Innate immunity to malaria: The good, the bad and the unknown.

Malaria is the cause of 600.000 deaths annually. However, these deaths represent only a tiny fraction of total malaria cases. Repeated natural infections with the causative agent, Plasmodium sp. parasites, induce protection from severe disease but not sterile immunity. Thus, immunity to Plasmodium is incomplete. Conversely, immunization with attenuated sporozoite stage parasites can induce sterile immunity albeit after multiple vaccinations. These different outcomes are likely to be influenced strongly by the innate immune response to different stages of the parasite lifecycle. Even small numbers of sporozoites can induce a robust proinflammatory type I interferon response, which is believed to be driven by the sensing of parasite RNA. Moreover, induction of innate like gamma-delta cells contributes to the development of adaptive immune responses. Conversely, while blood stage parasites can induce a strong proinflammatory response, regulatory mechanisms are also triggered. In agreement with this, intact parasites are relatively weakly sensed by innate immune cells, but isolated parasite molecules, notably DNA and RNA can induce strong responses. Thus, the innate response to Plasmodium parasite likely represents a trade-off between strong pro-inflammatory responses that may potentiate immunity and regulatory processes that protect the host from cytokine storms that can induce life threatening illness.