A salivary factor binds a cuticular protein and modulates biting by inducing morphological changes in the mosquito labrum

The mosquito proboscis is an efficient microelectromechanical system, which allows the insect to feed on vertebrate blood quickly and painlessly. Its efficiency is further enhanced by the insect saliva, although through unclear mechanisms. Here, we describe the initial trigger of an unprecedented feedback signaling pathway in Aedes mosquitoes affecting feeding behavior. We identified LIPS proteins in the saliva of Aedes mosquitoes that promote feeding in the vertebrate skin. LIPS show a new all-helical protein fold constituted by two domains. The N-terminal domain interacts with a cuticular protein (Cp19) located at the tip of the mosquito labrum. Upon interaction, the morphology of the labral cuticle changes, and this modification is most likely sensed by proprioceptive neurons. Our study identifies an additional role of mosquito saliva and underlines that the external cuticle is a possible site of key molecular interactions affecting the insect biology and its vector competence. [Display omitted] •LIPS-2 in the mosquito saliva controls intradermal probing before engorging blood•LIPS-2 binds Cp19, a cuticular protein found at the tip of the labrum•Binding of LIPS-2 causes a morphological change of the structures of the labrum•LIPS-2 structural characterization provides insights into its interaction with Cp19 Arnoldi et al. describe a novel role of the mosquito saliva, a feedback signaling pathway affecting intradermal probing preceding blood feeding. The initial trigger of this signaling pathway in Aedes mosquitoes is the interaction between LIPS-2, a salivary protein, and Cp19, a cuticular protein found at the tip of the mosquito mouth.