Bcl6 Sets a Threshold for Antiviral Signaling by Restraining IRF7 Transcriptional Program

Abstract

The coordination of restraining and priming of antiviral signaling constitute a fundamental aspect of immunological functions. However, we currently know little about the molecular events that can translate the pathogenic cues into the appropriate code for antiviral defense. Our present study reports a specific role of B cell lymphoma (Bcl)6 as a checkpoint in the initiation of the host response to cytosolic RNA viruses. Remarkably, Bcl6 specifically binds to the interferon-regulatory factor (IRF)7 loci and restrains its transcription, thereby functioning as a negative regulator for interferon (IFN)-β production and antiviral responses. The signal-controlled turnover of the Bcl6, most likely mediated by microRNA-127, coordinates the antiviral response and inflammatory sequelae. Accordingly, de-repression of Bcl6 resulted in a phenotypic conversion of macrophages into highly potent IFN-producing cells and rendered mice more resistant to pathogenic RNA virus infection. The failure to remove the Bcl6 regulator, however, impedes the antiviral signaling and exaggerates viral pneumonia in mice. We thus reveal a novel key molecular checkpoint to orchestrate antiviral innate immunity.

BCL6 modulates tissue neutrophil survival and exacerbates pulmonary inflammation following influenza virus infection

“…During viral infection, interferons (IFNs) are suggested to limit viral replication and promote an antiviral state for the host in the days early post-IAV infection (19). A recent report has suggested that BCL6 inhibition in macrophages could lead to enhanced type I IFN production on vesicular stomatitis virus infection (16). We evaluated IFN-α and IFN-λ levels in the lungs and bronchoalveolar lavage (BAL) fluid at 1 and 2 d postinfection (dpi).…”

“…Beyond its role in T cell and B cell responses (13), BCL6 has also been recognized as an antagonist for NF-κB-mediated gene transcription to repress the production of certain proinflammatory mediators in macrophages (14,15). A recent report has suggested that BCL6 expression in macrophages may repress the antiviral type I IFN production through its inhibition in IFN-regulatory factor 7 (Irf7) expression (16). However, the physiological function of BCL6 in regulating antiviral innate immune responses is currently unknown, since BCL6 germ line-deficient mice exhibit severe inflammation and autoimmunity (17).…”

Host Transcription Profile in Nasal Epithelium and Whole Blood of Hospitalized Children Under 2 Years of Age With Respiratory Syncytial Virus Infection

“…More importantly, it has been suggested that the short-lived, protective, neutralizing antibody response after RSV infection is due to an impaired development of Tfh cells, which are required for plasmablast generation and subsequent antibody formation [ 46 ]. B cell lymphoma 6 overexpression has recently been shown for the first time to promote inflammatory responses, but it inhibits antiviral signaling through repressing the IRF7 promoter activity [ 47 ]. The down-regulation of the ORM1 gene in the severe NP network suggests a possible correlation between severe RSV infection and uncontrolled inflammatory cytokine production.…”

BCL6 represses antiviral resistance in follicular T helper cells

“…We found that RI-BPI, a peptide inhibitor that can disrupt the association of the BCL6 BTB domain with its corepressors, was able to up-regulate Tfh ISG expression, suggesting the BCL6 BTB domain is critically important in suppressing ISG expression in Tfh cells. A recent report has also suggested that inhibition of the BCL6 BTB domain could boost type I IFN expression in myeloid cells [47]. Thus, the inhibition of the BCL6 BTB domain function may offer a unique opportunity to boost both type I IFN production and sensitivity to type I IFNs in IFN-responding cells.…”