The case for exploring innate memory in Plasmodium infection

In highly malaria-endemic areas, individuals can receive a bite from a Plasmodium-infected mosquito daily. Yet, most studies in the laboratory only assess a single infection, and our current understanding of malaria immunity does not fully explain how recurrent infections in the field impact pathogenesis and immunity upon re-infection. A growing body of literature suggests innate immune memory, in which epigenetic reprogramming regulates the immune response to sequential infections independently of adaptive immunity, may explain some of the dynamics of recurring Plasmodium infection in endemic areas. Here, we summarize the basic concepts of innate immune memory and findings that support its role in controlling Plasmodium infection and pathogenesis. Furthermore, we postulate that innate memory in non-immune cells, which is only beginning to be described in other disease systems, may have significant consequences in the context of the complex Plasmodium lifecycle.