Virus Infection Switches TLR-3-Positive Human Neurons To Become Strong Producers of Beta Interferon

Préhaud, Christophe; Mégret, Françoise; Lafage, Mireille; Lafon, Monique

doi:10.1128/jvi.79.20.12893-12904.2005

Cited by 316 publications

(294 citation statements)

References 77 publications

Supporting

Mentioning

270

Contrasting

Unclassified

Order By: Relevance

“…These receptors have been shown to initiate antiviral programs and activate innate immune responses in the CNS (35,44). Recently, human neuron-like NT2 cells were shown to also express TLR3 and to respond to poly(I:C) stimulation by producing IFN-␤ (38). Interestingly, we found that protection against CMV infection after poly(I:C) treatment was greater than that conferred by treatment with IFN-␣ in human astrocytes and primary brain cultures, indicating the efficiency of this signaling pathway in inducing an antiviral response in cells of the CNS.…”

Section: Discussionmentioning

confidence: 99%

Cytomegalovirus InducesInterferon-Stimulated Gene Expression and Is Attenuated by Interferon in the DevelopingBrain

Pol¹,

Robek

Ghosh³

et al. 2007

J Virol

View full text Add to dashboard Cite

Cytomegalovirus (CMV) is considered the most common infectious agent causing permanent neurological dysfunction in the developing brain. We have previously shown that CMV infects developing brain cells more easily than it infects mature brain cells and that this preference is independent of the host B-and T-cell responses. In the present study, we examined the innate antiviral defenses against mouse (m) and human ( Cytomegalovirus (CMV), a double-stranded DNA virus of the betaherpesvirus family, is considered the most common infectious agent that causes permanent neurological dysfunction of the developing brain (2, 62). Human CMV (hCMV) infections in the developing brain can lead to mental retardation, epilepsy, microcephaly, microgyria, hydrocephalus, and deafness (4, 21, 37). The developing brain is particularly sensitive to CMV infection (6,29,54,55,58) due to both the immature state of the systemic immune system and a preference of CMV for developing glia and neurons (61). CMV in the mature brain is less of a concern, except in immunocompromised individuals (22,23,32).Outside the brain, interferon (IFN) has been reported to limit some CMV infections (27,30,66). A number of reports have suggested that brain cells differ from cells of other organs relative to innate and systemic antiviral immune responses. The brain has some characteristics of an immunologically privileged region. For instance, although most cells outside the brain express major histocompatibility complex (MHC) class I molecules, neurons in the brain either do not express MHC class I or do so at a substantially reduced level (45). This may be beneficial due to the fact that neurons do not replicate, and so a vigorous attack by the immune system on virally infected postmitotic neurons may cause more problems than the virus itself. In the brain, functional receptors for IFN-␥ are expressed in all cells, but they are expressed at different levels, and actions of IFN-␣/␤ on microglia, astrocytes, and neurons have also been described (12,13,31,43). Most cells, including astrocytes and microglia, are able to produce IFN-␣/␤ as an initial nonspecific immune response against virus infection (52, 64); IFN-␥ is released by activated T lymphocytes as part of the specific immune response. The intrinsic IFN system provides the first line of defense against viral infections, including systemic CMV infections, and can delay viral replication allowing the activation of the systemic adaptive immune responses.One explanation for the increased pathogenesis in the developing brain compared to that in the mature brain is that the systemic immune system is too immature during development to fight CMV infection. T and B lymphocytes of the adaptive immune system, as well as other cells of the systemic immune system, including natural killer cells and macrophages/monocytes, are involved in combating CMV infections (2,5,8,9,10,20,46,49), and the efficacies of these systems increase with development. Another mechanism that might underlie the susceptibility of developing...

show abstract

Section: Discussionmentioning

confidence: 99%

Cytomegalovirus InducesInterferon-Stimulated Gene Expression and Is Attenuated by Interferon in the DevelopingBrain

Pol¹,

Robek

Ghosh³

et al. 2007

J Virol

View full text Add to dashboard Cite

show abstract

“…Microglia [16] Astrocytes [10,110] Neurons [112] Astrocytes [111] Microglia [15] Neurons [12] Astrocytes [58] Neurons [112] Neurons [12] TLR4 Microglia [16] Astrocytes [16,110] Microglia [15] Astrocytes [11,111] Neurons [12] Astrocytes [58] Neurons [12,13] …”

