expression plasmids encoding CJEV and CqVCP. The cell lysates were incubated with anti-V5 antibody-conjugated beads. The protein interactions were analysed by western blotting. e, The direct interaction between CqVCP and CJEV was detected by GST pull-down assay. Both CqVCP and CJEV were expressed and purified in E. coli. The GST or GST-CJEV fusion proteins were immobilized on glutathione beads, and 30 μg of purified CqVCP protein was incubated for a pull-down assay. The protein interactions were then detected by Coomassie blue in an SDS–PAGE gel. f,g, Detection of CJEV in EVs isolated from Cxq-1 cell supernatants by immunogold staining (f) and western blotting (g). Cxq-1 cells were transfected with a plasmid encoding CJEV. EVs were isolated from the supernatant by differential ultracentrifugation at 48 h posttransfection. Cxq-1 cells transfected with a GFP-expressing plasmid served as a negative control. h, Silencing CqVCP reduced the abundance of CJEV in mosquito EVs. Cxq-1 cells were transfected with CqVCP dsRNA. GFP dsRNA served as a control. At 48 h posttransfection, Cxq-1 cells were transfected with a plasmid encoding CJEV. EVs were isolated from the supernatant by differential ultracentrifugation at 48 h posttransfection and then assessed by western blotting. The results are representative images of 4 independent biological replicates. i, Co-localization of CqVCP (6 nm) with CJEV (18 nm) in EVs isolated from the haemolymph of JEV-infected Cx. quinquefasciatus, as detected by immunogold staining. j,k, Silencing CqVCP reduced the levels of JEV capsid proteins and genomes in EVs. Cx. quinquefasciatus were inoculated with 10 MID50 JEV via thoracic microinjection, and EVs were isolated from the haemolymph of infected mosquitoes by differential ultracentrifugation at 6 days postinfection. (j) Representative TEM images of immunogold staining (left panel) and quantitative analysis of TEM images (right panel) showed the presence of viral capsids in mosquito EVs. (k) The JEV genomes in mosquito EVs were detected by RT-qPCR. The data are presented as the mean ± s.e.m. from 4 independent biological replicates. Each dot represents data from a pool of EVs collected from the haemolymph of 20 JEV-infected mosquitoes. The P values were analysed with a two-tailed t test. a,c, Each dot represents data from an individual mosquito. The horizontal line represents the median. Statistical significance was evaluated with a two-tailed Mann–Whitney test. c, The number at the top of each column represents the number of infected mosquitoes/total number of mosquitoes. The limit of detection is illustrated by black dotted lines. d-g,i,j, The results are representative images of 3 independent biological replicates. f,i,j, Orange arrowheads indicate the JEV capsid, whereas black arrowheads indicate CqVCP. Scale bar, 50 nm. For quantitative analysis (j), randomly selected infectious EVs fields (n = 3) were analysed for statistical evaluation. The data are presented as the mean ± s.d. and were pooled from 3 independent biological replicates. Statistical significance was evaluated with the two-tailed t test.

Source Data

Extended Data Fig. 8 Infectivity of An. stephensi MSQ43 cells to flaviviruses and the interaction between mosquito VCPs and flaviviral capsids were analysed, with the latter detected by SPR assay.

a-c, The cells were infected with DENV2, ZIKV or JEV at an MOI of 0.01, respectively. Cell lysates were collected at 0, 24, 48, 72, and 96 h postinfection. Total RNA was extracted, and infectivity was detected by RT-qPCR. The viral load was normalized to that of Ae. aegypti actin (AAEL011197), Cx. quinquefasciatus actin (CPIJ012570) or An. stephensi actin (ASTEI20_033844). These data are presented as the mean ± s.e.m. Representatives from 2 independent experiments are shown. d-f, The binding affinity between mosquito VCPs and flaviviral capsids was measured by surface plasmon resonance (SPR). Mosquito VCPs and flaviviral capsids were expressed and purified in E. coli. The results are representative of 3 independent biological replicates.

