Basophil depletion alters host immunity, intestinal permeability and mammalian host-to-mosquito transmission in malaria.

Abstract

Abstract Malaria-induced bacteremia has been shown to result from intestinal mast cell (MC) activation (Chau et al. 2013, Potts et al. 2016, Céspedes et al. 2020). The appearance of MCs in the ileum and increased permeability to enteric bacteria are preceded by an early Th2-biased host immune response to infection, characterized by the appearance of IL-4, IL-10, mast cell protease (Mcpt)1 and Mcpt4, and an increase in circulating basophils and eosinophils. Given the functional similarities of basophils and MCs in the context of allergic inflammation and the capacity of basophils to produce IL-4 in large amounts, we sought to define the role of basophils in the development of increased intestinal permeability and in MC influx and the development of bacteremia in the context of malaria. Upon infection with non-lethal Plasmodium yoelii yoelii 17XNL, mice that lack basophils exhibited increased intestinal permeability and increased ileal MC numbers, without any increase in bacterial 16S ribosomal DNA copy numbers in the blood, relative to non-depleted mice. Analysis of cytokines, chemokines and MC-associated factors in the ileum revealed significantly increased TNFα and IL-13 at day 6 post infection (PI) in basophil-depleted mice compared to non-depleted mice. Moreover, network analysis revealed profound differences between depleted and non-depleted mice over time following infection in both systemic and local immune responses to parasites and translocated bacteria. Finally, basophil depletion was associated with significantly increased gametocytemia and parasite transmission to mosquitoes, suggesting that basophils play a previously undescribed role in controlling gametocytemia and in turn, mammalian host-to-mosquito transmission. This work was supported by NIH NIAID RO1 AI131609 to Shirley Luckhart.