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EM Cantin, P Lundberg, PV Welander, M Wang, C Edwards, N van Rooijen, H Openshaw; Evidence for a Novel TNF Receptor that Mediates Protection Against HSV-1 Mortality . Invest. Ophthalmol. Vis. Sci. 2002;43(13):4309.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose: To evaluate the role of TNF signaling during infection after corneal inoculation of HSV-1. Methods: C57BL/6 (B6) and mice lacking TNF (TNF-/-; B6), TNFR1 (p55-/-; 129xB6, N13), TNFR2 (p75-/-; 129xB6, N4) or both TNFR1 and TNFR2 (p55-/-p75-/-; B6, 129xB6, N4) were inoculated with HSV-1 on the right cornea. Mice were monitored for viral titers in target tissues (eyes, ganglia and brainstem) from day four to eight, mortality, titers in necropsied target tissues, antibody levels in survivors and nitric oxide production by peritoneal macrophages from soluble TNFR (sTNFR) treated (binds TNF but not LT) and TNF-/- mice. Results: Although mortality was greater in TNF -/- than B6 mice (56% versus 8%), there was no mortality difference in comparing p55-/-, p75-/-, or p55-/-p75-/- to B6 mice (range 8-14% versus 8%). As a population, viral titers in trigeminal ganglia (Tg) and brain stem were greater in p55-/- and TNF-/- mice compared to B6 despite the difference in mortality between these null mutant strains. Hyperproliferative responses of DLN T cells from p55-/- but not B6 mice, correlated with a higher frequency of infection in the contralateral Tg and persistence of HSV in the inoculated right eye and right Tg of p55-/- mice, suggesting that p55 signaling is involved in controlling spread of HSV-1. sTNFR or liposome-encapsulated CL2MBP (to deplete macrophages) treatment, increased mortality to 40% in B6 and 80% in p55-/- mice. Compared to B6 mice, macrophages from p55-/- and TNF-/- mice were defective in NO production after stimulation with IFN-γ and LPS. Additionally, HSV-specific antibody production was impaired in both p55-/- and TNF-/- mice. Conclusions: We conclude that (i), TNF mediated protection involves signaling via a novel TNFR since the p55-/-p75-/- mouse is resistant while the TNF-/- mouse is susceptible to HSV mortality, (ii) TNF signaling via p55 is involved in controlling HSV-1 spread and replication, (iii) macrophage derived TNF likely mediates these effects, (iv) antibody responses to HSV relies on TNF signaling through p55, but serum antibody does not correlate with protection against mortality and (v) defective macrophage production of NO in TNF-/- mice does not explain their greater susceptibility to HSV mortality compared to wild type mice, since the p55-/- are resistant despite defective NO production.
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