The gut microbiota has co-evolved with its host in a symbiotic relationship and plays a crucial role in maintaining host health and preventing disease. The regulation of gut microbiota homeostasis has mainly been studied from the perspective of host immune regulation. The mechanism by which the microbiota regulates its adaptation and colonization remain unknown. 

 

Mosquitoes depend on blood ingestion for propagation, while blood digestion induces hyper-oxidative stress on gut microbiota. The authors discovered that commensal Serratia bacteria form biofilm-like aggregates in the midgut of blood-fed mosquitoes, suggesting that high-order aggregation facilitates commensal colonization of the gut. They found that these bacterial aggregates are highly ordered and driven by OMVs(outer membrane vesicles). Furthermore, OMV biogenesis is controlled by an acyl-homoserine lactones (AHL) type quorum sensing (QS) circuit composed of a QS synthetase SueI and a QS receptor SueR. Using mass spectrometry, they identified that SueI synthesizes the N-hexanoyl-L-homoserine lactone (C6-HSL) QS signal molecule, which stimulates OMV biogenesis and promotes commensal gut colonization. Using comparative transcriptional analysis, the authors found that both C6-HSL treatment and SueR deletion lead to the same metabolic signaling remodeling pattern involving the activation of a critical phenylalanine cassette. The authors found that SueR binds to the promoter of the phenylalanine cassette to suppress its activation, while C6-HSL binding to SueR relieves this repression, leading to the activation of the phenylalanine cassette. This phenylalanine cassette is responsible for the conversion of phenylalanine to Acetyl-CoA and ATP, which serve as driving force for robust OMV biogenesis. Collectively, this study discovers that QS triggers the activation of phenylalanine metabolism to drive the biogenesis of Serratia OMVs in the gut. These OMVs contribute to the formation of bacterial aggregates and facilitate gut colonization (Fig. 1). 

 

Malaria remains one of the deadliest infectious diseases in the world. Despite substantial efforts and expenditures over the past few decades, malaria still remains a leading cause of morbidity and mortality. The stalling global progress in the fight against malaria prompts the urgent need to develop new intervention strategies. A promising strategy for blocking the transmission of malaria is to populate mosquitoes with anti-Plasmodium bacteria, known as paratransgenesis or symbiont-based transmission blocking strategy. However, the successful deployment of this strategy relies on effective colonization of anti-pathogen bacteria in the mosquito gut in high numbers. To implement this strategy in the field, it is important to find ways to promote effective adaptation of the anti-pathogen bacteria to the harsh gut environment of blood-fed mosquitoes. This study demonstrated that exposing mosquito to C6-HSL, an environmentally-friendly molecule, promotes gut colonization of the Plasmodium-blocking Serratia bacterium while enhancing its Plasmodium transmission-blocking efficacy. These findings suggest that QS molecules may be considered for use on bed nets or for indoor residual spraying to enhance the anti-parasitic gut bacteria colonization of mosquitoes, offering a new avenue for improving symbiont-based vector-borne disease control strategies

 

In summary, this study reveals a crucial role played by quorum sensing-activated phenylalanine metabolism in OMV biogenesis and commensal gut colonization, and identify a promising strategy for enhancing mosquito commensal resistance to pathogens by applying QS signal molecules to female mosquitoes.

 

 

 

Link: https://doi.org/10.1016/j.chom.2023.08.017