TY - JOUR
T1 - Crosstalk between the type 1 interferon and nuclear factor kappa B pathways confers resistance to a lethal virus infection
AU - Rubio, Daniel
AU - Xu, Ren Huan
AU - Remakus, Sanda
AU - Krouse, Tracy E.
AU - Truckenmiller, Mary Ellen
AU - Thapa, Roshan J.
AU - Balachandran, Siddharth
AU - Alcamí, Antonio
AU - Norbury, Christopher C.
AU - Sigal, Luis J.
N1 - Funding Information:
We thank Dr. Piwnica-Worms for the NF-kB luciferase reporter plasmid, Ms. Holly Gillin for secretarial assistance, Drs. Ali Alejo and Jennifer Smith-Gavin for helpful comments, James Oesterling for flow cytometry expertise, Dr. Samuel Litwin for some of the statistical analysis, and the Fox Chase Cancer Center Laboratory Animal, Cell Culture, Flow Cytometry, Biostatistics, and Sequencing facilities for services. This work was supported by NIAID grants U19AI083008 and R01AI065544 to L.J. Sigal and NCI grant CA006927 to the FCCC. D.R. was funded by a fellowship from Instituto de Salud Carlos III, Spanish Ministry of Health. A.A. was funded by the Spanish Ministry of Science and Innovation. The qPCR reagents and instrument were a gift from the Kirby Foundation.
PY - 2013/6/12
Y1 - 2013/6/12
N2 - Nuclear factor kappa B (NF-κB) and type 1 interferon (T1-IFN) signaling are innate immune mechanisms activated upon viral infection. However, the role of NF-κB and its interplay with T1-IFN in antiviral immunity is poorly understood. We show that NF-κB is essential for resistance to ectromelia virus (ECTV), a mouse orthopoxvirus related to the virus causing human smallpox. Additionally, an ECTV mutant lacking an NF-κB inhibitor activates NF-κB more effectively in vivo, resulting in increased proinflammatory molecule transcription in uninfected cells and organs and decreased viral replication. Unexpectedly, NF-κB activation compensates for genetic defects in the T1-IFN pathway, such as a deficiency in the IRF7 transcription factor, resulting in virus control. Thus, overlap between the T1-IFN and NF-κB pathways allows the host to overcome genetic or pathogen-induced deficiencies in T1-IFN and survive an otherwise lethal poxvirus infection. These findings may also explain why some pathogens target both pathways to cause disease.
AB - Nuclear factor kappa B (NF-κB) and type 1 interferon (T1-IFN) signaling are innate immune mechanisms activated upon viral infection. However, the role of NF-κB and its interplay with T1-IFN in antiviral immunity is poorly understood. We show that NF-κB is essential for resistance to ectromelia virus (ECTV), a mouse orthopoxvirus related to the virus causing human smallpox. Additionally, an ECTV mutant lacking an NF-κB inhibitor activates NF-κB more effectively in vivo, resulting in increased proinflammatory molecule transcription in uninfected cells and organs and decreased viral replication. Unexpectedly, NF-κB activation compensates for genetic defects in the T1-IFN pathway, such as a deficiency in the IRF7 transcription factor, resulting in virus control. Thus, overlap between the T1-IFN and NF-κB pathways allows the host to overcome genetic or pathogen-induced deficiencies in T1-IFN and survive an otherwise lethal poxvirus infection. These findings may also explain why some pathogens target both pathways to cause disease.
UR - https://www.scopus.com/pages/publications/84879103490
UR - https://www.scopus.com/pages/publications/84879103490#tab=citedBy
U2 - 10.1016/j.chom.2013.04.015
DO - 10.1016/j.chom.2013.04.015
M3 - Article
C2 - 23768494
AN - SCOPUS:84879103490
SN - 1931-3128
VL - 13
SP - 701
EP - 710
JO - Cell Host and Microbe
JF - Cell Host and Microbe
IS - 6
ER -