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Extended Data Fig. 9 Regulation of chimeric virus DENV2-CJEV infection and assessment of DENV2-CJEV dissemination in Culex.

a,b, Infection with the chimeric virus DENV2-CJEV was inhibited by GW4869 in Cxq-1 cells but not by the neutralizing anti-DENV-E antibody. Cxq-1 cells were infected at an MOI of 0.1 with DENV2-CJEV mixed with neutralizing antibodies (a) or a series of concentrations of GW4869 (b). The cell lysates were harvested at 24, 48, and 72 h postinfection. Total RNA was extracted, and the viral load was assessed by RT-qPCR. c,d, Silencing CqVCP impaired the chimeric virus DENV2-CJEV infection in Cxq-1 cells. Cxq-1 cells were transfected with GFP or CqVCP dsRNA, followed by infection at an MOI of 0.1 with the chimeric virus DENV2-CJEV at 48 h posttransfection. The cell lysates were harvested at 24, 48, 72, and 96 h post-infection. Infectivity was assessed by RT-qPCR (c) and fluorescence microscopy (d) at 72 h post-infection. d, DENV2-CJEV was stained with an anti-JEV-C antibody conjugated to Alexa Fluor 488, and CqVCP was stained with an anti-AaVCP polyclonal antibody conjugated to Alexa Fluor 546. Nuclei were stained with DAPI. Scale bar, 20 μm. e,f, Assessment of chimeric virus DENV2-CJEV dissemination in Cx. quinquefasciatus. Mosquitoes were intrathoracically inoculated with 3 FFU of the chimeric virus DENV2-CJEV. The parental DENV2 16681 strains served as a control. Viral load in heads (e) and salivary glands (f) was determined by RT-qPCR at the indicated time points after virus inoculation. g, Assessment of chimeric virus DENV2-CJEV infection in Aedes and Culex by oral feeding. A mixture containing fresh human blood (50% v/v) and supernatant from DENV2-CJEV-infected Vero cells (50% v/v) was used to feed Ae. aegypti or Cx. quinquefasciatus via an in vitro blood feeding system. A total of 3 × 106 FFU/ml DENV2-CJEV were used for oral infection. Mosquito infectivity was determined by RT-qPCR at 8 days after a bloodmeal. a-c, The viral load was normalized to that of Cx. quinquefasciatus actin (CPIJ012570). These data are presented as the mean ± s.e.m. Statistical significance was evaluated with a two-tailed t test. Representatives from 2 independent experiments are shown. e-g, The number at the top of each column represents the number of infected mosquitoes/total number of mosquitoes. Each dot represents data from a mosquito tissue (e, f) or a mosquito sample (g). The horizontal line represents the median and the limit of detection is illustrated by black dotted lines. The data were pooled from 2 independent biological replicates. a-c,e-g, Statistical significance was evaluated with a two-tailed t test (a-c) or a two-tailed Mann–Whitney test (e-g).

Source Data

Extended Data Fig. 10 Predicted modelling for the AaVCP and CDENV2 interaction.

