Interferon regulatory factor 2 protects mice from lethal viral neuroinvasion

Li, Melody M. H.; Bozzacco, Leonia; Hoffmann, Hans-Heinrich; Breton, Gaëlle; Loschko, Jakob; Xiao, Jing; Monette, Sébastien; Rice, Charles M.; MacDonald, Margaret R.

doi:10.1084/jem.20160303

Cited by 16 publications

(13 citation statements)

References 63 publications

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“…During SINV infection, the interferon responsive factor 2 (IRF2) was shown to contribute to the B cell response as IRF2 knockout mice succumbed to peripheral SINV infection, but not when WT B cells were adoptively transferred prior to infection. Surprisingly, SINV‐specific IgG antibodies at Day 7 post infection were diminished in the brain, but not the serum of IRF2 KO mice while SINV‐specific IgM antibodies remained unchanged 102 …”

Section: Arthropod and Zoonotic Neurotropic Rna Virusesmentioning

confidence: 94%

“…Surprisingly, SINVspecific IgG antibodies at Day 7 post infection were diminished in the brain, but not the serum of IRF2 KO mice while SINV-specific IgM antibodies remained unchanged. 102 Interestingly, while SINV-specific IgA ASCs were observed in the brain by Day 30 post infection, they were not found in the cLNs or spleen. While this observation may be explained by local differentiation within the CNS itself, there was no evidence of local ectopic follicle formation or GC formation.…”

Section: Similar To Mhv Infection T and B Cell Activation And Expansionmentioning

confidence: 94%

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B cells going viral in theCNS: Dynamics, complexities, and functions of B cells responding to viral encephalitis

Cardani‐Boulton

Boylan

Stetsenko

et al. 2022

Immunological Reviews

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Summary A diverse number of DNA and RNA viruses have the potential to invade the central nervous system (CNS), causing inflammation and injury to cells that have a limited capacity for repair and regeneration. While rare, viral encephalitis in humans is often fatal and survivors commonly suffer from permanent neurological sequelae including seizures. Established treatment options are extremely limited, predominantly relying on vaccines, antivirals, or supportive care. Many viral CNS infections are characterized by the presence of antiviral antibodies in the cerebral spinal fluid (CSF), indicating local maintenance of protective antibody secreting cells. However, the mechanisms maintaining these humoral responses are poorly characterized. Furthermore, while both viral and autoimmune encephalitis are associated with the recruitment of diverse B cell subsets to the CNS, their protective and pathogenic roles aside from antibody production are just beginning to be understood. This review will focus on the relevance of B cell responses to viral CNS infections, with an emphasis on the importance of intrathecal immunity and the potential contribution to autoimmunity. Specifically, it will summarize the newest data characterizing B cell activation, differentiation, migration, and localization in clinical samples as well as experimental models of acute and persistent viral encephalitis.

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Section: Arthropod and Zoonotic Neurotropic Rna Virusesmentioning

confidence: 94%

Section: Similar To Mhv Infection T and B Cell Activation And Expansionmentioning

confidence: 94%

B cells going viral in theCNS: Dynamics, complexities, and functions of B cells responding to viral encephalitis

Cardani‐Boulton

Boylan

Stetsenko

et al. 2022

Immunological Reviews

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“…is an interferon-stimulated gene (90,91), which may imply that this high stress centrality reflects a specific role for these factors in the interferon response. RUNX1 has high stress centrality, though is not as well connected as nodes such as MYC or MAZ ( Figure 4D).…”

Section: Runx1 Is a Highly Central And Essential Node Of The Mll-af4 mentioning

confidence: 99%

Phenotypic analysis of an MLL-AF4 gene regulatory network reveals indirect CASP9 repression as a mode of inducing apoptosis resistance

