Intercellular Communication Is Key for Protective IFN<i>α</i>/<i>β</i> Signaling During Viral Central Nervous System Infection

Hwang, Mi-Hyun; Bergmann, Cornelia C.

doi:10.1089/vim.2018.0101

Cited by 10 publications

(13 citation statements)

References 53 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Contrary to the long-held view of the brain as an immune-privileged organ, it is now clear that the brain parenchyma poses an intrinsic antiviral network, in which the antiviral cytokines known as type I interferons (IFNs) play a central role (32, 33). Detje et al were the first to show that the response of neuroectodermal cells (including neurones, astrocytes, and oligodendrocytes) to type I IFNs was essential for the protection of mice against vesicular stomatitis virus (VSV) encephalitis (34).…”

Section: A Brain Intrinsic Antiviral Interferon Network Combats Viralmentioning

confidence: 95%

“…These findings were subsequently reproduced in a model of herpes simplex virus (HSV1) encephalitis (35). All cell types of the central nervous system (CNS) are capable of mounting a type I IFN response, although the relative efficiency of this process appears to vary substantially (33, 36). In VSV models, interferon alpha/beta receptor (IFNAR) signaling within olfactory neurones (37) and astrocytes (38) was necessary to limit viral dissemination throughout the CNS, suggesting that type I IFNs act on viral target cells to control permissiveness and/or onward transmission.…”

Section: A Brain Intrinsic Antiviral Interferon Network Combats Viralmentioning

confidence: 99%

See 1 more Smart Citation

Microglia Are Essential to Protective Antiviral Immunity: Lessons From Mouse Models of Viral Encephalitis

Hatton

Duncan

2019

Front. Immunol.

View full text Add to dashboard Cite

Viral encephalitis is a rare but clinically serious consequence of viral invasion of the brain and insight into its pathogenesis is urgently needed. Important research questions concern the involvement of the host innate immune response in pathogenesis, key to which is the role played by microglia, resident macrophages of the brain parenchyma. Do microglia have a protective function, by coordinating the innate immune response to viral infection, or do they drive pathogenic neuroinflammation? Here we synthesize recent data from mouse models of acute viral encephalitis, which reveal an unambiguously protective role for microglia. Depletion of microglia, via blockade of colony-stimulating factor 1 receptor (CSF1R) signaling, led to increased viral replication accompanied by more severe neurological disease and heightened mortality. Whilst the underlying mechanism(s) remain to be defined, microglial interactions with T cells and phagocytosis of infected neurones appear to play a role. Paradoxically, the production of inflammatory cytokines was increased in several instances following viral infection in microglia-depleted brains, suggesting that: (i) cells other than microglia mediate inflammatory responses and/or (ii) microglia may exert a regulatory function. Under certain circumstances the microglial antiviral response might contribute negatively to longer-term neurological sequelae, although fewer studies have focused on this aspect in encephalitis models. Understanding regulation of the microglial response, and how it contributes to disease is therefore a priority for future studies. Collectively, these findings demonstrate the central role of microglia in pathogenesis, suggesting the exciting possibility that defects of microglial function might contribute to encephalitis susceptibility and/or outcome in humans.

show abstract

Section: A Brain Intrinsic Antiviral Interferon Network Combats Viralmentioning

confidence: 95%

Section: A Brain Intrinsic Antiviral Interferon Network Combats Viralmentioning

confidence: 99%

Microglia Are Essential to Protective Antiviral Immunity: Lessons From Mouse Models of Viral Encephalitis

Hatton

Duncan

2019

Front. Immunol.

View full text Add to dashboard Cite

show abstract

“…Uncontrolled viral replication, extensive viral dissemination throughout the CNS, and expanded tropism to neurons coincided with rapid mortality (18, 19). Early viral replication also induces cytokines and chemokines, some of which are IFNα/β dependent (20). Together, the early response regulates the adaptive immune response essential for reducing viral replication.…”

Section: Type I Ifn: Conductor Of the Early Anti-viral Responsementioning

confidence: 99%

“…While all CNS cell types have been shown to be capable of producing IFNα/β in vitro , the ability to induce IFNα/β in vivo depends on the specific virus, its replication cycle, cellular tropism and respective repertoire of PRRs and associated signaling factors. The disparities between CNS cells in their ability to produce and respond to IFNα/β in vivo have recently been reviewed (20). Our own studies with v2.2-1 revealed that oligodendrocytes (OLG) are poor inducers of IFNα/β relative to microglia consistent with low basal levels and limited diversity of PRRs detecting viral RNAs (24).…”

Section: Type I Ifn: Conductor Of the Early Anti-viral Responsementioning

confidence: 99%

Fine Tuning the Cytokine Storm by IFN and IL-10 Following Neurotropic Coronavirus Encephalomyelitis

Savarin

Bergmann

2018

Front. Immunol.

