Role of Interferon Regulatory Factor 3-Mediated Apoptosis in the Establishment and Maintenance of Persistent Infection by Sendai Virus

Abstract

Infection of cultured cells by paramyxoviruses causes cell death, mediated by a newly discovered apoptotic pathway activated by virus infection. The key proapoptotic protein in this pathway is interferon regulatory factor 3 (IRF-3), which upon activation by virus infection binds BAX, translocates it to mitochondria, and triggers apoptosis. When IRF-3-knockdown cells were infected with Sendai virus (SeV), persistent infection (PI) was established. The PI cells produced infectious SeV continuously and constitutively expressed many innate immune genes. Interferon signaling was blocked in these cells. The elevated levels of IRF-3-driven genes in the PI cells indicated that the amount of residual IRF-3 activated by endogenous SeV was high enough to drive the transcriptional effects of IRF-3 but too low to trigger its apoptotic activity. We confirmed this IRF-3 threshold idea by generating a tetracycline (Tet)-inducible cell line for IRF-3 expression, which enabled us to express various levels of IRF-3. PI could be established in the Tet-off cell line, and as expected, when doxycycline was withdrawn, the cells underwent apoptosis. Finally, we tested for PI establishment in 12 mouse embryo fibroblasts by natural selection. Eleven lines became persistently infected; although seven out of them had low IRF-3 levels, four did not. When one of the latter four was further analyzed, we observed that it expressed a very low level of caspase 3, the final executor protease of the apoptotic pathway. These results demonstrated that SeV PI can arise from infection of normal wild-type cells, but only if they can find a way to impair the IRF-3-dependent apoptotic pathway.

Transfected Poly(I:C) Activates Different dsRNA Receptors, Leading to Apoptosis or Immunoadjuvant Response in Androgen-independent Prostate Cancer Cells

“…Besides its key role in antiviral immunity, IRF3 activation by virus infection is essential for triggering a direct apoptotic response, as manifested by the fact that infected cells are not killed in the absence of IRF3 and become persistently infected (53)(54)(55). In agreement, we have recently demonstrated that IRF3 mediates apoptosis in response to dsRNA in androgensensitive PCa cells (56) as well as, as previously observed, in melanoma and fibrosarcoma cells (57).…”

Lymphocytic Choriomeningitis Virus Differentially Affects the Virus-Induced Type I Interferon Response and Mitochondrial Apoptosis Mediated by RIG-I/MAVS

“…The ability of LCMV to block RIG-I/MAVS-mediated induction of IFN-I but not apoptosis seemed contradictory to recent studies by Chattopadhyay and colleagues that revealed a lower activation threshold of IRF3 for the IFN-I response than for apoptosis (51). To address this apparent contradiction, we evaluated the role of RIG-I and MAVS in virus-induced apoptosis in LCMV-pi cells.…”

Response of Mammalian Macrophages to Challenge with the Chlorovirus Acanthocystisturfacea Chlorella Virus 1

“…RAW264.7 cells challenged with infectious ATCV-1 exhibited a cytopathic effect and/or died by 72 h. Virus-activated apoptosis is a key antiviral mechanism that limits viral replication (19) but could also contribute to viral persistence through macrophage phagocytosis of apoptotic virus-infected cells (20). Cleavage of caspase 3 (21) and binding of annexin V to phosphatidylserine at the cell membrane (22) are hallmarks of apoptotic cell death.…”