Section: Tlr3mentioning

confidence: 99%

Evaluating the role of Toll-like receptors in diseases of the central nervous system

Carty

Bowie

2011

Biochemical Pharmacology

134

View full text Add to dashboard Cite

A key part of the innate immune system is a network of pattern recognition receptors (PRRs) and their associated intracellular signalling pathways. Toll-like receptors (TLRs) are one such group of PRRs that detect pathogen associated molecular patterns (PAMPs). Activation of the TLRs with their respective agonists results in the activation of intracellular signalling pathways leading to the expression of proinflammatory mediators and anti-microbial effector molecules. Activation of the innate immune system through TLRs also triggers the adaptive immune response, resulting in a comprehensive immune program to eradicate invading pathogens. It is now known that immune surveillance and inflammatory responses occur in the central nervous system (CNS). Furthermore it is becoming increasingly clear that TLRs have a role in such CNS responses andare also implicated in the pathogenesis of a number of conditions in the CNS, such as Alzheimer's, stroke and multiple sclerosis. This is likely due to the generation of endogenous TLR agonists in these conditions which amplifies a detrimental neurotoxic inflammatory response. However TLRs in some situations can be neuroprotective, if triggered in a favourable context. This review aims to examine the recent literature on TLRs in the CNS thus demonstrating their importance in a range of infectious and non-infectious diseases of the brain.

show abstract

“…Induction of Type 1 IFN gene expression is an essential component of innate immunity (22,23). Recent studies (24) have also shown that neurons produce high levels of IFN-␤ through TLR 3 signaling.…”

mentioning

confidence: 99%

IFN-β Provides Immuno-Protection in the Retina by Inhibiting ICAM-1 and CXCL9 in Retinal Pigment Epithelial Cells

Hooks

Nagineni

Hooper

et al. 2008

The Journal of Immunology

View full text Add to dashboard Cite

The retinal pigment epithelial (RPE) cell is a potent regulatory cell that facilitates normal physiologic processes and plays a critical role in a variety of retinal diseases. We evaluated IFN-β production in human RPE cells through TLR signaling and investigated the effects of IFN-β on RPE cells. RPE cells treated with poly(I:C) or infected with an RNA virus produce IFN-β. Kinetic studies revealed that IFN-β levels continue to increase over a 48-h period and this was associated with the up-regulation of IRF-7 gene expression, a known positive feedback molecule for IFN-β production. Microarray analysis revealed that in IFN-β treated cells, 480 genes of 22,283 genes were up or down-regulated by >2-fold. We hypothesize that IFN-β induction during TLR signaling in the retina is an immunosuppressive factor produced to limit immunopathologic damage. Cytokine activation of RPE cells results in the production of the chemokines, CXCL9 and CXCL10, and the adhesion molecule, ICAM-1. Pretreatment of RPE cells with IFN-β resulted in inhibition of ICAM-1 production and elimination of CXCL9 production. This treatment did not alter CXCL10 production. Anti-IFN-β Ab blocked the inhibitory action of IFN-β. Real time PCR analysis revealed that IFN-β treatment inhibited gene expression of sICAM-1 and CXCL9. The results indicate a critical role for RPE cell derived IFN-β in the down-regulation of CXCL9 and ICAM-1 expression in the retina and suggest that the inhibition of CXCL9 is an immuno-suppressive mechanism that protects the retina from excessive inflammation.

show abstract

Virus Infection Switches TLR-3-Positive Human Neurons To Become Strong Producers of Beta Interferon

Cited by 316 publications

References 77 publications

Cytomegalovirus InducesInterferon-Stimulated Gene Expression and Is Attenuated by Interferon in the DevelopingBrain

Cytomegalovirus InducesInterferon-Stimulated Gene Expression and Is Attenuated by Interferon in the DevelopingBrain

Evaluating the role of Toll-like receptors in diseases of the central nervous system

IFN-β Provides Immuno-Protection in the Retina by Inhibiting ICAM-1 and CXCL9 in Retinal Pigment Epithelial Cells

Contact Info

Product

Resources

About