Holobiont perspectives on tripartite interactions among microbiota, mosquitoes, and pathogens

Abstract

Mosquito-borne diseases like dengue and malaria cause a significant global health burden. Unfortunately, current insecticides and environmental control strategies aimed at the vectors of these diseases are only moderately effective in decreasing disease burden. Understanding and manipulating the interaction between the mosquito holobiont (i.e., mosquitoes and their resident microbiota) and the pathogens transmitted by these mosquitoes to humans and animals could help in developing new disease control strategies. Different microorganisms found in the mosquito's microbiota affect traits related to mosquito survival, development, and reproduction. Here, we review the physiological effects of essential microbes on their mosquito hosts; the interactions between the mosquito holobiont and mosquito-borne pathogen (MBP) infections, including microbiota-induced host immune activation and Wolbachia-mediated pathogen blocking (PB); and the effects of environmental factors and host regulation on the composition of the microbiota. Finally, we briefly overview future directions in holobiont studies, and how these may lead to new effective control strategies against mosquitoes and their transmitted diseases.

Fig. 1. Mosquito holobiont: the chimera of the mosquito, its microbiota, and interactions between them.

The microbiota represents the complex of all microbes that live in or on the host body by mutualism or commensalism, including bacteria, fungi, viruses, and protists. They are generally considered to be non-pathogenic. Different mosquito populations and species can share similar microbiota, which may depend on various factors related to the host, microbiota, environmental factors, host-microbiota combinations, hologenomic variation, and other factors.

Fig. 2. Schematic diagram of the microbiota-mosquito-pathogen interactions.

A The mosquito microbiota modulates mosquito pathogen infection by stimulating host immune signal regulation or secreting effectors, or by enhancing intracellular/extracellular viral infection through different mechanisms. Meanwhile, viral infection can alter the composition of the mosquito microbiota. B Wolbachia induces a PB effect by disrupting or competing for cellular cholesterol and lipid homeostasis in viral infection. C Wolbachia induces a PB effect by stimulating mosquito immunity. (1) Wolbachia activates the IMD, Toll, and JAK/STAT pathways to increase the expression of downstream effectors. (2) Wolbachia directly kills pathogens through the ROS pathway, which may participate in other immune processes. (3) Wolbachia induces homology degradation of viral RNA by the RNAi pathway. Blue arrows: the process of a Wolbachia-induced PB effect mediated through mosquito immunity; Blue arrows with a triangle (in box B): Wolbachia-induced PB in viral transmission. Black arrows: other microbiota-induced pathogen inhibition.

Fig. 3. Schematic representation of the acquisition and composition of mosquito microbiota.

A Mosquito larval microbiota are determined by food resources, environmental changes, larval-mediated filtration, and their microhabitat conditions. B Mosquito adult microbiota are determined by various environmental factors or genetic factors, such as genetic variation in activation of different signal pathways. C Mosquito pupal microbiota are determined by larval secretion and/or inheritance from larvae. Dotted boxes with different colors: the mosquito microbes at different life stages identified at the genus level refer to some recently published studies, the bold purple font indicates the shared bacteria in larva, pupa, and adult stages, and the bold black font indicates the specific bacteria. The black arrows indicate mosquito life history. The red arrows indicate environmental factors regulating mosquito microbiota, and the yellow arrows indicate mosquito host-mediated regulation role on its microbiota.

Fig. 4. Strategies of holobiont manipulation for mosquito control and pathogen transmission.

We face increasing challenges from vector mosquitoes and mosquito-borne diseases, including rapid invasion by vectors leading to expanded distributions, high adaptive potential of host mosquitoes, challenges in outbreaks of new vectors, and the increasing resistance of mosquitoes to various pesticides and repellents. Mosquitoes and microorganisms (bacteria, fungi, viruses, and protists) interact as a holobiont. Holobiont manipulation provide new promising strategies for mosquito-borne diseases control. The application of omics techniques are providing new effective methods to help understand mechanisms underlying mosquito-microbiota interactions.