Interferon-Mediated Innate Immune Responses against Malaria Parasite Liver Stages

Abstract

Summary: Mosquito-transmitted malaria parasites infect hepatocytes and asymptomatically replicate as liver stages. Using RNA sequencing, we show that a rodent malaria liver-stage infection stimulates a robust innate immune response including type I interferon (IFN) and IFNγ pathways. Liver-stage infection is suppressed by these infection-engendered innate responses. This suppression was abrogated in mice deficient in IFNγ, the type I IFN α/β receptor (IFNAR), and interferon regulatory factor 3. Natural killer and CD49b+CD3+ natural killer T (NKT) cells increased in the liver after a primary infection, and CD1d-restricted NKT cells, which secrete IFNγ, were critical in reducing liver-stage burden of a secondary infection. Lack of IFNAR signaling abrogated the increase in NKT cell numbers in the liver, showing a link between type I IFN signaling, cell recruitment, and subsequent parasite elimination. Our findings demonstrate innate immune sensing of malaria parasite liver-stage infection and that the ensuing innate responses can eliminate the parasite. : Malaria is a devastating infectious disease caused by Plasmodium parasites. The parasites first infect the liver and replicate, yet little is known about the innate immune responses to this obligate stage of infection. Miller et al. demonstrate that malaria liver infection induces a pronounced type I IFN-mediated innate immune response. This causes IFNγ-secreting NKT cells to enter the liver, which can limit subsequent infection. The results demonstrate a link between liver infection, type I IFN signaling, cell recruitment, and subsequent parasite elimination.