NF-κB activation induced by hepatitis A virus and Newcastle disease virus occurs by different pathways depending on the structural pattern of viral nucleic acids.
NF-κB is activated by hepatitis B virus and hepatitis C virus and is assumed to contribute to viral persistence, leading to the development of hepatocellular cancer by inhibition of apoptosis mediated by cytotoxic T cells. Whether hepatitis A virus (HAV), which does not cause chronic infection, activates NF-κB is a topic of controversy. Here, we confirm that HAV activates NF-κB and show that HAV enhances the activation of NF-κB by poly(I-C), but it inhibits the activation of NF-κB by Newcastle disease virus (NDV), a paramyxovirus. In addition, HAV inhibits NF-κB activation induced by overexpressed MAVS (mitochondrial antiviral signaling protein). We conclude from these findings that NF-κB induction occurs in cells infected with HAV by dsRNA, independently of mitochondrial-transduced RIG-I/MDA-5 signaling, whereas the induction of NF-κB in cells infected by NDV is mediated by RIG-I signaling, independenly of viral dsRNA. This is supported by experiments in which the different RNA inducers of RIG-I and MDA-5 are sequestered and which also show that poly(I-C) and HAV, but not NDV, are functionally equivalent in inducing NF-κB activity. Furthermore, we demonstrate that HAV interferes with the protein kinase R (PKR) activity and PKR activation induced by dsRNA, and that HAV-induced activation of NF-κB therefore does not take place via the PKR-induced pathway. As assumed for hepatitis B and C virus infections, NF-κB activation could attenuate the effects of cytotoxic T cells and may contribute to prolonged as well as relapsing courses of hepatitis A.
Department of Virology, University of Bremen, Leobener Straße/UFT, 28359, Bremen, Germany.
Dajana
D
Paulmann
Simone
S
Bortmann
Florian
F
Grimm
Iris
I
Berk
Leena
L
Kraemer
Angelika
A
Vallbracht
Andreas
A
Dotzauer
D000818:Animals; D002460:Cell Line; D015967:Gene Expression Regulation, Viral / Q000276:immunology; D030041:Hepatitis A virus / Q000276:immunology*; D006801:Humans; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D009522:Newcastle disease virus / Q000276:immunology*; D012367:RNA, Viral / Q000235:genetics / Q000378:metabolism*
D016328:NF-kappa B; D012367:RNA, Viral