Influence of Perineurial Cells and Toll-Like Receptors 2 and 9 on Herpes simplex Type 1 Entry to the Central Nervous System in Rat Encephalitis

Abstract

Herpes simplex encephalitis (HSE) is a rare disease with high mortality and significant morbidity among survivors. We have previously shown that susceptibility to HSE was host-strain dependent, as severe, lethal HSE developed after injection of human Herpes simplex type 1 virus (HSV-1) into the whiskers area of DA rats, whereas PVG rats remained completely asymptomatic. In the present study we investigated the early immunokinetics in these strains to address the underlying molecular mechanisms for the observed difference. The virus distribution and the immunological responses were compared in the whiskers area, trigeminal ganglia and brain stem after 12 hours and the first four days following infection using immunohistochemistry and qRT-PCR. A conspicuous immunopathological finding was a strain-dependent difference in the spread of the HSV-1 virus to the trigeminal ganglia, only seen in DA rats already from 12 hpi. In the whiskers area infected perineurial cells were abundant in the susceptible DA strain after 2 dpi, whereas in the resistant PVG rats HSV-1 spread was confined only to the epineurium. In both strains activation of Iba1+/ED1+ phagocytic cells followed the distribution pattern of HSV-1 staining, which was visible already at 12 hours after infection. Notably, in PVG rats higher mRNA expression of Toll-like receptors (Tlr) -2 and -9, together with increased staining for Iba1/ED1 was detected in the whiskers area. In contrast, all other Tlr-pathway markers were expressed at higher levels in the susceptible DA rats. Our data demonstrate the novel observation that genetically encoded properties of the host nerve and perineurial cells, recruitment of phagocyting cells together with the low expression of Tlr2 and -9 in the periphery define the susceptibility to HSV-1 entry into the nervous system.

The Calcitonin Receptor Gene Is a Candidate for Regulation of Susceptibility to Herpes simplex Type 1 Neuronal Infection Leading to Encephalitis in Rat

“…While high virus titers were observed in the DA rats, no traces of HSV-1 could be detected in the resistant PVG, nor live virus was retrieved from the trigeminal ganglia or the brain stem using qRT-PCR [10] or immunohistochemistry [11]. These findings support the notion of an underlying genetic difference affecting the ability of HSV-1 to enter the nervous system of PVG rats.…”

“…The procedure of tissue preparation from the whiskers area, trigeminal ganglia and brain stem and qRT-PCR was described in our previous study [11]. The following targets were analyzed: Ccdc132 , Calcr and Tfpi2 .…”

“…The procedure used and antibodies were described in a previous study [11]. In addition mouse anti-calcitonin receptor (1∶100) (Dako, Denmark) was used to stain expression of Calcitonin receptor in the different compartments.…”

Toll-like receptors in health and disease in the brain: mechanisms and therapeutic potential

“…This coincided with a reduction in immune cell infiltrates at the site of infection and increased viral load [147, 149]. Indirect evidence for TLR2 and TLR9 in a rat model of HSV encephalitis was demonstrated by the finding that rat strains which are permissive for viral infection did not display elevations in TLR2 and TLR9 expression, whereas strains resistant to viral infection did [150]. This heightened expression of TLR2 and TLR9 is most likely explained by increased phagocyte recruitment into the CNS, as HSV susceptible rat strains showed delayed phagocytic cell infiltration into sites of infection.…”

Virus-Induced Encephalitis and Innate Immune Responses – A Focus on Emerging or Re-Emerging Viruses

“…A further anti-viral property of the IRF is through its binding to the pro-apoptotic protein Bax and translocation to the mitochondria with activation of the mitochondrial apoptotic pathway, terminating virus replication (Chattopadhyay et al, 2010). Viruses can activate more than one TLR and it is known for example that TLR9 as well as TLR2 in dendritic cells and neuronal cells can respond to HSV to drive a protective IFN- antiviral response (Bereczky-Veress et al, 2010;Sato et al, 2006). RNA viruses such as HIV, Rabies and WNV are more likely to be recognized by TLR3 and/or TLR7 or 8 expressed by microglia and neuronal cells (Prehaud et al, 2005;Szretter et al, 2010;Wang et al, 2004).…”