Reinventing malaria control: hierarchical intervention strategies for African settings based on the microbiota-barrier-innate immunity axis

Abstract

Malaria control is challenged by parasite drug resistance and inadequate vaccine protection. Although mosquito gut microbes regulate Plasmodium development, integrated analyses of microbiota-Plasmodium-host interactions are lacking. Innate immunity imbalance is the primary driver of disease pathogenesis. This review proposes a unified “microbiota-barrier-innate immunity” axis hypothesis. Under physiological conditions, gut microbiota modulates host innate immunity via metabolites and maintains barrier integrity. However, Plasmodium infection disrupts this axis, causing microbiota imbalance, metabolic derangement, intestinal barrier leakage. The ensuing innate immune dysfunction exacerbates the pathology of malaria. Based on this, we constructed a hierarchical three-tier foundational-targeted-precision intervention pyramid tailored to diverse settings, particularly African regions, with endogenous and technological feasibility. This framework, progressing from foundational nutritional regulation and targeted microbial intervention to precision bioengineering, provides an implementable malaria control strategy for resource-limited African areas, addressing drug resistance and vaccine shortages. It offers a translatable eco-immunological approach to accelerate global malaria elimination.