A look into the future: Using a transcriptomic meta-analysis of Diptera-Wolbachia systems to project the sustainability of arboviral control strategies

Background An effective strategy for arboviral control consists in transfecting Aedes aegypti mosquitoes with the intracellular bacteria Wolbachia pipientis, which reduces host viral susceptibility and spreads itself into wild populations via reproductive manipulations. However, the prospect of losing the efficacy of this strategy underscores the need for deepening the mechanistic knowledge of Diptera-Wolbachia systems and identifying relevant Wolbachia effects that could decline upon adaptation of A. aegypti transfections. A systematic comparison of publicly available Diptera-Wolbachia transcriptomic datasets could yield progress in this matter. Methodology/Principal findings We derived differentially expressed gene (DEG) sets from previously published Diptera-Wolbachia transcriptomic datasets, subjected them to enrichment analysis of Gene Ontology terms, and intersected the results to identify patterns of host gene/function regulation by Wolbachia. A putative farnesoic acid methyl transferase (AAEL004667) and a flavin-containing monooxygenase (AAEL000834) were consistently upregulated in transfected A. aegypti and linked to cytoplasmic incompatibility and viral susceptibility, being proposed as novel targets of study. Genes implicated in viral blocking —GNBPA1, PGRPS1, DEFC, Tf1, serine-type endopeptidases and endopeptidase inhibitors— were consistently upregulated in transfected A. aegypti but not in native infections, indicating that they could lose responsiveness to Wolbachia over time and should be considered to keep the efficacy of arboviral control. The commonality of chitinase regulation by Wolbachia was identified and proposed as an explanation for the loss of desiccation resistance in transfected A. aegypti’s eggs, which is a main obstacle for the introgression of Wolbachia in mosquito populations. Conclusions/Significance The present work points out relevant gene targets to consider for arboviral control sustainability and provides new hypotheses for deepening the understanding of Diptera-Wolbachia systems. Author Summary Arboviral diseases (e.g. dengue), which are mainly transmitted by the mosquito Aedes aegypti, impose a global public health crisis. An effective strategy for controlling the spread of these diseases is to artificially infect A. aegypti populations with the bacteria Wolbachia pipientis, which reduces its capacity to transmit arboviruses. However, future adaptive changes in the novel A. aegypti-Wolbachia association could diminish the efficacy of this approach. To prevent this, it is crucial to have a solid biological understanding of Wolbachia infections and predictions about specific changes that artificial infections could undergo. By analyzing publicly available biological data from Wolbachia-infected mosquitoes and flies we were able to propose new hypotheses regarding general aspects of Wolbachia infection and to identify antiviral effects of Wolbachia in A. aegypti that could decline over time, thus providing relevant information for keeping sustainability of a key arboviral control strategy.