Host-cell sensors for Plasmodium activate innate immunity against liver-stage infection
Peter Liehl1, Vanessa Zuzarte-Luís1, Jennie Chan2
1Instituto de Medicina Molecular, Faculdade de Medicina Universidade de Lisboa, Lisboa, Portugal.
Abstract:
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-α/β 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.
Insights
Scientists discovered that Plasmodium parasites trigger a type I interferon (IFN) immune response in the liver during malaria infection. This innate immunity, involving Plasmodium RNA and Mda5, helps the host fight liver-stage parasites.
Area of Science:
- Immunology
- Infectious Diseases
- Hepatology
Background:
- Malaria is caused by Plasmodium parasites, which replicate silently in the liver before infecting red blood cells.
- The host immune system was thought to be unaware of this liver-stage infection.
Purpose of the Study:
- To investigate the host immune response during the liver stage of Plasmodium infection.
- To identify pathogen-associated molecular patterns (PAMPs) and cellular sensors involved in detecting Plasmodium in the liver.
Main Methods:
- Identification of Plasmodium RNA as a PAMP.
- Analysis of the type I interferon (IFN) pathway activation via Mda5, Mavs, Irf3, and Irf7.
- Assessment of host resistance mediated by IFN signaling in hepatocytes and immune cells.
Main Results:
- Plasmodium RNA activates a type I IFN response through the Mda5 sensor pathway.
- This response is initiated by liver-resident cells and propagated by hepatocytes.
- Type I IFN signaling is crucial for immune cell-mediated resistance to liver-stage Plasmodium, and can be enhanced by other PAMPs like HCV RNA.
Conclusions:
- The liver possesses functional sensor mechanisms for Plasmodium parasites.
- A type I IFN-driven innate immune response is critical for controlling liver-stage malaria.
- Targeting this pathway could offer new strategies for malaria prevention and treatment.
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