Systems analysis shows a role of cytophilic antibodies in shaping innate tolerance to malaria.

Natural immunity to malaria develops over time with repeated malaria episodes, but protection against severe malaria and immune regulation limiting immunopathology, called tolerance, develops more rapidly. Here, we comprehensively profile the blood immune system in patients, with or without prior malaria exposure, over 1 year after acute symptomatic Plasmodium falciparum malaria. Using a data-driven analysis approach to describe the immune landscape over time, we show that a dampened inflammatory response is associated with reduced γδ T cell expansion, early expansion of CD16+ monocytes, and parasite-specific antibodies of IgG1 and IgG3 isotypes. This also coincided with reduced parasitemia and duration of hospitalization. Our data indicate that antibody-mediated phagocytosis during the blood stage infection leads to lower parasitemia and less inflammatory response with reduced γδ T cell expansion. This enhanced control and reduced inflammation points to a potential mechanism on how tolerance is established following repeated malaria exposure.