Arthropod-borne viruses (arboviruses) pose a significant threat to global health, causing human disease with increasing geographic range and severity. The recent availability of the genome sequences of medically important mosquito species has kick-started investigations into the molecular basis of how mosquito vectors control arbovirus infection. Here, we discuss recent findings concerning the role of the mosquito immune system in antiviral defense, interactions between arboviruses and fundamental cellular processes such as apoptosis and autophagy, and arboviral suppression of mosquito defense mechanisms. This knowledge provides insights into co-evolutionary processes between vector and virus and also lays the groundwork for the development of novel arbovirus control strategies that target the mosquito vector.

Diseases caused by arthropod-borne viruses (arboviruses), such as Dengue, West Nile, and Chikungunya, constitute a major global health burden and are increasing in incidence and geographic range. The natural microbiota of insect vectors influences various aspects of host biology, such as nutrition, reproduction, metabolism, and immunity, and recent studies have highlighted the ability of insect-associated bacteria to reduce vector competence for arboviruses and other pathogens. This reduction can occur through mechanisms, such as immune response activation, resource competition, or the production of anti-viral molecules. Studying the interactions between insect vectors and their microbiota is an important step toward developing alternative strategies for arbovirus transmission control.

The release of Wolbachia-infected mosquitoes is a promising disease intervention strategy that aims to control dengue and other arboviral infections. While early field trials and modelling studies suggest promising epidemiological and entomological outcomes, the overall cost effectiveness of the technology is not well studied in a resource rich setting nor under the suppression approach that aims to suppress the wild-type mosquito population through the release of Wolbachia-infected males. We used economical and epidemiological data from 2010 to 2020 to first ascertain the economic and health costs of dengue in Singapore, a high income nation where dengue is hyper-endemic. The hypothetical cost effectiveness of a national Wolbachia suppression program was then evaluated historically from 2010 to 2020. We estimated that the average economic impact of dengue in Singapore from 2010 to 2020 in constant 2010US$ ranged from $1.014 to $2.265 Billion. Using empirically derived disability weights, we estimated a disease burden of 7,645–21,262 DALYs from 2010–2020. Under an assumed steady-state running cost of a national Wolbachia suppression program in Singapore, we conservatively estimate that Wolbachia would cost an estimated $50,453–$100,907 per DALYs averted and would lead to an estimated $329.40 Million saved in economic costs over 2010 to 2020 under 40% intervention efficacy. Wolbachia releases in Singapore are expected to be highly cost-effective and its rollout must be prioritised to reduce the onward spread of dengue.

Gut bacteria-host interactions have been implicated in the pathogenesis of numerous human diseases, but few mechanisms have been described. The genetically tractable nematode worm Caenorhabditis elegans can be infected with pathogenic bacteria, such as the human gut commensal Enterococcus faecalis, via feeding, making it a good model for studying these interactions. An RNAi screen of 17 worm candidate genes revealed that knockdown of the transcription factor nhr-49, a master regulator of fat metabolism, shortens worm lifespan upon infection with E. faecalis (and other potentially pathogenic bacteria) compared to Escherichia coli. The functional similarity of nhr-49 to the mammalian peroxisome proliferator-activated receptors (PPARs) suggests that this is mediated through a link between fatty acid metabolism and innate immunity. In addition, knockdown of either dlg-1 or ajm-1, which encode physically interacting proteins in the C. elegans epithelial junction, also reduces worm lifespan upon E. faecalis challenge, demonstrating the importance of the intestinal epithelium as an immune barrier. The protective roles identified for nhr-49, dlg-1, and ajm-1 suggest mechanistic interactions between the gut microbiota, host fatty acid metabolism, innate immunity, and epithelial junction integrity that are remarkably similar to those implicated in human metabolic and inflammatory diseases.

The Incompatible Insect Technique (IIT) strategy involves the release of male mosquitoes infected with the bacterium Wolbachia. Regular releases of male Wolbachia-infected mosquitoes can lead to the suppression of mosquito populations, thereby reducing the risk of transmission of vector-borne diseases such as dengue. However, due to imperfect sex-sorting under IIT, fertile Wolbachia-infected female mosquitoes may potentially be unintentionally released into the environment, which may result in replacement and failure to suppress the mosquito populations. As such, mitigating Wolbachia establishment requires a combination of IIT with other strategies. We introduced a simple compartmental model to simulate ex-ante mosquito population dynamics subjected to a Wolbachia-IIT programme. In silico, we explored the risk of replacement, and strategies that could mitigate the establishment of the released Wolbachia strain in the mosquito population. Our results suggest that mitigation may be achieved through the application of a sterile insect technique. Our simulations indicate that these interventions do not override the intended wild type suppression of the IIT approach. These findings will inform policy makers of possible ways to mitigate the potential establishment of Wolbachia using the IIT population control strategy.

Matings between male Aedes aegypti mosquitoes infected with wAlbB strain of Wolbachia and wildtype females yield non-viable eggs. We evaluated the efficacy of releasing wAlbB-infected Ae. aegypti male mosquitoes to suppress dengue. We specified the protocol of a two-arm cluster-randomized test-negative controlled trial (cRCT) and emulated it using a nationally representative test-negative/positive database of individuals reporting for febrile illness to any public hospital, general practitioner or polyclinic. We retrospectively built a cohort of individuals who reside in Wolbachia locations vs a comparator control group who do not reside in Wolbachia locations, using a nationally representative database of all individuals whom report for febrile illness and were tested for dengue at the Environmental Health Institute/hospital laboratories/commercial diagnostic laboratories, through general practitioner clinic, polyclinic or public/private hospital from epidemiological week (EW) 1 2019 to EW26 2022. We emulated a constrained randomization protocol used in cRCTs to balance dengue risk between intervention and control arms in the pre-intervention period. We used the inverse probability weighting approach to further balance the intervention and control groups using a battery of algorithmically selected sociodemographic, environmental and anthropogenic variables. Intention-to-treat analyses were conducted to estimate the risk reduction of dengue given Wolbachia exposure. Intention-to-treat analyses revealed that, compared with controls, Wolbachia releases for 3, 6 and ≥12 months was associated to 47% (95% confidence interval: 25–69%), 44% (33–77%) and 61% (38–78%) protective efficacy against dengue, respectively. When exposed to ≥12 months of Wolbachia releases, protective efficacies ranged from 49% (13–72%) to 77% (60–94%) across years. The proportion of virologically confirmed dengue cases was lower overall in the intervention arm. Protective efficacies were found across all years, age and sex subgroups, with higher durations of Wolbachia exposure associated to greater risk reductions of dengue. Results demonstrated that Wolbachia-mediated sterility can strengthen dengue control in tropical cities, where dengue burden is the greatest.