HSV-1-induced activation of NF-κB protects U937 monocytic cells against both virus replication and apoptosis

Abstract

The transcription factor nuclear factor-kappa B (NF-κB) is a crucial player of the antiviral innate response. Intriguingly, however, NF-κB activation is assumed to favour herpes simplex virus (HSV) infection rather than restrict it. Apoptosis, a form of innate response to viruses, is completely inhibited by HSV in fully permissive cells, but not in cells incapable to fully sustain HSV replication, such as immunocompetent cells. To resolve the intricate interplay among NF-κB signalling, apoptosis and permissiveness to HSV-1 in monocytic cells, we utilized U937 monocytic cells in which NF-κB activation was inhibited by expressing a dominant-negative IκBα. Surprisingly, viral production was increased in monocytic cells in which NF-κB was inhibited. Moreover, inhibition of NF-κB led to increased apoptosis following HSV-1 infection, associated with lysosomal membrane permeabilization. High expression of late viral proteins and induction of apoptosis occurred in distinct cells. Transcriptional analysis of known innate response genes by real-time quantitative reverse transcription-PCR excluded a contribution of the assayed genes to the observed phenomena. Thus, in monocytic cells NF-κB activation simultaneously serves as an innate process to restrict viral replication as well as a mechanism to limit the damage of an excessive apoptotic response to HSV-1 infection. This finding may clarify mechanisms controlling HSV-1 infection in monocytic cells.

A DNA-sensing–independent role of a nuclear RNA helicase, DHX9, in stimulation of NF-κB–mediated innate immunity against DNA virus infection

“…For instance, loss of NF-κB p50 in mice causes an inability to efficiently control MHV-68 infection, thereby leading to persistent virus replication in the lungs and high levels of latently infected B cells in the spleen ( 38 ). NF-κB activation in monocytes plays a key role in the inhibition of HSV-1 replication ( 39 ). Besides, NF-κB inhibitors abrogated the expression of antiviral genes in response to HSV-2 infection in human cervical epithelial cells ( 40 ).…”

Epstein‐Barr virus LMP2A utilizes Syk and PI3K to activate NF‐κB in B‐cell lymphomas to increase MIP‐1α production

“…Data show that the LMP2A‐mediated increase is abolished in the presence of the NF‐κB inhibitor (Figure A), suggesting that LMP2A ultimately activates NF‐κB in human B‐cell lines to enhance MIP‐1α production. NF‐κB is a transcription factor that binds to the MIP‐1α promoter to increase MIP‐1α by increasing MIP‐1α RNA levels . If LMP2A uses NF‐κB to increase MIP‐1α levels by increasing MIP‐1α transcription, we would hypothesize that LMP2A‐positive cells would express higher levels of MIP‐1α RNA.…”

“…NF-κB is a transcription factor that binds to the MIP-1α promoter 43 to increase MIP-1α by increasing MIP-1α RNA levels. [44][45][46] If LMP2A uses NF-κB to increase MIP-1α levels by increasing MIP-1α transcription, we would hypothesize that LMP2A-positive cells would express higher levels of MIP-1α RNA. As shown in Figure 3B, LMP2Aexpressing cells produce more MIP-1α transcripts than LMP2Anegative cells.…”

A Systems Approach to Study Immuno- and Neuro-Modulatory Properties of Antiviral Agents

“…In addition, the approach can use other immune stimuli, including ZIKV, CHIKV, HSV-1, and HIV-1, which infect human monocytes as well as other cell types, which represent natural targets for different viruses [ 47 , 48 , 49 , 50 ]. For example, we showed recently that SaliPhe, obatoclax, and gemcitabine affected transcription, translation and posttranslational modifications of cellular factors as well as metabolic pathways in ZIKV-infected human RPE cells [ 22 ].…”