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Science. 2016 Apr 22;352(6284):463-6. doi: 10.1126/science.aaf3926.

Mx1 reveals innate pathways to antiviral resistance and lethal influenza disease.

Author information

1
Department of Immunobiology, Yale School of Medicine, New Haven, CT 06520, USA.
2
Program in Cellular and Molecular Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
3
Section of Infectious Diseases, Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut, USA.
4
Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut, USA.
5
Department of Pathology, Yale School of Medicine, New Haven, CT 06520, USA.
6
Department of Immunobiology, Yale School of Medicine, New Haven, CT 06520, USA. Howard Hughes Medical Institute, Yale School of Medicine, New Haven, CT 06520, USA.
7
Section of Rheumatology, Department of Internal Medicine, Yale School of Medicine, New Haven, CT 06520, USA.
8
Institut für Medizinische Mikrobiologie und Hygiene, Institute of Virology, University Medical Center Freiburg, Hermann-Herder-Strasse 11, 79104 Freiburg, Germany.
9
Department of Immunobiology, Yale School of Medicine, New Haven, CT 06520, USA. Howard Hughes Medical Institute, Yale School of Medicine, New Haven, CT 06520, USA. akiko.iwasaki@yale.edu.

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.

PMID:
27102485
PMCID:
PMC5465864
DOI:
10.1126/science.aaf3926
[Indexed for MEDLINE]
Free PMC Article

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