Toll like receptors and acute retinal necrosis syndrome- evaluating the association
Department of Biological Sciences, Tata Institute of Fundamental Research, Mumbai, Maharashtra; Institute of Life Sciences, Bhubaneswar, Odisha, India
Dr. S Pathak
Department of Biological Sciences, Tata Institute of Fundamental Research, Mumbai, Maharashtra; Institute of Life Sciences, Bhubaneswar, Odisha
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Pathak S. Toll like receptors and acute retinal necrosis syndrome- evaluating the association.J Postgrad Med 2014;60:237-238
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Pathak S. Toll like receptors and acute retinal necrosis syndrome- evaluating the association. J Postgrad Med [serial online] 2014 [cited 2021 Mar 5 ];60:237-238
Available from: https://www.jpgmonline.com/text.asp?2014/60/3/237/138714
Acute retinal necrosis syndrome is a well-known, potentially devastating, necrotizing vaso-oclusive retinitis affecting both healthy and immunocompromised patients. , It is caused by several members of the herpes virus family, including the herpes simplex virus (HSV)-1, HSV-2, and varicella zoster virus. ,,,
In this issue of the journal, Moses et al.  report the induction of Toll-like receptor 3 (TLR3), TLR4, and TLR9 in the retinal pigment epithelial (ARPE-19) cell line in response to HSV-1 and HSV-2 infection. However, they do not comment upon the possible ligands of these TLRs. Villalba et al. (2012)  have reported the induction of TLR2 and TLR4 by HSV-1 infection in primary astrocytic culture and linked the TLR expression to viral replication as well as induction of endogenous ligands such as serum amyloid A. It is therefore likely that a similar mechanism is involved in increased TLR3, TLR4, and TLR9 expression on retinal pigment epithelial cells and this needs to be investigated further.
TLRs play a key role in the induction of immune and inflammatory responses to pathogens. They recognize conserved products of microbial metabolism, such as LPS, peptidoglycan, dsRNA, etc., and alert the immune system to the entry of pathogens. Activation of TLRs induces the expression of pro-inflammatory cytokines and costimulatory molecules that are crucial to initiation of adaptive responses. TLR3, TLR4, and TLR9 are especially important in antiviral defense, as their engagement by viral products can trigger the production of interferon (IFN)-α, IFN-β, and IFN-λ, which are vital for antiviral immunity  Indeed, TLR3-dependent induction of these three cytokines is critical for primary immunity to HSV-1 in the central nervous system in children  Based on the evidence that TLR3 ligands have been shown to be protective against encephalitis in a mouse model, the authors in their article justifiably argue that TLRs may be responsible for the antiviral response in HSV infections. However, downstream consequences of TLR engagement in vivo remain to be clarified.
TLR-mediated responses may either be beneficial or detrimental in the immunoprivileged central nervous system, depending upon the strength and timing of the activating signal (van Noort and Bsibsi, 2009).  TLRs may play a similar role in the eye, another immunoprivileged site, and may in fact be involved in precipitation of acute retinitis. Recent reports suggest that besides the virus, T cells, macrophages, and cytokines are actively involved in HSV retinitis (Zheng and Atherton, 2005).  Pro-inflammatory cytokines produced in response to the infection-such as TNF-α and IFN-γ-would be especially important in this context. Indeed, TNF-α has been shown to participate in the pathology of HSV-1 retinitis. Local inhibition of TNF-α mRNA by intraocular TNF-α antisense-oligonucleotide injection has been shown to reduce ocular inflammatory bystander damage and to reduce incidence and severity of retinitis in the mouse model (Grajewski et al., 2012).  The report by Moses et al. should thus be an impetus for further research in the role TLRs in pathology versus protection in HSV-retinitis in particular and HSV-CNS infections in general.
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