IRF-3 activation by Sendai virus infection is required for cellular apoptosis and avoidance of persistence.
Here, we report that specific manipulations of the cellular response to virus infection can cause prevention of apoptosis and consequent establishment of persistent infection. Infection of several human cell lines with Sendai virus (SeV) or human parainfluenza virus 3, two prototypic paramyxoviruses, caused slow apoptosis, which was markedly accelerated upon blocking the action of phosphatidylinositol 3-kinases (PI3 kinases) in the infected cells. The observed apoptosis required viral gene expression and the action of the caspase 8 pathway. Although virus infection activated PI3 kinase, as indicated by AKT activation, its blockage did not inhibit JNK activation or IRF-3 activation. The action of neither the Jak-STAT pathway nor the NF-kappaB pathway was required for apoptosis. In contrast, IRF-3 activation was essential, although induction of the proapototic protein TRAIL by IRF-3 was not required. When IRF-3 was absent or its activation by the RIG-I pathway was blocked, SeV established persistent infection, as documented by viral protein production and infectious virus production. Introduction of IRF-3 in the persistently infected cells restored the cells' ability to undergo apoptosis. These results demonstrated that in our model system, IRF-3 controlled the fate of the SeV-infected cells by promoting apoptosis and preventing persistence.
Peters
Kristi
K
Department of Molecular Genetics, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA.
Chattopadhyay
Saurabh
S
Sen
Ganes C
GC
D017209:Apoptosis; D053181:Caspase 8 / Q000378:metabolism; D002460:Cell Line; D020868:Gene Silencing; D006801:Humans; D050838:Interferon Regulatory Factor-3 / Q000235:genetics / Q000378:metabolism*; D051058:Oncogene Protein v-akt / Q000378:metabolism; D010224:Parainfluenza Virus 3, Human / Q000276:immunology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010253:Respirovirus Infections / Q000276:immunology*; D029082:Sendai virus / Q000276:immunology*
D050838:Interferon Regulatory Factor-3; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051058:Oncogene Protein v-akt; D053181:Caspase 8