TLR2 and TLR9 Synergistically Control Herpes Simplex Virus Infection in the Brain

Abstract

Viruses are recognized by the innate immune system through pattern recognition receptors (PRRs). For instance, HSV virions and genomic DNA are recognized by TLR2 and TLR9, respectively. Although several viruses and viral components have been shown to stimulate cells through TLRs, only very few studies have defined essential roles for single TLRs in innate immune defense in vivo. This could suggest that PRRs act in concert to mount the first line of defense against virus infections. To test this hypothesis we have examined the host response of C57BL/6, TLR2−/−, TLR9−/−, and TLR2/9−/− mice toward HSV-2 infection. After a systemic infection, the cytokine serum response was markedly reduced in the double knockout mice, but only partly affected in either strain of the single knockout mice. This was supported by in vitro data showing that HSV-induced cytokine expression relayed on TLR2 and TLR9 in a cytokine- and cell type-dependent manner. With respect to the cellular response to infection, we found that recruitment but not activation of NK cells was impaired in TLR2/9−/− mice. Importantly, the viral load in the brain, but not liver, was significantly higher in the brain of TLR2/9−/− mice whereas the viral loads in organs of single knockout mice were statistically indistinguishable from C57BL/6 mice. In the brain we found that TNF-α and the IFN-stimulated gene CXCL9 were expressed during infection and were dependent on either TLR2 or TLR9. Thus, TLR2 and TLR9 synergistically stimulate innate antiviral activities, thereby protecting against HSV infection in the brain.

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

“…In the case of HSV this appears to be the case. TLR2 detects an unknown molecule from the HSV viron, while TLR9 detects CpG [97]. Consequently it has been found that TLR2 and TLR9 function synergistically to respond to HSV infection in the brain [97].…”

“…TLR2 detects an unknown molecule from the HSV viron, while TLR9 detects CpG [97]. Consequently it has been found that TLR2 and TLR9 function synergistically to respond to HSV infection in the brain [97]. HSV loads in the brain were found to be greater in the TLR2/9 double knockouts compared with brains from either the single knockouts.…”

“…So while TLR2 in isolation might contribute to the pathogenesis of HSV, mediated by the release of cytokines and chemokines, TLR2 and TLR9 together appear to be required for an effective immune response to HSV, particularly in the brain [97]. Further evidence in support of a role for TLRs in response to HSV infection came from the observation that MyD88 knockout mice develop lethal encephalitis following intranasal infection with HSV [97].…”

“…Further evidence in support of a role for TLRs in response to HSV infection came from the observation that MyD88 knockout mice develop lethal encephalitis following intranasal infection with HSV [97]. Therefore TLR2 and TLR9 function together to confer resistance against HSV infection in the brain.…”

TLR7 and TLR9 Trigger Distinct Neuroinflammatory Responses in the CNS

“…TLR7 regulates the innate immune response to retrovirus and West Nile virus infections of the CNS, and TLR9 has been implicated in mediating the innate immune response to herpes simplex virus infection in the brain. [12][13][14][15][16] TLR7 and TLR9 agonists have been analyzed for their potential use in the therapeutic treatment of CNS maladies from glioblastomas to viral infection. However, responses to stimulation of these receptors in the CNS often differ, particularly in neonates.…”