Mx1 reveals innate pathways to antiviral resistance and lethal influenza disease
- 22 April 2016
- journal article
- other
- Published by American Association for the Advancement of Science (AAAS) in Science
- Vol. 352 (6284), 463-466
- https://doi.org/10.1126/science.aaf3926
Abstract
Influenza A virus (IAV) causes up to half a million deaths worldwide annually, 90% of which occur in older adults. We show that IAV-infected monocytes from older humans have impaired antiviral interferon production but retain intact inflammasome responses. To understand the in vivo consequence, we used mice expressing a functional Mx gene encoding a major interferon-induced effector against IAV in humans. In Mx1-intact mice with weakened resistance due to deficiencies in Mavs and Tlr7, we found an elevated respiratory bacterial burden. Notably, mortality in the absence of Mavs and Tlr7 was independent of viral load or MyD88-dependent signaling but dependent on bacterial burden, caspase-1/11, and neutrophil-dependent tissue damage. Therefore, in the context of weakened antiviral resistance, vulnerability to IAV disease is a function of caspase-dependent pathology.Keywords
Funding Information
- NIH (AI081884, AI062428, AI064705, HHSN272201100019C, K24 AG02489, T32 AI007019-36, T32 AI007019-38, T32 AI055403, 5T32HL066987-13, F31 AG039163, R01HL102101, R01HL125501, K24 AG042489, P30 AG21342)
- Deutsche Forschungsgemeinschaft (DFG) (SFB1160/P13)
- Howard Hughes Medical Institute
This publication has 47 references indexed in Scilit:
- The Thermodynamic Basis for Viral RNA Detection by the RIG-I Innate Immune SensorPublished by Elsevier BV ,2012
- Neutrophil extracellular traps promote deep vein thrombosis in miceJournal of Thrombosis and Haemostasis, 2011
- Impaired Interferon Signaling in Dendritic Cells From Older Donors Infected In Vitro With West Nile VirusThe Journal of Infectious Diseases, 2011
- Age-associated impaired plasmacytoid dendritic cell functions lead to decreased CD4 and CD8 T cell immunityAGE, 2010
- Influenza Enhances Susceptibility to Natural Acquisition of and Disease due toStreptococcus pneumoniaein FerretsThe Journal of Infectious Diseases, 2010
- Global patterns of 16S rRNA diversity at a depth of millions of sequences per sampleProceedings of the National Academy of Sciences of the United States of America, 2010
- QIIME allows analysis of high-throughput community sequencing dataNature Methods, 2010
- Influenza virus activates inflammasomes via its intracellular M2 ion channelNature Immunology, 2010
- Influenza-Induced Production of Interferon-Alpha is Defective in Geriatric IndividualsJournal of Clinical Immunology, 2010
- The Specific and Essential Role of MAVS in Antiviral Innate Immune ResponsesImmunity, 2006