Abstract
Malaria, caused by parasites in the genus Plasmodium and vectored by Anopheles mosquitoes, remains an enormous public health burden throughout much of the world, with 627,000 deaths and 241 million cases reported by the World Health Organization in 2020. Bacteremia, the presence of bacteria in the bloodstream, is a potentially life-threatening complication that contributes to morbidity and mortality associated with malaria and occurs across the spectrum of ages and disease severities. Malaria-induced bacteremia has previously been shown in mouse models to result from intestinal mast cell (MC) influx or mastocytosis. However, the upstream drivers of mastocytosis in the ileum following infection remain unclear. Interestingly, basophils, short-lived circulating granulocytes associated with allergic inflammation, have been shown to increase in number preceding the onset of MC influx and increased intestinal permeability. The role of basophils in malaria disease biology is not well understood, but given that they are strongly activated by malaria parasites and early cytokine signals such as IL-18 following infection, and their ability to release cytokines and mediators that can activate MCs, we sought to define a role for these cells in the development of mastocytosis, intestinal permeability and bacteremia during malaria infection. Remarkably, our studies showed these cells to be protective against the development of increased intestinal permeability and MC influx, with no effect on bacterial burdens. The depletion of basophils also altered the intestinal and systemic immune response to both parasites and translocating bacteria, suggesting these cells play a role in fine-tuning the immune response to infection. Additionally, we found that while basophil depletion did not alter overall parasitemia, it did increase the number of gametocytes (sexual stage parasites) in circulation and in turn, the intensity of infection in the mosquito vector. Our subsequent studies demonstrated that the protective effects of basophils on the intestinal barrier are at least partially mediated via IL-18 signaling. The effect of IL-18 signaling via basophils on transmission is complex, as mice lacking the IL-18 receptor on basophils showed no difference in gametocyte numbers but were less likely to infect mosquitoes. Future directions of this work should be directed at uncovering the mechanism(s) by which basophils effect gametocyte numbers and transmission, as this could have implications for malaria control efforts.