Persistent expression of chemokine and chemokine receptor RNAs at primary and latent sites of herpes simplex virus 1 infection

Abstract

Inflammatory cytokines and infiltrating T cells are readily detected in herpes simplex virus (HSV) infected mouse cornea and trigeminal ganglia (TG) during the acute phase of infection, and certain cytokines continue to be expressed at lower levels in infected TG during the subsequent latent phase. Recent results have shown that HSV infection activates Toll-like receptor signaling. Thus, we hypothesized that chemokines may be broadly expressed at both primary sites and latent sites of HSV infection for prolonged periods of time. Real-time reverse transcriptase-polymrease chain reaction (RT-PCR) to quantify expression levels of transcripts encoding chemokines and their receptors in cornea and TG following corneal infection. RNAs encoding the inflammatory-type chemokine receptors CCR1, CCR2, CCR5, and CXCR3, which are highly expressed on activated T cells, macrophages and most immature dendritic cells (DC), and the more broadly expressed CCR7, were highly expressed and strongly induced in infected cornea and TG at 3 and 10 days postinfection (dpi). Elevated levels of these RNAs persisted in both cornea and TG during the latent phase at 30 dpi. RNAs for the broadly expressed CXCR4 receptor was induced at 30 dpi but less so at 3 and 10 dpi in both cornea and TG. Transcripts for CCR3 and CCR6, receptors that are not highly expressed on activated T cells or macrophages, also appeared to be induced during acute and latent phases; however, their very low expression levels were near the limit of our detection. RNAs encoding the CCR1 and CCR5 chemokine ligands MIP-1α, MIP-1β and RANTES, and the CCR2 ligand MCP-1 were also strongly induced and persisted in cornea and TG during the latent phase. These and other recent results argue that HSV antigens or DNA can stimulate expression of chemokines, perhaps through activation of Toll-like receptors, for long periods of time at both primary and latent sites of HSV infection. These chemokines recruit activated T cells and other immune cells, including DC, that express chemokine receptors to primary and secondary sites of infection. Prolonged activation of chemokine expression could provide mechanistic explanations for certain aspects of HSV biology and pathogenesis.

The Chemokine Receptor CXCR4 Mediates Recruitment of CD11c+Conventional Dendritic Cells Into the Inflamed Murine Cornea

“… 65 Of note, several studies report CXCL12 expression to be very low in steady-state, increasing following inflammation/damage. 39 , 61 , 63 , 65 Our data are in accordance with these reports, where the levels of CXCL12 expression in the corneal epithelium and stroma increased following suture placement.…”

“…Moreover, the similarity of the “induction ratio” (relative expression in HSV-infected/relative expression in sham-infected cornea) to that of the other chemokine receptors reported in their paper is interesting to note, as it indicates an increase in CXCR4 following scarification in the sham group. 61 Our results revealed that approximately 60% of steady-state cDCs in the naïve cornea were CXCR4 positive. This percentage decreased to an average of 35% of total cDCs following suture placement.…”

“…Whereas the CXCR4/CXCL12 pathway in DC homing to the cornea has not been directly investigated, Cook et al 61 found elevated corneal CXCR4 gene expression in parallel to CCR1, 2, and 5, 3 days after infection when examining the expression profile of chemokines (including CCL3/4, RANTES, and monocyte chemoattractant protein-1 [MCP]-1), as well as chemokine receptors (including CCR1-7 and CXCR4) in a murine model of herpes simplex virus (HSV)-1 infection. Moreover, the similarity of the “induction ratio” (relative expression in HSV-infected/relative expression in sham-infected cornea) to that of the other chemokine receptors reported in their paper is interesting to note, as it indicates an increase in CXCR4 following scarification in the sham group.…”

Defense against HSV-1 in a murine model is mediated by iNOS and orchestrated by the activation of TLR2 and TLR9 in trigeminal ganglia

“…This control most likely occurs through the production of cytokines such as IFN gamma, especially in the trigeminal ganglia [19,24,25]. IFN gamma is produced mainly by T lymphocytes [26], and one of its major actions is to increase iNOS and ROS production for killing pathogens [26,27].…”

Herpes Simplex Virus 1 Suppresses the Function of Lung Dendritic Cells via Caveolin-1

“…DCs can be recruited to the lungs and in the cornea of the eye, where they contribute to host defense (8,9). Studies have shown that diphtheria toxin (DT)-induced depletion of DCs in CD11c-DTR mice (in which the DT receptor [DTR] is expressed under the control of the CD11c promoter) inhibited the migration of natural killer cells and neutrophils to locally infected cornea, resulting in severe pathology (10,11).…”