Immunostimulatory Defective Viral Genomes from Respiratory Syncytial Virus Promote a Strong Innate Antiviral Response during Infection in Mice and Humans.
Human respiratory syncytial virus (RSV) is a major cause of severe respiratory illness in children and susceptible adults. RSV blocks the development of the innate antiviral immune response and can grow to high titers in the respiratory tract. Here we demonstrate that immunostimulatory defective viral genomes (iDVGs) that are naturally generated during RSV replication are strong inducers of the innate antiviral response to RSV in mice and humans. In mice, RSV iDVGs stimulated the expression of antiviral genes, restricted viral replication, and prevented weight loss and lung inflammation. In human cells, the antiviral response to RSV iDVGs was dominated by the expression of IFN-λ1 over IFN-β and was driven by rapid intranuclear accumulation of the transcription factor IRF1. RSV iDVGs were detected in respiratory secretions of hospitalized patients, and their amount positively correlated with the level of expression of antiviral genes in the samples. Infection of explanted human lung tissue from different donors revealed that most humans can respond to RSV iDVGs and that the rate of accumulation of iDVGs during infection directly correlates with the quality of the antiviral response. Taken together, our data establish iDVGs as primary triggers of robust antiviral responses to RSV and provide the first evidence for an important biological role for naturally occurring iDVGs during a paramyxovirus infection in humans.
Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
Yan
Y
Sun
Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
Deepika
D
Jain
Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
Cynthia J
CJ
Koziol-White
Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
Emmanuelle
E
Genoyer
Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
Micah
M
Gilbert
Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
Karla
K
Tapia
Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
Reynold A
RA
Panettieri
Department of Pathology and Laboratory of Medicine, Perelman School of Medicine at the University of Pennsylvania and Clinical Virology Laboratory, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, United States of America.
Richard L
RL
Hodinka
Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
Carolina B
CB
López
D000818:Animals; D002460:Cell Line; D002522:Chlorocebus aethiops; D005260:Female; D015967:Gene Expression Regulation, Viral; D016679:Genome, Viral; D054884:Host-Pathogen Interactions; D006801:Humans; D007113:Immunity, Innate; D016899:Interferon-beta / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D007372:Interferons; D007378:Interleukins / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D008168:Lung / Q000276:immunology / Q000473:pathology / Q000821:virology; D008807:Mice, Inbred BALB C; D009305:Nasopharynx / Q000276:immunology / Q000473:pathology / Q000821:virology; D034622:RNA Interference; D020545:Respiratory Mucosa / Q000276:immunology / Q000473:pathology / Q000821:virology*; D018357:Respiratory Syncytial Virus Infections / Q000276:immunology / Q000473:pathology / Q000821:virology*; D018113:Respiratory Syncytial Virus, Human / Q000235:genetics / Q000276:immunology / Q000302:isolation & purification / Q000502:physiology*; D046509:Tissue Culture Techniques; D014709:Vero Cells; D056189:Viral Tropism; D014779:Virus Replication; D000095022:Interferon Lambda
D016899:Interferon-beta; D007372:Interferons; D007378:Interleukins; C000624353:interferon-lambda, human; D000095022:Interferon Lambda