Abstract
Purpose: :
To determine the effect of TLR4 on the incidence of HSV-1 induced acute retinal necrosis (ARN) and on activation of immune response genes during HSV-1 infection.
Methods: :
TLR4 mutant and wild type BALB/cJ mice were infected with HSV-1 via anterior chamber (AC) inoculation. At different times p.i., mice were sacrificed, the uninoculated contralateral eye was enucleated, and immunohistochemistry and qPCR array for immune response genes were performed. Cultured RPE cells isolated from TLR4 mutant and wild type mice were infected with HSV-1.
Results: :
The incidence of ARN in the uninoculated contralateral eye was significantly reduced in HSV-1 infected TLR4 mutant mice (1/6) compared with that in control mice (5/6). Quantitative PCR array analysis of the contralateral eye of TLR4 mutant mice at day 9 p.i. showed that 14 of 384 immunologically related genes were upregulated and 85 of 384 genes were down regulated compared with the wild type control mice. IL6, L-selectin, CCL11, complement 3, IFNalpha 2, 14 and calpastatin were among the14 upregulated genes. Following HSV-1 infection of cultured RPE cells, IL6 mRNA was upregulated in cells from TLR4 mutant mice compared with cells from control mice. TLR8, TNF-alpha induced protein 6, some members of the TNF ligand superfamily, Interleukin family, CXCL, CCL, IFNalpha 9 and B, phospholipase A2 were among the down regulated genes.
Conclusions: :
The reduced incidence of ARN in TLR4 mutant mice suggests that functional TLR4 is required for efficient neuronal transport of virus from the injected eye to the retina of the uninjected eye. Lack of functional TLR4 also changes the pattern of immune response gene activation during HSV-1 infection which, in turn, affects the outcome of HSV-1 infection following AC inoculation
Keywords: herpes simplex virus • anterior chamber • retinitis