Hematopoietic cell–derived interferon controls viral replication and virus-induced disease

Abstract

Type I interferon (IFN-I) strongly inhibits viral replication and is a crucial factor in control- IntroductionInterferon is a polypeptide which has strong antiviral capacity. [1][2][3] Mice lacking the type I interferon (IFN-I) receptor are unable to limit widespread dissemination of several mouse pathogenic viruses, 4 which highlights the antiviral activity in vivo. Interferons are produced by a wide variety of cell types that are capable of responding to specific microbial elements (eg, double-and single-stranded RNA or DNA of viral origin) via pattern recognition receptors (PRRs). Some PRRs are widely expressed, whereas others are limited to specific cell populations. For instance, RIG-I, 5,6 TLR3, 7-9 and TLR9 10-13 induce IFN-I in a wide variety of hematopoietic and nonhematopoietic cell types as diverse as macrophages, fibroblasts, 14,15 endothelial cells, hepatocytes, 16-18 microglia, and even neurons. 19 In contrast, interferon-inducing Toll-like receptor 7 (TLR7) has only been reported on murine bone marrow (BM)-derived plasmacytoid dendritic cells. 20,21 Two main pathways have been characterized to induce IFN-I production: one through cytoplasmic PRRs, mainly the helicases RIG-I or MDA-5, 5 and the second through transmembrane PRRs, namely TLR3, TLR4, TLR7, and TLR9. [22][23][24][25] After virus recognition by the cytosolic PRRs or TLRs, Tank-binding kinase 1 (TBK1) is activated and induces phosphorylation of the transcription factors IRF3 and IRF7, which form homo-and heterodimers, and migrate into the nucleus. 26,27 IRF3 homodimers induce IFN-␤ production, but are not essential. In contrast, IRF7 (homo-and heterodimers with IRF3) is essential for the production of IFN-␣ via both cytosolic and transmembrane PRR pathways. 23 While irf3 Ϫ/Ϫ mice are still able to produce IFN-I, mice deficient in IRF7 are severely impaired in the production of IFN-I. Therefore, IRF7 has been assigned the master regulator of interferon. 28,29 Although many nonimmune cells possess the molecular elements that may allow them to produce IFN-I, the extent to which they participate in an effective IFN-I response during viral infection is not clear. In this report, we analyzed the contribution of hematopoietic versus nonhematopoietic cells in the production of IFN-I. As expression of IRF7 is essential for production of IFN-I, we used BM chimeras generated from irf7 Ϫ/Ϫ and wild-type (WT) mice. We found that during systemic viral infections, IFN-I from a BM-derived source was essential for the control of virus replication and inhibition of viral spread to peripheral organs. In addition, hematopoietic cell-derived IFN-I controlled disease onset and the extent of pathology. For personal use only. on April 11, 2019. by guest www.bloodjournal.org From cells at a multiplicity of infection (MOI) of 0.01 and plaqued on Vero cells. Lymphocytic choriomeningitis virus (LCMV) strain WE was originally obtained from F. Lehmann-Grube (Heinrich Pette Institute, Hamburg, Germany) and was propagated in L929 cells. Virus titers were measured usin...

Differential Impact of Interferon Regulatory Factor 7 in Initiation of the Type I Interferon Response in the Lymphocytic Choriomeningitis Virus-Infected Central Nervous System versus the Periphery

“…The above-mentioned findings clearly do not conform to recent observations pointing to an absolutely pivotal role of the IRF7 signaling pathway regarding the type I IFN response in the blood of mice systemically infected with LCMV (32). This could indicate that signaling pathways different from those relevant in the periphery were involved in transmitting the sensing of LCMV in the CNS.…”

“…The above-mentioned results could indicate that activation of either IRF3 or IRF7 individually would suffice for the induction of a nearly complete type I IFN response in the LCMV-infected CNS. In contrast, IRF7 is believed to represent the master regulator of the type I IFN transcriptional response in mice undergoing systemic viral infection (20,32). In order to ascertain that the observed tissue-related difference in the regulation of the type I IFN response is real, the following experiments were conducted.…”

Reactive oxygen species delay control of lymphocytic choriomeningitis virus

“…Tetramer production, surface and intracellular flow cytometry measurement (FCM) staining was performed as described previously. 55 Briefly, single-cell suspensions from spleen and liver tissues, and peripheral blood lymphocytes were stained using PE-labeled gp33 major histocompability complex (MHC) class I tetramers (gp33/H-2D b ) for 15 min at 37 1C, followed by staining with anti-CD8-PerCP (BD Biosciences, San Jose, CA, USA) for 30 min at 4 1C. For determination of their activation status, lymphocytes were stained with anti-PD-1 and anti-IL-7Ra (BD Biosciences) for 30 min at 4 1C.…”

Type I Interferon Limits the Capacity of Bluetongue Virus To Infect Hematopoietic Precursors and Dendritic Cells In Vitro and In Vivo

“…Infection of mice with reovirus T1L, another member of the Reoviridae family, led to fatal disease when BM cells were not able to respond to the IFN-I they produced (20). Similarly, IFN-I secreted by HSCs seems to be essential to control systemic viral infections such as those by mouse hepatitis virus (MHV) or vesicular stomatitis virus (VSV) (31).…”

“…Infection of HSCs is one of the strategies used by viruses to disrupt the hema-topoiesis as a means to cause immunosuppression (30). Furthermore, during systemic viral infections, IFN-I from HSCs has been proved to be essential for the control of viral replication and dissemination to different organs (31 …”