Early and sustained innate immune response defines pathology and death in nonhuman primates infected by highly pathogenic influenza virus

The mechanisms responsible for the virulence of the highly pathogenic avian influenza (HPAI) and of the 1918 pandemic influenza virus in humans remain poorly understood. To identify crucial components of the early host response during these infections by using both conventional and functional genomi...

Full description

Saved in:

Bibliographic Details
Published in:	Proceedings of the National Academy of Sciences - PNAS Vol. 106; no. 9; pp. 3455 - 3460
Main Authors:	Baskin, Carole R, Bielefeldt-Ohmann, Helle, Tumpey, Terrence M, Sabourin, Patrick J, Long, James P, García-Sastre, Adolfo, Tolnay, Airn-E, Albrecht, Randy, Pyles, John A, Olson, Pam H, Aicher, Lauri D, Rosenzweig, Elizabeth R, Murali-Krishna, Kaja, Clark, Edward A, Kotur, Mark S, Fornek, Jamie L, Proll, Sean, Palermo, Robert E, Sabourin, Carol L, Katze, Michael G
Format:	Journal Article
Language:	English
Published:	United States National Academy of Sciences 03-03-2009 National Acad Sciences
Subjects:	Animals Avian flu Biological Sciences Cell Movement - immunology Cynomolgus Cytokines Dendritic cells Dendritic Cells - cytology Dendritic Cells - immunology Endothelial cells Gene Expression Profiling Genomics H5N1 subtype influenza A virus Humans Immunity, Innate - immunology Infections Influenza A virus Influenza A Virus, H1N1 Subtype - immunology Influenza A Virus, H1N1 Subtype - pathogenicity Influenza A Virus, H5N1 Subtype - immunology Influenza A Virus, H5N1 Subtype - pathogenicity Influenza virus Lung Diseases - pathology Lung Diseases - virology Lungs Lymph Nodes - immunology Macaca Macaca fascicularis Male Monkeys & apes Orthomyxoviridae Orthomyxoviridae Infections - immunology Orthomyxoviridae Infections - metabolism Orthomyxoviridae Infections - pathology Orthomyxoviridae Infections - virology Pandemics Pathology Primates Proteins Survival Rate T-Lymphocytes - cytology T-Lymphocytes - immunology Time Factors Tropism Virus Replication Viruses Vietnam
Online Access:	Get full text
Tags:	Add Tag No Tags, Be the first to tag this record!

Description
Summary:	The mechanisms responsible for the virulence of the highly pathogenic avian influenza (HPAI) and of the 1918 pandemic influenza virus in humans remain poorly understood. To identify crucial components of the early host response during these infections by using both conventional and functional genomics tools, we studied 34 cynomolgus macaques (Macaca fascicularis) to compare a 2004 human H5N1 Vietnam isolate with 2 reassortant viruses possessing the 1918 hemagglutinin (HA) and neuraminidase (NA) surface proteins, known conveyors of virulence. One of the reassortants also contained the 1918 nonstructural (NS1) protein, an inhibitor of the host interferon response. Among these viruses, HPAI H5N1 was the most virulent. Within 24 h, the H5N1 virus produced severe bronchiolar and alveolar lesions. Notably, the H5N1 virus targeted type II pneumocytes throughout the 7-day infection, and induced the most dramatic and sustained expression of type I interferons and inflammatory and innate immune genes, as measured by genomic and protein assays. The H5N1 infection also resulted in prolonged margination of circulating T lymphocytes and notable apoptosis of activated dendritic cells in the lungs and draining lymph nodes early during infection. While both 1918 reassortant viruses also were highly pathogenic, the H5N1 virus was exceptional for the extent of tissue damage, cytokinemia, and interference with immune regulatory mechanisms, which may help explain the extreme virulence of HPAI viruses in humans.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Author contributions: C.R.B., H.B.-O., T.M.T., P.J.S., A.G.-S., K.M.-K., R.E.P., C.L.S., and M.G.K. designed research; H.B.-O., P.J.S., J.P.L., A.-E.T., R.A., J.A.P., P.H.O., L.D.A., E.R.R., and M.S.K. performed research; A.G.-S. contributed reagents/analytic tools; C.R.B., H.B.-O., A.-E.T., K.M.-K., E.A.C., M.S.K., J.L.F., S.P., and C.L.S. analyzed data; and C.R.B., H.B.-O., T.M.T., A.G.-S., K.M.-K., J.L.F., S.P., R.E.P., C.L.S., and M.G.K. wrote the paper. Communicated by Roy Curtiss III, Arizona State University, Tempe, AZ, January 5, 2009
ISSN:	0027-8424 1091-6490
DOI:	10.1073/pnas.0813234106