Blood feeding, microbiota, and layered mosquito immunity: from pathway phenotypes to vector competence

Mosquitoes impose a significant epidemiological burden on public health through the transmission of malaria parasites and arboviruses. Vector competence, the ability of a mosquito to acquire, maintain, and transmit pathogens, is tightly linked to immune regulation, but immune phenotypes in mosquitoes cannot be interpreted only as pathogen-triggered activation of canonical pathways. Following blood feeding, female mosquitoes undergo extensive physiological remodeling, including endocrine reprogramming, microbiota shifts, oxidative and barrier stress, digestive and metabolic activation, and coordinated modulation of immune function. Because pathogen acquisition occurs within this same physiological window, mosquito immunity must be interpreted in relation to the blood-fed state in which infection unfolds. In this review, we provide a conceptual synthesis of mosquito immune function around this blood-meal-centered framework, with emphasis on how microbiota dynamics, epithelial physiology, hemocyte activity, and systemic endocrine and nutritional signals shape immune capacity and vector competence. We then examine how conserved immune modules, including Toll, IMD, JAK/STAT, JNK, RNA interference, and complement-like systems, act against bacteria, fungi, malaria parasites, and arboviruses, highlighting the distinction between pathway activation, effector function, tissue tolerance and repair, altered permissiveness, and pathogen restriction. We further discuss juvenile hormone, ecdysone, insulin-like signaling, and vertebrate-derived blood factors as systemic inputs that shape immune competence rather than reproduction alone. Finally, we propose that blood feeding can establish an anticipatory immune state, defined here as physiological preconditioning by recurrent feeding-associated cues rather than pathogen-specific prediction. This framework helps explain why the same immune pathways can restrict infection, preserve tissue integrity, or indirectly modulate transmission by altering tissue permissiveness.