Host-cell sensors for Plasmodium activate innate immunity against liver-stage infection
Department of Medicine, Division of Infectious Diseases and Immunology
Adaptor Proteins, Signal Transducing; Animals; Blotting, Western; DEAD-box RNA Helicases; Enzyme-Linked Immunosorbent Assay; Flow Cytometry; Gene Expression Profiling; Green Fluorescent Proteins; Immunity, Innate; Immunohistochemistry; Interferon Regulatory Factor-3; Interferon Regulatory Factor-7; Interferon Type I; Liver; Luciferases; Mice; Mice, Inbred C57BL; Mice, Transgenic; Microarray Analysis; Oligonucleotides; Plasmodium; Real-Time Polymerase Chain Reaction; Signal Transduction; Statistics, Nonparametric
Before they infect red blood cells and cause malaria, Plasmodium parasites undergo an obligate and clinically silent expansion phase in the liver that is supposedly undetected by the host. Here, we demonstrate the engagement of a type I interferon (IFN) response during Plasmodium replication in the liver. We identified Plasmodium RNA as a previously unrecognized pathogen-associated molecular pattern (PAMP) capable of activating a type I IFN response via the cytosolic pattern recognition receptor Mda5. This response, initiated by liver-resident cells through the adaptor molecule for cytosolic RNA sensors, Mavs, and the transcription factors Irf3 and Irf7, is propagated by hepatocytes in an interferon-alpha/beta receptor-dependent manner. This signaling pathway is critical for immune cell-mediated host resistance to liver-stage Plasmodium infection, which we find can be primed with other PAMPs, including hepatitis C virus RNA. Together, our results show that the liver has sensor mechanisms for Plasmodium that mediate a functional antiparasite response driven by type I IFN.
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Citation: Nat Med. 2014 Jan;20(1):47-53. doi: 10.1038/nm.3424. Epub 2013 Dec 22. Link to article on publisher's site
Liehl, Peter; Chan, Jennie; Golenbock, Douglas T.; Fitzgerald, Katherine A.; and Mota, Maria M., "Host-cell sensors for Plasmodium activate innate immunity against liver-stage infection" (2014). Infectious Diseases and Immunology Publications and Presentations. 187.