Dendritic cells, macrophages, NK and CD8+ T lymphocytes play pivotal roles in controlling HSV-1 in the trigeminal ganglia by producing IL1-beta, iNOS and granzyme B

Abstract

BackgroundHerpes simplex virus type 1 (HSV-1) cause not only mild symptoms but also blindness and encephalitis. It was previously shown that the immune response against HSV-1 occurs mainly in the trigeminal ganglia (TG) and that Toll-like receptors 2 and 9 (TLR2/9) are important in mediating this response. It was also demonstrated that iNOS (nitric oxide synthase) and interleukin 1 beta (IL-1β) play an essential role in the defense against HSV-1 infection. Importantly, the present work aimed to identify the primary cells responsible for iNOS and IL-1β production and search for other important molecules and cells that might or might not depend on TLR2/9 receptors to mediate the immune response against HSV-1.MethodsC57BL/6 (wild type, WT) and TLR2/9−/− mice were infected by the intranasal route with HSV-1 (1 × 106 p.f.u.). Cells were obtained from the TG and spleen tissues and the profile of immune cells was determined by flow cytometry in infected and mock infected WT and knockout mice. The percentage of cells producing iNOS, IL-1β, granzyme B and perforin was also determined by flow cytometry. Chemokine monocyte chemoattractant protein-1 (MCP1) was measured by Cytometric Bead Array (CBA) in the TG, spleen and lung. Expression of type I interferons (IFNs), interleukins (IL) 5 and 10, IL-1β and granzyme B were quantified by real time PCR.ResultsThe results indicate that dendritic cells (DCs) and monocytes/macrophages (Mo/Mϕ) were the main sources of IL-1β and iNOS, respectively, which, together with type I IFNs, were essential for the immune response against HSV-1. Additionally, we showed that granzyme B produced by CD8+ T and NK lymphocytes and MCP-1 were also important for this immune response. Moreover, our data indicate that the robust production of MCP-1 and granzyme B is either TLR-independent or down regulated by TLRs and occurs in the TG of TLR2/9−/− infected mice.ConclusionTaken together, our data provide strong evidence that the responses mediated by DCs, Mo/Mϕ, NK and CD8+ T lymphocytes through IL-1β, iNOS and granzyme B production, respectively, together with the production of type I IFN early in the infection, are crucial to host defense against HSV-1.Electronic supplementary materialThe online version of this article (doi:10.1186/s12985-017-0692-x) contains supplementary material, which is available to authorized users.

Herpes Simplex Virus Type 1 Interactions with the Interferon System

“…TLR2 is a plasma membrane receptor, which upon binding viral glycoproteins, signals through myeloid differentiation factor 88 (MyD88) and tumor necrosis factor receptor associated factor (TRAF) 6 to activate the nuclear factor-κB (NF-κB) pathway ( Figure 1 ). This induces the degradation of I-κBα (an inhibitor of NF-κB), allowing NF-κB to translocate to the nucleus leading to the expression of several pro-inflammatory cytokines and chemokines in several human and mouse cell types, including epithelial, immune, and neuronal cells [ 34 , 41 , 42 , 43 , 44 ]. HSV-1 activation of TLR2 can also signal through TRIF-related adaptor molecule (TRAM) and MyD88 for IFN production ( Figure 1 ).…”

“…While originally thought to be immune privilege, neurons are also capable of responding to IFN to control HSV-1 infections at all stages of the HSV-1 life cycle. HSV-1 infected TG neurons obtained from mice are also capable of producing their own type I IFN [ 41 ]. IFNβ treatment of rat sensory neurons results in the phosphorylation of STAT1 and transcription of several ISGs, including ISG15 [ 195 , 196 ].…”

Genital HSV-1 DNA detection is associated with a low inflammatory profile in HIV-uninfected South African women

“…Compared with women with no detectable genital HSV-1 DNA, the presence of HSV-1 DNA was associated with significant decreases in genital concentrations of G-CSF, IL-7, IL-4, PDGF-ββ, IL-6, IL-1β, MIP-1α, MIP-1β and TNF-α. Raised concentrations of IL-4, MIP-1α, TNF-α, IL-1β, IL-6, IL-7 and G-CSF have each been associated with the control of HSV-1 infection in murine models, [31][32][33][34][35][36][37][38][39] suggesting that the reduction in these cytokine concentrations may reflect the detection of HSV-1 DNA in the context of a loss of viral immune control. The presence of HSV-1 DNA was also associated with significant decreases in genital concentrations of five of nine proinflammatory cytokines integral to defining the relationship between inflammation and HIV risk (IL-6, IL-1β, MIP-1α, MIP-1β and TNF-α).…”

Insights into the pathogenesis of herpes simplex encephalitis from mouse models

“…In the infected CNS, once thought to be off-limits to the immune system, the activation of resident cells and the infiltration of immune cells can either restrict viral replication to limit inflammation, or contribute directly to lethal encephalitis. Trafficking lymphocytes can be detected as early as day 5 post-HSV-1 infection in the TG, where TLR2- and TLR9-dependent pathways drive the production of granzyme B and perforin by cytotoxic NK and CD8 + T cells, of iNOS by macrophages, and of IL-1β by conventional DCs (Lucinda et al 2017 ). The infected TG are also noted for their high expression of CCL2 in susceptible Tlr2 −/− Tlr9 −/− mice, which leads to further recruitment of monocytes and T cells to the CNS.…”