Research ArticleDengue

Modeling the impact on virus transmission of Wolbachia-mediated blocking of dengue virus infection of Aedes aegypti

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Science Translational Medicine  18 Mar 2015:
Vol. 7, Issue 279, pp. 279ra37
DOI: 10.1126/scitranslmed.3010370
  • Fig. 1. Susceptibility of wild-type and wMelPop-infected mosquitoes to DENV infection.

    Each row represents the results of feeding cohorts of wild-type (WT) and wMelPop-infected mosquitoes on viremic blood collected from human dengue cases. The log10 viral titer (RNA copies/ml) in plasma of the donor blood is given in the first column (also indicated by the horizontal bars). Other columns indicate the numbers of mosquitoes with detectable abdomen or salivary gland infection over the total numbers fed on blood from that donor. Only mosquitoes with detectable abdominal infection, a prerequisite for disseminated infection, were tested for salivary gland infection. Background color of table cells indicates the proportion of mosquitoes with detectable infection [0% (dark green) to 100% (red)].

  • Fig. 2. Susceptibility of WT and wMel-infected mosquitoes to DENV infection.

    Each row represents the results of feeding cohorts of WT and wMel-infected mosquitoes on viremic blood collected from human dengue cases. The log10 viral titer (RNA copies/ml) in plasma of the donor blood is given in the first column (also indicated by the horizontal bars). Results indicate the numbers of mosquitoes with detectable abdomen or saliva infection over the total numbers fed on blood from that donor at four time points after feeding (days 7, 10, 14, and 18). Background color of table cells indicates the proportion of mosquitoes with detectable infection [0% (dark green) to 100% (red)].

  • Fig. 3. wMel attenuates DENV infection of abdomen tissues.

    (A to D) Shown is the mean log10 titer (RNA copies per abdomen) of virus measured in mosquito abdomens (average over mosquitoes with detectable virus at any time point) of WT (circles) and wMel-infected (triangles) mosquitoes with DENV-infected abdomen tissues, binned by integer interval of log10 viral titer in the donor human blood. (A) to (D) show results for DENV1 to DENV4, respectively. Error bars show SEM.

  • Fig. 4. Mosquito infection model fit to the empirical evidence of wMel-mediated blocking of DENV infection.

    (A to C) Observed (“Data”) and median posterior fitted (“Model”) proportions (with exact binomial confidence intervals) of WT and wMel-infected mosquitoes with detectable virus in abdomen, stratified by (A) serotype, (B) end time point, and (C) log10 donor plasma virus titer band. (D to F) Same as for panels (A) to (C) but showing the proportion of dengue-infected mosquitoes (that is, with detectable virus in abdomen) that also had detectable infectious virus in saliva for the baseline model. (G to I) Same as for panels (D) to (F) but for the alternative saliva model.

  • Fig. 5. Performance of the mosquito infection model.

    (A) Shown is the behavior of the abdominal infection model illustrating the dependence of the probability of infection on viral titer in donor blood, serotype, and Wolbachia infection status. (B) Shown is the behavior of the saliva infection model showing dependence of the probability of detectable infection in saliva (conditional on abdominal infection) as a function of the days elapsed since the infecting blood meal, serotype, and Wolbachia infection status. (C) Same as (B) but for the alternative saliva infection model where wMel infection affects only the EIP. All graphs show mean posterior predictions.

  • Fig. 6. Estimated reduction in transmissibility of DENV (quantified by serotype-specific R0) caused by wMel infection.

    Median posterior estimates and 95% CIs are shown. Baseline scenario assumes that data on infectious saliva translates directly to human infectiousness. Higher/lower dose scenarios assume a 10-fold higher/lower infectious dose for mosquito-to-human transmission than estimated using saliva infection model. Average dose assumes same infectious dose for all serotypes (average across serotypes) for mosquito-to-human transmission. Same viral profile uses a model of human viral kinetics that is the same for all serotypes. Alternative model uses the alternative saliva infection model where wMel infection affects only the EIP.

  • Table 1. Assessment of the differences in tissue infection rates in wMel versus wild-type mosquitoes using the sign test.

    The experimental data were treated as pairs of binomial observations corresponding to the proportions infected of the wMel and wild-type mosquito groups fed on a particular blood sample, which were sampled on a specific day. The table rows present the number of observation pairs for which the proportion of wMel mosquitoes infected was less than, equal to, or greater than the proportion of wild-type mosquitoes infected for different data subsets. Subsets are shown that stratify the observations by tissue type, DENV serotype, and the day after infection that mosquitoes were assayed. The two-sided P value is given, with P values <0.05 shown in italics.

