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1.
Nat Med ; 20(1): 47-53, 2014 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-24362933

RESUMEN

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/ß 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.


Asunto(s)
Inmunidad Innata/inmunología , Interferón Tipo I/inmunología , Hígado/parasitología , Plasmodium/inmunología , Transducción de Señal/inmunología , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Animales , Western Blotting , ARN Helicasas DEAD-box/inmunología , Ensayo de Inmunoadsorción Enzimática , Citometría de Flujo , Perfilación de la Expresión Génica , Proteínas Fluorescentes Verdes , Inmunohistoquímica , Factor 3 Regulador del Interferón/metabolismo , Factor 7 Regulador del Interferón/metabolismo , Helicasa Inducida por Interferón IFIH1 , Hígado/inmunología , Luciferasas , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Análisis por Micromatrices , Oligonucleótidos/genética , Plasmodium/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Estadísticas no Paramétricas
2.
Immunity ; 37(5): 867-79, 2012 Nov 16.
Artículo en Inglés | MEDLINE | ID: mdl-23142781

RESUMEN

The genome of vertebrates contains endogenous retroviruses (ERVs) that are largely nonfunctional relicts of ancestral germline infection by exogenous retroviruses. However, in some mouse strains ERVs are actively involved in disease. Here we report that nucleic acid-recognizing Toll-like receptors 3, 7, and 9 (TLR 3, TLR7, and TLR9) are essential for the control of ERVs. Loss of TLR7 function caused spontaneous retroviral viremia that coincided with the absence of ERV-specific antibodies. Importantly, additional TLR3 and TLR9 deficiency led to acute T cell lymphoblastic leukemia, underscoring a prominent role for TLR3 and TLR9 in surveillance of ERV-induced tumors. Experimental ERV infection induced a TLR3-, TLR7-, and TLR9-dependent group of "acute-phase" genes previously described in HIV and SIV infections. Our study suggests that in addition to their role in innate immunity against exogenous pathogens, nucleic acid-recognizing TLRs contribute to the immune control of activated ERVs and ERV-induced tumors.


Asunto(s)
Retrovirus Endógenos/genética , Ácidos Nucleicos/genética , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Receptores Toll-Like/genética , Receptores Toll-Like/metabolismo , Viremia/genética , Animales , Anticuerpos Antivirales/genética , Anticuerpos Antivirales/inmunología , Línea Celular , Retrovirus Endógenos/inmunología , Retrovirus Endógenos/metabolismo , Inmunidad Innata/genética , Inmunidad Innata/inmunología , Células Asesinas Naturales/inmunología , Células Asesinas Naturales/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ácidos Nucleicos/inmunología , Ácidos Nucleicos/metabolismo , Oncogenes/genética , Oncogenes/inmunología , Leucemia-Linfoma Linfoblástico de Células T Precursoras/inmunología , Leucemia-Linfoma Linfoblástico de Células T Precursoras/metabolismo , Receptores Toll-Like/inmunología , Viremia/inmunología , Viremia/metabolismo
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