Intact TRL 9 and type I interferon signaling pathways are required to augment HSV-1 induced corneal CXCL9 and CXCL10

Abstract

Herpes simplex virus type 1 ocular infection elicits a potent inflammatory response including the production of the chemokines, CXCL9 and CXCL10, in mice. Since HSV-1 nucleic acid is recognized by pattern receptors including Toll-like receptor (TLR) 9, we tested the hypothesis that TLR9 is necessary for the early augmentation of CXCL10 following HSV-1 infection. Similar to wild type controls, TLR9 deficient mice constitutively expressed CXCL10 in the cornea. Following infection or stimulation with the deoxycytidylate-phosphate-deoxyguanylate (CpG) motif, CXCL10 levels were significantly elevated in the cornea of wild type but not TLR9 or type I interferon receptor deficient mice. The reduced CXCL10 response in the cornea of TLR deficient mice was correlative with an increase in virus shedding and a reduction in neutrophil infiltration. This is the first report that shows enhanced CXCL10 expression following neurotropic viral replication requires both intact TLR 9 and type I interferon signaling pathways.

CD4+ T cell migration into the cornea is reduced in CXCL9 deficient but not CXCL10 deficient mice following herpes simplex virus type 1 infection

“…Both resident corneal cells and infiltrating leukocytes generate the chemokines detected in the present study including CXCL9 and CXCL10 [11,[34][35][36][37]. Out of the six chemokines investigated, only CCL2 levels were associated with sensitivity to infection since CXCL10−/ − mice possessed significantly more virus and expressed elevated levels of CCL2 in the cornea in comparison to the less sensitive WT or CXCL9−/− mice.…”

The role of chemokines during herpes simplex virus-1 infection

“…TLR9 signaling has little impact on the course of HSV-1 infection in mouse models. Although early chemokine production during acute HSV-1 infection is reduced in the absence of TLR9, particularly for the monocyte and granulocyte chemoattractants, CCL2 and CXCL1 respectively, neither viral burdens within the nervous system nor survival are affected (47,48). IRAK-4 is required for normal NF-kB activation and type I IFN (IFNalpha/beta) production following TLR stimulation (49,50) for all TLRs except TLRs 3 and 4 for which IRAK-4 is required for normal NF-kB activation but not IFN production (51).…”

“…Early chemokine expression is dominated by production of ELR+ CXC chemokines CXCL1/2/8, CCL2, and CXCL10 (48,(60)(61)(62)(63). CXCL1/2/8 chemoattracts PMNs through the receptors CXCR1/2, while CCL2 recruits monocytes through CCR2.…”

Oligoadenylate Synthetase/Protein Kinase R Pathways and αβ TCR+ T Cells Are Required for Adenovirus Vector: IFN-γ Inhibition of Herpes Simplex Virus-1 in Cornea

“…TLRs are activated, leading to production of CXC chemokines (73), also induced by IFN-␥, which act as chemoattractants for T and NK cells (72). Although IFN-␥ indirectly activates chemokines that function as chemoattractants for leukocytes, it could be argued that with IFN-␥ treatment, infectious virus levels and viral Ag levels are lower, and therefore, there will be less immune cell infiltration.…”