    TissueSerotypeDayn pairs
    where
    pwMel < pWT
    n pairs
    where
    pwMel = pWT
    n pairs
    where
    pwMel > pWT
    P value
    (for accepting
    pwMel = pWT)
    AllAll4155140.0004
    All73931
    All10162060.053
    All14161830.0044
    AbdomenAll186820.29
    DENV1All172550.017
    DENV2All61051
    DENV3All6420.29
    DENV4All121620.013
    AllAll571413< 0.0001
    All74520.69
    All102272< 0.0001
    All1422260.0037
    Saliva (conditional)All189030.15
    DENV1All304110.0043
    DENV2All11410.0063
    DENV3All6210.13
    DENV4All10400.002
    AllAll591610< 0.0001
    All74620.69
    All102272< 0.0001
    All142433< 0.0001
    Saliva (unconditional)All189030.15
    DENV1All31590.0007
    DENV2All11410.0063
    DENV3All7300.0156
    DENV4All10400.002
  • Table 2. Mathematical model parameter estimates.
    ParameterDescriptionMedian estimate
    (95% CI)*
    Abdomen model
    δwMelDose-response intercept for wMel-infected
    mosquitoes
    −1.12 (−3.22, 0.33)
    θDENV1Infectious dose parameter for DENV15.90 (4.53, 6.58)
    θDENV2Infectious dose parameter for DENV26.78 (5.88, 7.66)
    θDENV3Infectious dose parameter for DENV38.41 (7.17, 10.29)
    θDENV4Infectious dose parameter for DENV49.50 (8.34, 12.27)
    γDose response shape parameter2.88 (1.66, 3.97)
    ρabdomenOverdispersion parameter for abdomen model0.46 (0.38, 0.53)
    Saliva modelBaselineAlternative
    εwMelScaling of infectious dose parameters for
    wMel-infected versus wild-type mosquitoes
    3.41 (0.66, 11.2)Fixed at 1
    κPower on infectivity growth with time3.80 (1.99, 6.59)3.40 (2.02, 5.04)
    βWTTimescale of infectivity saturation in saliva
    of wild-type mosquitoes
    12.3 (9.5, 30.8)11.6 (8.7, 19.6)
    βwMelTimescale of infectivity saturation in saliva
    of wMel-infected mosquitoes
    12.8 (7.3, 32.5)20.7 (15.4, 40.9)
    φDENV1Infectious dose parameter for DENV10.52 (0.13, 0.81)0.60 (0.30, 0.97)
    φDENV2Infectious dose parameter for DENV21.57 (0.37, 2.99)1.79 (0.80, 3.44)
    φDENV3Infectious dose parameter for DENV30.94 (0.23, 2.15)1.11 (0.46, 2.33)
    φDENV4Infectious dose parameter for DENV40.99 (0.24, 1.95)1.13 (0.50, 2.32)
    ρsalivaOverdispersion parameter for abdomen model0.19 (0.13, 0.27)0.19 (0.13, 0.27)

    *Median estimates and 95% CIs of parameters of the mathematical models (Eqs. 3 and 4) used to fit the abdomen and saliva infection data on wMel-infected and wild-type mosquitoes are shown. Time unit is days. †For the saliva model, estimates are shown for the best-fitting baseline model and an alternative model where the phenotypic effect of wMel infection is forced to act on the parameter β, determining EIP.

    Supplementary Materials

    • Supplementary Material for:

      Modeling the impact on virus transmission of Wolbachia-mediated blocking of dengue virus infection of Aedes aegypti

      Neil M. Ferguson,* Duong Thi Hue Kien, Hannah Clapham, Ricardo Aguas, Vu Tuan Trung, Tran Nguyen Bich Chau, Jean Popovici, Peter A. Ryan, Scott L. O'Neill, Elizabeth A. McGraw, Vo Thi Long, Le Thi Dui, Hoa L. Nguyen, Nguyen Van Vinh Chau, Bridget Wills, Cameron P. Simmons

      *Corresponding author. E-mail: neil.ferguson{at}imperial.ac.uk

      Published 18 March 2015, Sci. Transl. Med. 7, 279ra37 (2015)
      DOI: 10.1126/scitranslmed.3010370

      This PDF file includes:

      • Table S1. Study population characteristics.
      • Table S2. List of primers and probes used.
      • Fig. S1. Human DENV viremia kinetics.

      [Download PDF]

      Other Supplementary Material for this manuscript includes the following:

      • Supplementary data (Microsoft Excel format): Mosquito biting study data.

      [Download Data File]

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