a, Predicted interaction model between AaVCP and CDENV2. The monomeric structure of AaVCP was predicted by AlphaFold 2, and the structure of CDENV2 was available in the PDB database (PDB: 1R6R). The docking model of the AaVCP–CDENV2 complex was generated by PyRosetta. Residues with interatomic distances within 3 Å were selected for further analysis. b, The top 10 predicted models ranked by score. The potential interfaces of each model are presented in the table. c, Presentation of potential interfaces and corresponding peptides based on the predicted model. d, The N-terminally conjugated TAT47-57 confers cell-penetrating properties to peptides, as measured by fluorescence microscopy. Ae. aegypti mosquitoes were microinjected with 250 μM FITC-labelled TAT47-57-717 aa~729 aa peptide. Haemocytes were collected at 12 h postinjection followed by fluorescence microscopy detection. Mosquitoes microinjected with TAT47-57-717 aa~729 aa peptide served as a mock control. Nuclei were stained with DAPI. Scale bar, 20 μm. Representative fluorescence images from 2 independent biological replicates are shown. e, Regulation of DENV2 infection in Ae. aegypti by the introduction of peptides targeting the potential interfaces. A mixture of 10 MID50 DENV2 with the indicated peptides at various concentrations was intrathoracically inoculated into Ae. aegypti. f, Structural superposition of multiple flaviviral capsid proteins onto the predicted VCP-CDENV2 complex. Each capsid protein is colour-coded as shown. The corresponding residues of the capsids that interact with the VCP 723rd and 728th residues are labeled. g, Partial sequence alignment of capsid proteins from multiple mosquito-borne flaviviruses. The red-highlighted regions indicate completely identical amino acids and the blue-bordered region denotes amino acid residues with high evolutionary conservation. MVEV, Murray Valley encephalitis virus; WNV, West Nile virus; SLEV, St. Louis encephalitis virus. The accession numbers are as follows: DENV1 (P33478), DENV2 (P29991), DENV3 (P27915), DENV4 (Q2YHF2), JEV (P0DOH8), MVEV (P05769), WNV (P06935), SLEV (QJD26115), ZIKV (Q32ZE1). h-j, The binding affinity between AaVCP and the CDENV2 mutants was measured by SPR assay. AaVCP and CDENV2 mutant proteins were expressed and purified in E. coli. The results are representative of 3 independent biological replicates.

Source Data

Extended Data Fig. 11 In vivo ectopic expression of CqVCPE723D/E728N in Cx. quinquefasciatus and visualization of DENV2 propagation in the Culex tissues.

a-c, In vivo ectopic expression of CqVCPE723D/E728N in Cx. quinquefasciatus. The transfection complexes were introduced into Cx. quinquefasciatus via thoracic microinjection. (a) Plasmids were transfected with the Roche X-tremeGENE HP DNA Transfection Reagent. Mosquitoes microinjected with empty vector served as a control. The protein expression of CqVCPE723D/E728N in mosquitoes was assessed at 3 days posttransfection by western blotting (a,b) and fluorescence microscopy (c). CqVCPE723D/E728N was stained with an anti-myc tag antibody (c). d,e, Propagation of DENV2 in haemocytes (d) and tissues (e) of Cx. quinquefasciatus was detected by fluorescence microscopy. Mosquitoes were transfected with expression plasmids encoding CqVCPE723D/E728N. Both the empty vector and the plasmid encoding wild-type CqVCP served as controls. Mosquitoes were intrathoracically microinjected with 3 FFU of the DENV2 16681 strain at 3 days posttransfection. Propagation of DENV2 in mosquitoes was determined by fluorescence microscopy at 9 days postinfection. DENV2 was stained with an anti-DENV-C antibody, and CqVCPE723D/E728N was stained with an anti-myc tag antibody. c-e, Nuclei were stained with DAPI. Scale bar, 5 μm (c, d) or 100 μm (e). The representative fluorescence images from 3 independent biological replicates are shown.

Supplementary information

Supplementary Information

Supplementary Fig. 1: Raw blot and gel source images. Supplementary Fig. 2: Infectivity of the chimeric viruses in C6/36 and Vero cells. Supplementary Table 1: List of ranking scores of EV proteins in the haemolymph of Ae. aegypti (score >50). Supplementary Table 2: AaVCP-derived peptides for an inhibition assay. Supplementary Table 3: Primers for RT–qPCR, dsRNA template synthesis and gene cloning

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Supplementary Data 1

Sequences of the open reading frames encoding flavivirus capsid, the two chimeric viruses, and the DENV2 replicon

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Niu, J., Ma, J., Zhu, Y. et al. Mosquito–capsid interactions contribute to flavivirus vector specificity. Nature (2026). https://doi.org/10.1038/s41586-026-10100-x

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