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Dengue virus infection modifies mosquito blood-feeding behavior to increase transmission to the host - PubMed

  • ️Sat Jan 01 2022

Dengue virus infection modifies mosquito blood-feeding behavior to increase transmission to the host

Benjamin Wong Wei Xiang et al. Proc Natl Acad Sci U S A. 2022.

Abstract

Mosquito blood-feeding behavior is a key determinant of the epidemiology of dengue viruses (DENV), the most-prevalent mosquito-borne viruses. However, despite its importance, how DENV infection influences mosquito blood-feeding and, consequently, transmission remains unclear. Here, we developed a high-resolution, video-based assay to observe the blood-feeding behavior of Aedes aegypti mosquitoes on mice. We then applied multivariate analysis on the high-throughput, unbiased data generated from the assay to ordinate behavioral parameters into complex behaviors. We showed that DENV infection increases mosquito attraction to the host and hinders its biting efficiency, the latter resulting in the infected mosquitoes biting more to reach similar blood repletion as uninfected mosquitoes. To examine how increased biting influences DENV transmission to the host, we established an in vivo transmission model with immuno-competent mice and demonstrated that successive short probes result in multiple transmissions. Finally, to determine how DENV-induced alterations of host-seeking and biting behaviors influence dengue epidemiology, we integrated the behavioral data within a mathematical model. We calculated that the number of infected hosts per infected mosquito, as determined by the reproduction rate, tripled when mosquito behavior was influenced by DENV infection. Taken together, this multidisciplinary study details how DENV infection modulates mosquito blood-feeding behavior to increase vector capacity, proportionally aggravating DENV epidemiology. By elucidating the contribution of mosquito behavioral alterations on DENV transmission to the host, these results will inform epidemiological modeling to tailor improved interventions against dengue.

Keywords: blood-feeding behavior; dengue virus; epidemiology; mosquito; transmission.

Copyright © 2022 the Author(s). Published by PNAS.

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Conflict of interest statement

The authors declare no competing interest.

Figures

Fig. 1.
Fig. 1.

Description of the behavioral assay. (A) Mosquito blood-feeding behavioral stages. (B) Observation chamber. (C) Viral load in whole mosquitoes at 10 d postoral infection with DENV or postoral feeding on noninfectious blood meal (Ctrl). Bars show geometric means ± 95% CI from 20 mosquitoes in each condition. (D and E) Behavioral assay device. An anesthetized mouse with a shaved belly was positioned on the upper deck, before lowering the upper deck onto the lower deck, which contained four observation chambers. Mosquitoes were video recorded for 30 min. (F) Examples of video-recorded pictures showing probing initiation (F’), proboscis insertion (F’’), and blood ingestion with abdomen swelling (F’’’). (G) Schematic of the high-resolution, high-throughput behavioral assay.

Fig. 2.
Fig. 2.

DENV infection increases mosquito attraction to the host. (A) Schematic of the ordination of host-seeking behavioral parameters into biologically interpretable factors and example of Factor 1. (B) Factor analysis of host-seeking behavior. Bars show factor score means ± SEM. Variance explained by each factor is detailed. *P value < 0.055 as determined by unpaired t test. (C) Univariate analysis of host-seeking behavior. Bars indicate median ± 95% CI for three behavior parameters that were significantly (P value < 0.05 as determined by Mann–Whitney U test) different between infection (DENV) and control (Ctrl) conditions. (B and C) N infected = 52 and N control = 65. (D) Mosquito attraction to the mouse in large cages; N = 30 for each condition.

Fig. 3.
Fig. 3.

DENV-infection hinders probing efficiency. (A) Schematic of the ordination of biting behavioral parameters into biologically interpretable factors and example of Factor 1. (B) Factor analysis of the biting behavior. Bars show factor score means ± SEM. Variance explained by each factor is detailed. *P value < 0.055 as determined by unpaired t test. (C) Univariate analysis of the biting behavior. Bars indicate median ± 95% CI for eight behavior parameters that were significantly (P value < 0.05 as determined by Mann–Whitney U test) different between infection (DENV) and control (Ctrl) conditions. 1Parameters were calculated only with individuals that blood-fed. (B and C) N infected = 33 and N control = 46.

Fig. 4.
Fig. 4.

Mosquitoes transmit DENV at each successive probe. (A) Schematic of the transmission assay. (B and C) DENV infection in skin (B) and the corresponding draining lymph nodes (C) from three mice successively bitten by the same infected mosquito. Infection rate indicates the number of infected tissues over the number of tissues bitten by different mosquitoes. Violin plots indicate median (thick line) and quartiles (dotted lines). Eight mosquitoes were analyzed, and each had bitten three different mice, totaling 24 different mice. Dots with the same color represent bites by the same mosquito.

Fig. 5.
Fig. 5.

R0 is increased by infection-induced changes on mosquito blood-feeding behavior. The impact of infection on host-seeking and biting behaviors separately and together was mathematically modeled.

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