Host-pathogen interactions in malaria: cross-kingdom signaling and mitochondrial regulation

Abstract

Malaria parasite-host interactions are complex and have confounded available drugs and the development of vaccines. Further, we now appreciate that interventions for malaria elimination and eradication must include therapeutics with intrinsic transmission blocking activity to treat the patient and prevent disease spread. Studies over the past 15 years have revealed significant conservation in the response to infection in mosquito and human hosts. More recently, we have recognized that conserved cell signaling cascades in mosquitoes and humans dictate infection outcome through the regulation of mitochondrial function and biogenesis, which feed back to host immunity, basic intermediary metabolism, and stress responses. These responses - reflected clearly in the primeval insect host - provide fertile ground for innovative strategies for both treatment and transmission blocking.

Figure 1

Host-pathogen interactions in malaria. During infection with P. falciparum, both human and mosquito hosts exhibit responses that reflect physiological changes to infection (insulin/IGF-1) and to parasite PAMPs (PfGPIs, hemozoin). In particular, remarkably conserved protein kinase signaling pathways are networked to regulate epithelial and endothelial barrier function, which can dictate infection success and pathology, as well as mitochondrial biogenesis and function to control immunity through NF-κB-dependent and -independent responses.