<i>Ifit2</i>
            Deficiency Results in Uncontrolled Neurotropic Coronavirus Replication and Enhanced Encephalitis via Impaired Alpha/Beta Interferon Induction in Macrophages

Butchi, Niranjan B.; Hinton, David R.; Stohlman, Stephen A.; Kapil, Parul; Fensterl, Volker; Sen, Ganes C.; Bergmann, Cornelia C.

doi:10.1128/jvi.02272-13

Cited by 51 publications

(87 citation statements)

References 66 publications

(128 reference statements)

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“…Rather, the spread of RABV through the brains of Ifit2 Ϫ/Ϫ mice occurred in an accelerated but otherwise unchanged fashion. These results are comparable to those of prior studies of WNV and VSV, where Ifit2 knockout resulted in the faster spread of the virus from peripheral tissue to the CNS (25,27).…”

Section: Discussionsupporting

confidence: 87%

“…Ifit1 is an in vivo restriction factor for the positive-stranded RNA viruses WNV (22) and Japanese encephalitis virus (JEV) (23) but not the negative-stranded influenza virus (IAV) (24), La Crosse encephalitis virus, Oropouche virus, or Ebola virus. Ifit2 is also a restriction factor for WNV (25), as well as for several negative-stranded RNA viruses: Sendai virus (26), MHV (27), and the rhabdovirus vesicular stomatitis virus (VSV) (28,29).…”

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confidence: 99%

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Ifit2 Is a Restriction Factor in Rabies Virus Pathogenicity

Davis

Fensterl

Lawrence

et al. 2017

J Virol

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Understanding the interactions between rabies virus (RABV) and individual host cell proteins is critical for the development of targeted therapies. Here we report that interferon-induced protein with tetratricopeptide repeats 2 (Ifit2), an interferon-stimulated gene (ISG) with possible RNA-binding capacity, is an important restriction factor for rabies virus. When Ifit2 was depleted, RABV grew more quickly in mouse neuroblastoma cells This effect was replicated, where Ifit2 knockout mice displayed a dramatically more severe disease phenotype than wild-type mice after intranasal inoculation of RABV. This increase in pathogenicity correlated to an increase in RABV mRNA and live viral load in the brain, as well as to an accelerated spread to brain regions normally affected by this RABV model. These results suggest that Ifit2 exerts its antiviral effect mainly at the level of viral replication, as opposed to functioning as a mechanism that restricts viral entry/egress or transports RABV particles through axons. Rabies is a fatal zoonotic disease with a nearly 100% case fatality rate. Although there are effective vaccines for rabies, this disease still takes the lives of about 50,000 people each year. Victims tend to be children living in regions without comprehensive medical infrastructure who present to health care workers too late for postexposure prophylaxis. The protein discussed in our report, Ifit2, is found to be an important restriction factor for rabies virus, acting directly or indirectly against viral replication. A more nuanced understanding of this interaction may reveal a step of a pathway or site at which the system could be exploited for the development of a targeted therapy.

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Section: Discussionsupporting

confidence: 87%

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confidence: 99%

Ifit2 Is a Restriction Factor in Rabies Virus Pathogenicity

Davis

Fensterl

Lawrence

et al. 2017

J Virol

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“…This infiltrate typically contains monocytes, which differentiate into MU or activated microglial phenotypes in the brain, and these have been implicated in several diseases. Thus, inflammatory MU infiltration precedes the onset and peak of disease symptoms in neurotropic coronavirus infection [40]. In lymphocytic choriomeningitis virus (LCMV), monocytes (as well as neutrophils) play a highly pathogenic role [41].…”

Section: Monocyte Infiltration In Cns Pathologiesmentioning

confidence: 99%

The plasticity of inflammatory monocyte responses to the inflamed central nervous system

Ashhurst

Vreden

Niewold

et al. 2014

Cellular Immunology

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Over the last three decades it has become increasingly clear that monocytes, originally thought to have fixed, stereotypic responses to foreign stimuli, mediate exquisitely balanced protective and pathogenic roles in disease and immunity. This balance is crucial in core functional organs, such as the central nervous system (CNS), where minor changes in neuronal microenvironments and the production of immune factors can result in significant disease with fatal consequences or permanent neurological sequelae. Viral encephalitis and multiple sclerosis are examples of important human diseases in which the pathogenic contribution of monocytes recruited from the bone marrow plays a critical role in the clinical expression of disease, as they differentiate into macrophage or dendritic cells in the CNS to carry out effector functions. While antigen-specific lymphocyte populations are central to the adaptive immune response in both cases, in viral encephalitis a prominent macrophage infiltration may mediate immunopathological damage, seizure induction, and death. However, the autoimmune response to non-replicating, non-infectious, but abundant, self antigen has a different disease progression, associated with differentiation of significant numbers of infiltrating monocytes into dendritic cells in the CNS. Whilst a predominant presence of macrophages or dendritic cells in the inflamed CNS in viral encephalitis or multiple sclerosis is well described, the way in which the inflamed CNS mobilizes monocytes in the bone marrow to migrate to the CNS and the key drivers that lead to these specific differentiation pathways in vivo are not well understood. Here we review the current understanding of factors facilitating inflammatory monocyte generation, migration and entry into the brain, as well as their differentiation towards macrophages or dendritic cells in viral and autoimmune disease in relation to their respective disease outcomes.

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“…This interaction inhibits mRNA translation or sequesters viral RNA, respectively, both of which inhibit the viral life cycle (107)(108)(109)(110). Intriguingly, most viruses avoid IFIT1 action; murine Ifit2, however, is quite effective against viruses, strongly protecting against pathogenesis by a number of viruses, such as VSV, WNV, mouse hepatitis virus (MHV), and SeV (94,99,100,111). Several ISG proteins inhibit the entry of enveloped viruses into cells by altering the cell membrane surface, thereby preventing fusion of viral and cellular membranes.…”

Section: Antiviral Actions Of Interferon-induced Proteinsmentioning

confidence: 98%

No Love Lost Between Viruses and Interferons

2015

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The interferon system protects mammals against virus infections. There are several types of interferons, which are characterized by their ability to inhibit virus replication and resultant pathogenesis by triggering both innate and cell-mediated immune responses. Virus infection is sensed by a variety of cellular pattern-recognition receptors and triggers the synthesis of interferons, which are secreted by the infected cells. In uninfected cells, cell surface receptors recognize the secreted interferons and activate intracellular signaling pathways that induce the expression of interferon-stimulated genes; the proteins encoded by these genes inhibit different stages of virus replication. To avoid extinction, almost all viruses have evolved mechanisms to defend themselves against the interferon system. Consequently, a dynamic equilibrium of survival is established between the virus and its host, an equilibrium that can be shifted to the host's favor by the use of exogenous interferon as a therapeutic antiviral agent.

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Ifit2 Deficiency Results in Uncontrolled Neurotropic Coronavirus Replication and Enhanced Encephalitis via Impaired Alpha/Beta Interferon Induction in Macrophages

Cited by 51 publications

References 66 publications

Ifit2 Is a Restriction Factor in Rabies Virus Pathogenicity

Ifit2 Is a Restriction Factor in Rabies Virus Pathogenicity

The plasticity of inflammatory monocyte responses to the inflamed central nervous system

No Love Lost Between Viruses and Interferons

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