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

Abstract

Dengue is the most common arboviral infection of humans and is a public health burden in more than 100 countries. Aedes aegypti mosquitoes stably infected with strains of the intracellular bacterium Wolbachia are resistant to dengue virus (DENV) infection and are being tested in field trials. To mimic field conditions, we experimentally assessed the vector competence of A. aegypti carrying the Wolbachia strains wMel and wMelPop after challenge with viremic blood from dengue patients. We found that wMelPop conferred strong resistance to DENV infection of mosquito abdomen tissue and largely prevented disseminated infection. wMel conferred less resistance to infection of mosquito abdomen tissue, but it did reduce the prevalence of mosquitoes with infectious saliva. A mathematical model of DENV transmission incorporating the dynamics of viral infection in humans and mosquitoes was fitted to the data collected. Model predictions suggested that wMel would reduce the basic reproduction number, R0, of DENV transmission by 66 to 75%. Our results suggest that establishment of wMelPop-infected A. aegypti at a high frequency in a dengue-endemic setting would result in the complete abatement of DENV transmission. Establishment of wMel-infected A. aegypti is also predicted to have a substantial effect on transmission that would be sufficient to eliminate dengue in low or moderate transmission settings but may be insufficient to achieve complete control in settings where R0 is high. These findings develop a framework for selecting Wolbachia strains for field releases and for calculating their likely impact.

Figure 1

Susceptibility of WT and wMelPop-infected mosquitoes to DENV infection. Each row represents the results of feeding cohorts of WT and wMelPop infected mosquitoes on viremic blood collected from human dengue cases. The log10 viral titer (RNA copies/ml) in plasma in 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 pre-requisite 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).

Figure 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 in 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 post-feeding (day 7, 10, 14 and 18). Background color of table cells indicates the proportion of mosquitoes with detectable infection (0%=dark green to 100%=red).

Figure 3

wMel attenuates DENV infection of abdomen tissues. Shown is the mean log10 titer (RNA copies/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–D show results for DENV1-4, respectively. Error bars show standard error of the mean.

Figure 4

Mosquito infection model fit to the empirical evidence of wMel-mediated blocking of DENV infection. (A–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; (C) log10 donor plasma virus titer band. Panels D–F, as for panels AC, but showing the proportion of dengue-infected mosquitoes (i.e. with detectable virus in abdomen) that also had detectable infectious virus in saliva for the baseline model. Panels G–I, as for panels D–F but for the alternative saliva model.

Figure 5

Performance of the mosquito infection model. (A) Shown is the behavior of the abdominal infection model illustrating 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 upon 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.

Figure 6

Estimated reduction in transmissibility of DENV (quantified by serotype specific R₀) caused by wMel infection. Median posterior estimates and 95% credible intervals are shown. ‘Baseline’ scenario: assumes data on infectious saliva translates directly to human infectiousness. ‘Higher/Lower dose’ scenarios: assume 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.