Self Cite

View full text Add to dashboard Cite

The central nervous system (CNS) is vulnerable to several viral infections including herpes viruses, arboviruses and HIV to name a few. While a rapid and effective immune response is essential to limit viral spread and mortality, this anti-viral response needs to be tightly regulated in order to limit immune mediated tissue damage. This balance between effective virus control with limited pathology is especially important due to the highly specialized functions and limited regenerative capacity of neurons, which can be targets of direct virus cytolysis or bystander damage. CNS infection with the neurotropic strain of mouse hepatitis virus (MHV) induces an acute encephalomyelitis associated with focal areas of demyelination, which is sustained during viral persistence. Both innate and adaptive immune cells work in coordination to control virus replication. While type I interferons are essential to limit virus spread associated with early mortality, perforin, and interferon-γ promote further virus clearance in astrocytes/microglia and oligodendrocytes, respectively. Effective control of virus replication is nonetheless associated with tissue damage, characterized by demyelinating lesions. Interestingly, the anti-inflammatory cytokine IL-10 limits expansion of tissue lesions during chronic infection without affecting viral persistence. Thus, effective coordination of pro- and anti-inflammatory cytokines is essential during MHV induced encephalomyelitis in order to protect the host against viral infection at a limited cost.

show abstract

“…Intercellular communication via cytokine/chemokine signaling drives inflammatory responses during viral infections of the CNS [ 40 , 57 ]. Infection of CNS tissue with WNV in vivo [ 21 , 58 ] and in ex vivo [ 41 ] and in vitro [ 23 ] models of WNV pathogenesis results in increased expression of proinflammatory cytokines and chemokines associated with microglial activation including C-X-C motif chemokine 10 (CXCL10), CXCL1, CCL5, CCL3, CCL2, tumor necrosis factor alpha (TNF-α), TNF-related apoptosis-inducing ligand (TRAIL), and interleukin-6 (IL-6) [ 40 ].…”

Section: Microglia Become Activated During Wnv Infectionmentioning

confidence: 99%

The Role of Microglia during West Nile Virus Infection of the Central Nervous System

2020

View full text Add to dashboard Cite

Encephalitis resulting from viral infections is a major cause of hospitalization and death worldwide. West Nile Virus (WNV) is a substantial health concern as it is one of the leading causes of viral encephalitis in the United States today. WNV infiltrates the central nervous system (CNS), where it directly infects neurons and induces neuronal cell death, in part, via activation of caspase 3-mediated apoptosis. WNV infection also induces neuroinflammation characterized by activation of innate immune cells, including microglia and astrocytes, production of inflammatory cytokines, breakdown of the blood-brain barrier, and infiltration of peripheral leukocytes. Microglia are the resident immune cells of the brain and monitor the CNS for signs of injury or pathogens. Following infection with WNV, microglia exhibit a change in morphology consistent with activation and are associated with increased expression of proinflammatory cytokines. Recent research has focused on deciphering the role of microglia during WNV encephalitis. Microglia play a protective role during infections by limiting viral growth and reducing mortality in mice. However, it also appears that activated microglia are triggered by T cells to mediate synaptic elimination at late times during infection, which may contribute to long-term neurological deficits following a neuroinvasive WNV infection. This review will discuss the important role of microglia in the pathogenesis of a neuroinvasive WNV infection. Knowledge of the precise role of microglia during a WNV infection may lead to a greater ability to treat and manage WNV encephalitis.

show abstract

Intercellular Communication Is Key for Protective IFNα/β Signaling During Viral Central Nervous System Infection

Cited by 10 publications

References 53 publications

Microglia Are Essential to Protective Antiviral Immunity: Lessons From Mouse Models of Viral Encephalitis

Microglia Are Essential to Protective Antiviral Immunity: Lessons From Mouse Models of Viral Encephalitis

Fine Tuning the Cytokine Storm by IFN and IL-10 Following Neurotropic Coronavirus Encephalomyelitis

The Role of Microglia during West Nile Virus Infection of the Central Nervous System

Contact Info

Product

Resources

About