Mx1 reveals innate pathways to antiviral resistance and lethal influenza disease.
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.
Department of Immunobiology, Yale School of Medicine, New Haven, CT 06520, USA.
Padmini S
PS
Pillai
Department of Immunobiology, Yale School of Medicine, New Haven, CT 06520, USA.
Ryan D
RD
Molony
Program in Cellular and Molecular Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
Kimberly
K
Martinod
Department of Immunobiology, Yale School of Medicine, New Haven, CT 06520, USA.
Huiping
H
Dong
Department of Immunobiology, Yale School of Medicine, New Haven, CT 06520, USA.
Iris K
IK
Pang
Department of Immunobiology, Yale School of Medicine, New Haven, CT 06520, USA.
Michal C
MC
Tal
Department of Immunobiology, Yale School of Medicine, New Haven, CT 06520, USA.
Angel G
AG
Solis
Department of Immunobiology, Yale School of Medicine, New Haven, CT 06520, USA.
Piotr
P
Bielecki
Section of Infectious Diseases, Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut, USA.
Subhasis
S
Mohanty
Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut, USA.
Mark
M
Trentalange
Department of Pathology, Yale School of Medicine, New Haven, CT 06520, USA.
Robert J
RJ
Homer
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.
Richard A
RA
Flavell
Program in Cellular and Molecular Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
Denisa D
DD
Wagner
Section of Rheumatology, Department of Internal Medicine, Yale School of Medicine, New Haven, CT 06520, USA.
Ruth R
RR
Montgomery
Section of Infectious Diseases, Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut, USA.
Albert C
AC
Shaw
Institut für Medizinische Mikrobiologie und Hygiene, Institute of Virology, University Medical Center Freiburg, Hermann-Herder-Strasse 11, 79104 Freiburg, Germany.
Peter
P
Staeheli
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.
Akiko
A
Iwasaki
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D001424:Bacterial Infections / Q000209:etiology / Q000276:immunology*; D020170:Caspase 1 / Q000378:metabolism; D020169:Caspases / Q000378:metabolism; D053471:Caspases, Initiator; D005260:Female; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics / Q000276:immunology*; D009980:Influenza A virus / Q000276:immunology*; D007251:Influenza, Human / Q000150:complications / Q000276:immunology*; D016899:Interferon-beta / Q000276:immunology; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D009000:Monocytes / Q000276:immunology; D064547:Myxovirus Resistance Proteins / Q000235:genetics / Q000502:physiology*; D009504:Neutrophils / Q000276:immunology; D009976:Orthomyxoviridae Infections / Q000276:immunology*; D012141:Respiratory Tract Infections / Q000276:immunology* / Q000382:microbiology; D051199:Toll-Like Receptor 7 / Q000235:genetics / Q000378:metabolism; D019562:Viral Load; D055815:Young Adult
D048868:Adaptor Proteins, Signal Transducing; D020170:Caspase 1; D020169:Caspases; D053471:Caspases, Initiator; D016899:Interferon-beta; D008562:Membrane Glycoproteins; D064547:Myxovirus Resistance Proteins; D051199:Toll-Like Receptor 7; C512612:MAVS protein, mouse; C579070:Mx1 protein, mouse; C477038:Tlr7 protein, mouse; C101136:Casp4 protein, mouse