Herpes simplex virus 1 interaction with Toll-like receptor 2 contributes to lethal encephalitis

Abstract

Human neonates infected with herpes simplex virus 1 (HSV-1) develop one of three distinct patterns of infection: (i) infection limited to the skin, eye or mouth; (ii) infection of the CNS; or (iii) disseminated infection. The disseminated form usually involves the liver, adrenal gland, and lung, and resembles the clinical picture of bacterial sepsis. This spectrum of symptoms in HSV-1-infected neonates suggests that inflammatory cytokines play a significant role in the pathogenesis of the disease. Recent studies suggest that the Toll-like receptors (TLRs) may play an important role in the induction of inflammatory cytokines in response to viruses. TLRs are mammalian homologues of Toll, a Drosophila protein that is essential for host defense against infection. Engagement of TLRs by bacterial, viral, or fungal components leads to the production and release of cytokines and other antimicrobial products. Here, we demonstrate that TLR2 mediates the inflammatory cytokine response to HSV-1 by using both transfected cell lines and knockout mice. Studies of infected mice revealed that HSV-1 induced a blunted cytokine response in TLR2 ؊/؊ mice. Brain levels of monocyte chemoattractant protein 1 chemokine were significantly lower in TLR2 ؊/؊ mice than in either wild-type or TLR4 ؊/؊ mice. TLR2 ؊/؊ mice had reduced mortality compared with wild-type mice. The differences between TLR2 ؊/؊ mice and both wild-type and TLR4 ؊/؊ mice in the induction of monocyte chemoattractant protein 1, brain inflammation, or mortality could not be accounted for on the basis of virus levels. Thus, these studies suggest the TLR2-mediated cytokine response to HSV-1 is detrimental to the host.cytokines ͉ viral pathogenesis

The in vitro immunomodulatory activity of a synthetic brassinosteroid analogue would account for the improvement of herpetic stromal keratitis in mice

“…Corneal epithelial cells constitute the first line of defense against the virus and, together with conjunctival cells, are known to release inflammatory cytokines including IL-1␣ and TNF-␣ (probably through TLR signaling and NF-B activation) associated with the pathophysiology of ocular disease [8,15,16]. It is known that regulation of TNF-␣ and IL-1␤ synthesized as a consequence of NF-B activation affects inflammation in the eye [7].…”

“…HSV-1 stimulates toll-like receptor (TLR) 2 resulting in the activation of NF-B, which leads to the synthesis of proinflammatory cytokines, such as TNF-␣, IL-1␤ and IL-6 [7,8]. Triggering of NF-B activation is particularly relevant during HSV-1 infection because the virus harbors several consensusbinding sites for NF-B in their promoters, and this factor is utilized by HSV-1 to enhance its replication [9].…”

p53 Is a Host Cell Regulator during Herpes Simplex Encephalitis

“…Many host cell factors have been reported to regulate HSV-1 replication and/or pathogenicity in the CNS, as determined using experiments performed in genetically modified mice (33)(34)(35)(36)(37)(38)(39)(40)(41)(42)(43)(44)(45)(46)(47). Notably, most of the host cell factors identified were regulators of innate and/or acquired immunity (33)(34)(35)(36)(37)(39)(40)(41)(42)(43)(44)(45)(46)(47).…”

“…Notably, most of the host cell factors identified were regulators of innate and/or acquired immunity (33)(34)(35)(36)(37)(39)(40)(41)(42)(43)(44)(45)(46)(47). For instance, knockout of IPS-1, STING, TRIF, or ZDHHC impaired IFN-I responses in the brain, thereby increasing viral replication (39,42,43).…”

PRRs in pathogen recognition

“…TLR2 is involved in the recognition of measles virus, human cytomegalovirus and HSV-1 [44][45][46]. The fusion (F) protein from respiratory syncytial virus (RSV) is recognized by TLR4.…”