Harman

Thorne

Jamilly

et al. 2020

Preprint

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ABSTRACTRegulatory interactions mediated by transcription factors (TFs) make up complex networks that control cellular behavior. Fully understanding these gene regulatory networks (GRNs) offers greater insight into the consequences of disease-causing perturbations than studying single TF binding events in isolation. Chromosomal translocations of the Mixed Lineage Leukemia gene (MLL) produce MLL fusion proteins such as MLL-AF4, causing poor prognosis acute lymphoblastic leukemias (ALLs). MLL-AF4 is thought to drive leukemogenesis by directly binding to genes and inducing aberrant overexpression of key gene targets, including anti-apoptotic factors such as BCL-2. However, this model minimizes the potential for circuit generated regulatory outputs, including gene repression. To better understand the MLL-AF4 driven regulatory landscape, we integrated ChIP-seq, patient RNA-seq and CRISPR essentiality screens to generate a model GRN. This GRN identified several key transcription factors, including RUNX1, that regulate target genes using feed-forward loop and cascade motifs. We used CRISPR screening in the presence of the BCL-2 inhibitor venetoclax to identify functional impacts on apoptosis. This identified an MLL-AF4:RUNX1 cascade that represses CASP9, perturbation of which disrupts venetoclax induced apoptosis. This illustrates how our GRN can be used to better understand potential mechanisms of drug resistance acquisition.Graphical abstract captionA network model of the MLL-AF4 regulatory landscape identifies feed-forward loop and cascade motifs. Functional screening using CRISPR and venetoclax identified an MLL-AF4:RUNX1:CASP9 repressive cascade that impairs drug-induced cell death.

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“…Overexpression of ISG15 in Ifnar− / −, Isg15− / − , or CD1 mice infected with SINV reduces mortality and decreases SINV replication without affecting viral dissemination by promoting protein conjugation between ISG15 and UbE1L (Giannakopoulos et al 2009 ; Lenschow et al 2005 , 2007 ; Zhang et al 2007 ). Peripheral infection of Irf2− / − mice with the neurovirulent but non-neuroinvasive SVN strain of SINV leads to viral replication in the brain, clinical encephalitis, and death, indicating that IRF2, an ISG that negatively regulates IFN signaling, protects mice from neuroinvasion through promotion of immune cell development (Li et al 2016 ). Mice deficient in zinc antiviral protein (ZAP), a type I IFN-induced antiviral protein that binds viral mRNAs and inhibits virus replication, and deficient in the related but type I IFN-independent TIPARP have increased mortality compared to WT mice following SINV infection (Kozaki et al 2015 , 2017 ; Wang et al 2016 ).…”

Section: Effect Of Host Genetics On Experimental Alphavirus Infectionmentioning

confidence: 99%

Genetic control of alphavirus pathogenesis

Baxter

Heise

2018

Mamm Genome

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Alphaviruses, members of the positive-sense, single-stranded RNA virus family Togaviridae, represent a re-emerging public health concern worldwide as mosquito vectors expand into new geographic ranges. Members of the alphavirus genus tend to induce clinical disease characterized by rash, arthralgia, and arthritis (chikungunya virus, Ross River virus, and Semliki Forest virus) or encephalomyelitis (eastern equine encephalitis virus, western equine encephalitis virus, and Venezuelan equine encephalitis virus), though some patients who recover from the initial acute illness may develop long-term sequelae, regardless of the specific infecting virus. Studies examining the natural disease course in humans and experimental infection in cell culture and animal models reveal that host genetics play a major role in influencing susceptibility to infection and severity of clinical disease. Genome-wide genetic screens, including loss of function screens, microarrays, RNA-sequencing, and candidate gene studies, have further elucidated the role host genetics play in the response to virus infection, with the immune response being found in particular to majorly influence the outcome. This review describes the current knowledge of the mechanisms by which host genetic factors influence alphavirus pathogenesis and discusses emerging technologies that are poised to increase our understanding of the complex interplay between viral and host genetics on disease susceptibility and clinical outcome.

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Interferon regulatory factor 2 protects mice from lethal viral neuroinvasion

Abstract: Li et al. describe a novel role for IRF2, previously known as a negative regulator of type I IFN signaling, in protection of mice from lethal viral neuroinvasion by facilitating the proper localization of B cells and antibodies to the central nervous system.

Cited by 16 publications

References 63 publications

B cells going viral in theCNS: Dynamics, complexities, and functions of B cells responding to viral encephalitis

B cells going viral in theCNS: Dynamics, complexities, and functions of B cells responding to viral encephalitis

Phenotypic analysis of an MLL-AF4 gene regulatory network reveals indirect CASP9 repression as a mode of inducing apoptosis resistance

Genetic control of alphavirus pathogenesis

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