MAMMALIAN IMMUNE SYSTEM

Mammalian Immune System Generates Response to Viruses

Mammalian Immune System Generates Response to Viruses

Introduction

Innate recognition of viruses by the mammalian immune system is critical in providing both the immediate antiviral effects, mediated in large part by type I IFNs, and in inducing appropriate classes of adaptive immune responses required for clearing viral infection. Distinct mechanisms are used to recognize viruses and the viral replication intermediates produced during viral infections. Whereas most cells use the retinoic acid inducible gene-I to recognize certain ssRNA virus infections and melanoma differentiation-associated gene 5 to recognize picornaviruses, plasmacytoid dendritic cells (pDCs) use exclusively the Toll-like receptors (TLRs) to recognize ssRNA and dsDNA viruses. More recently, a TLR-independent cytosolic recognition of DNA has been shown to play a major role in the induction of type I IFNs.

For innate recognition of herpes viruses, at least three pathways have been described. The first pathway involves the detection of viral genomic dsDNA by the TLR9. This pathway is used by the pDCs to recognize Herpes simplex virus (HSV)-1 and HSV-2. TLR9-mediated recognition also represents the predominant pathways in non-pDCs, such as splenic CD11c_ DCs upon HSV-1 infection. Further, systemic inoculation of UVirradiated HSV-2 results in IFN_ production in a myeloid differentiation factor (MyD) 88 and TLR9-dependent manner. (Honda et al, 2005, 772-777) Similarly, in vivo recognition of a beta herpes virus, murine cytomegalovirus, has been shown to depend on TLR9 and MyD88. The second type of TLR-herpesvirus interaction occurs when virions engage surface TLR2 on DCs and macrophages. Peritoneal macrophages and microglial cells secrete inflammatory cytokines in response to HSV-1 in a TLR2- dependent manner. The third type of viral recognition results in a MyD88-independent, IFN regulating factor (IRF)-7-dependent pathway. This third pathway has been demonstrated to play a major role during systemic infection with HSV-1, because IFN_ secretion and suppression of viral replication depended mostly on IRF7 and to a much lesser extent on MyD88.

Although these three distinct pathways of herpesvirus recognition are known to exist, the relative contributions of these pathways in viral recognition vs. viral pathogenesis are unclear. The ability of HSV-1 to trigger TLR2 has been shown to be responsible for the exacerbation of neonatal herpes encephalitis, because neonatal mice deficient in TLR2 secreted less IL-6 and had a higher rate of survival compared with WT mice upon lethal HSV-1 challenge. Further, the ability of HSV-1 and HSV-2 to activate TLR2 has been postulated to play a role in the sepsis-like disease associated with human neonatal herpes infection. These studies suggested that inflammatory responses induced by TLR2 engagement by HSV leads to immunopathology in the infected host. However, these studies used laboratory strains of HSV, and the clinical and epidemiological relevance of TLR2-activating HSV-1 and HSV-2, hereby termed HSV-1TLR2* and HSV-2TLR2*, are unknown. Thus, in this study, we examined the occurrence of the HSV-1TLR2* and HSV-2TLR2* in both the laboratory strains and the human clinical isolates from a variety of tissues and mucosal secretions. We show that HSVTLR2* constituted a minor population of HSV found ...