Allergy and malaria: Control of parasite transmission and opportunities for transmission-blocking interventions

In both animal models and humans, malaria is associated with L-arginine deficiency, elevated levels of histamine and intestinal mast cells (MCs) as well as early activation of basophils. Tissue resident MCs and circulating basophils are central effector cells in allergic inflammation. In addition to connecting allergic inflammation to intestinal barrier damage in malaria, we have implicated MCs and basophils in transmission of the mouse parasite Plasmodium yoelii to Anopheles stephensi. Specifically, depletion of basophils and ablation of MC protease 4 (Mcpt4) and the MC-derived cytokine interleukin (IL)-10 in mice were associated with increased transmission of P. yoelii to A. stephensi. Conversely, depletion of the IL-18 receptor from murine basophils was associated with decreased P. yoelii transmission success. IL-18 is increased early in malaria and, together with IL-3, stimulates MCs and basophils to produce histamine, IL-4, and IL-13. Histamine is an important insect neuromodulator and its presence in blood makes it available to feed mosquitoes. In this context, we showed that provisioning A. stephensi with malaria-associated levels of histamine enhanced infection success with both P. yoelii and the human parasite Plasmodium falciparum. These observations demonstrate that malaria-induced allergic inflammation controls parasite transmission and could inform novel strategies for malaria control.