Beyond immunity: a transcriptomic landscape of Plasmodium’s modulation of mosquito metabolic pathways

The focus of mosquito- Plasmodium interactions has predominantly been centered on mosquito immunity, revealing key mechanisms by which mosquitoes attempt to combat Plasmodium infection. However, recent evidence suggests that beyond immunity, a multitude of mosquito physiological and metabolic pathways play crucial roles in determining whether the parasite completes its development within the mosquito. We review which of these metabolic pathways are potentially modulated by Plasmodium , revealing a fragmented and occasionally contradictory state of knowledge. We then present a comprehensive transcriptomic analysis of Plasmodium -infected and uninfected mosquitoes, examining gene expression of crucial genes across different stages of the parasite’s development. These genes range from key enzymes and proteins involved in gut structure and function, to genes involved in egg production and resorption, salivary gland invasion and mosquito behaviour. For this purpose, we use a non-model system consisting of the avian malaria parasite Plasmodium relictum , an invasive parasite threatening bird biodiversity across the world, and its natural vector, the mosquito Culex pipiens . Our results reveal how at each stage of its development within the mosquito, Plasmodium modulates a myriad of mosquito metabolic pathways, in ways that potentially favour its survival and the completion of its life cycle. We discuss whether this constitutes sufficient evidence of parasite-driven manipulation or whether the changes are simply the mosquito’s response to the infection, which the parasite may serendipitously exploit to enhance its fitness. Our study extends the comparative transcriptomic analyses of malaria-infected mosquitoes beyond human and rodent parasites, and provides insights into the degree of conservation of metabolic pathways and into the selective pressures exerted by Plasmodium parasites on their vectors.