Tumor Necrosis Factor (TNF) Protects Resistant C57BL/6 Mice against Herpes Simplex Virus-Induced Encephalitis Independently of Signaling via TNF Receptor 1 or 2

Abstract

Tumor necrosis factor (TNF) is a multifunctional cytokine that has a role in induction and regulation of host innate and adaptive immune responses. The importance of TNF antiviral mechanisms is reflected by the diverse strategies adopted by different viruses, particularly members of the herpesvirus family, to block TNF responses. TNF binds and signals through two receptors, Tnfrsf1a (TNF receptor 1 [TNFR1], or p55) and Tnfrsf1b (TNFR2, or p75). We report here that herpes simplex virus 1 (HSV-1) infection of TNF ؊/؊ mice on the resistant C57BL/6 genetic background results in significantly increased susceptibility (P < 0.0001, log rank test) to fatal HSV encephalitis (HSE) and prolonged persistence of elevated levels of virus in neural tissues. In contrast, although virus titers in neural tissues of p55 ؊/؊ N13 mice were elevated to levels comparable to what was found for the TNF ؊/؊ mice, the p55 ؊/؊ N13 mice were as resistant as control C57BL/6 mice (P > 0.05). The incidence of fatal HSE was significantly increased by in vivo neutralization of TNF using soluble TNFR1 (sTNFR1) or depletion of macrophages in C57BL/6 mice (P ‫؍‬ 0.0038 and P ‫؍‬ 0.0071, respectively). Strikingly, in vivo neutralization of TNF in HSV-1-infected p55 ؊/؊ p75 ؊/؊ mice by use of three independent approaches (treatment with soluble p55 receptor, anti-TNF monoclonal antibody, or in vivo small interfering RNA against TNF) resulted in significantly increased mortality rates (P ‫؍‬ 0.005), comparable in magnitude to those for C57BL/6 mice treated with sTNFR1 (P ‫؍‬ 0.0018). Overall, these results indicate that while TNF is required for resistance to fatal HSE, both p55 and p75 receptors are dispensable. Precisely how TNF mediates protection against HSV-1 mortality in p55 ؊/؊ p75 ؊/؊ mice remains to be determined.Early innate and subsequent adaptive immune responses to viral and bacterial pathogens are critically dependent on the tumor necrosis factor (TNF) superfamily of cytokines. These TNF superfamily cytokines act as effectors of host defense and regulate peripheral lymphoid tissue organogenesis and differentiation of natural killer cells and lymphoid cells (42,46). TNF, a multifunctional cytokine produced primarily by activated macrophages (70), functions as a key regulator of leukocyte trafficking by affecting chemokine expression and stimulating antigen presentation, which it does by inducing dendritic cell maturation (26, 58). TNF exists in two forms, a precursor 26-kDa membrane-bound form (mTNF) and a 17-kDa soluble form (sTNF), both of which are bioactive (46, 71). TNF and the closely related ligand lymphotoxin-␣ (LT) bind as homotrimers to two receptors, TNF receptor 1 (TNFR1, or p55) and TNFR2 (p75), which are widely expressed on most cell types (71). Activation of p55 generally results in gene activation that leads to induction of inflammatory and cytotoxic responses, while activation of TNFR2 is associated with thymocyte proliferation and T-cell activation. In response to TNF binding, lipopolysaccharide (LPS) and several other s...

The ribonucleotide reductase R1 subunits of herpes simplex virus types 1 and 2 protect cells against TNFα- and FasL-induced apoptosis by interacting with caspase-8

“…One can hypothesize that low levels of TNFR1 are sufficient to trigger apoptosis or that TNFa signals through TNFR2 or through a third, unknown TNFR. The existence of such an unknown TNF receptor was invoked to explain how TNFa could protect against fatal HSV-1 encephalitis in TNFR1 -/-TNFR2 -/-mice [71]. A much clearer conclusion on the importance of HSV-1 R1 in counteracting DR-induced apoptosis was obtained here with respect to the Fas pathway.…”

Tumor Necrosis Factor Alpha-Induced Recruitment of Inflammatory Mononuclear Cells Leads to Inflammation and Altered Brain Development in Murine Cytomegalovirus-Infected Newborn Mice

“…Treatment of infected mice with neutralizing TNF-␣ antibodies increased the mortality in infected mice, suggesting an important role for TNF-␣ early in the control of virus infection in the brain, presumably through its effect on the recruitment of inflammatory monocyte/macrophage populations (38). TNF-␣ has also been shown to be protective in murine models of herpes simplex virus (HSV) encephalitis and in clearance of lymphocytic choriomeningitis virus (LCMV) (40,41). In contrast to these findings, other studies have argued that TNF-␣ facilitates WNV neuroinvasion by disrupting the integrity of the blood-brain barrier, a mechanism that may also contribute to increases in mononuclear cell infiltration into the infected CNS (42).…”

Role of the UL41 Protein of Pseudorabies Virus in Host Shutoff, Pathogenesis and Induction of TNF-.ALPHA. Expression

“…TNF- has been shown to be an important cytokine in the innate immune response against various infections, including HSV. In acute infection, the lowest survival rate was observed in TNF- knock out mice infected with HSV-1 via the corneal rout [18,20]. In an encephalitis mouse model, HSV-1 was lethal to TNF- deficient mice, and the brain viral loads were higher than that in wild type mice, indicating that TNF- is a crucial factor in protection against HSV-1 infection [23].…”

“…infected spleen cells: Cantin and coworkers demonstrated that deficient of TNF- activity results in significantly increased susceptibility to fatal HSV encephalitis (HSVE) in C57BL/6 mice and prolonged persistence of elevated levels of virus in neural tissues [18]. To understand whether TNF- contributes to the basis for this reduced pathogenicity of these 2 PRV viruses in mice, we compared that the TNF- expression level in the spleen cells isolated from mice infected with wt PRV and the vhs mutant virus 41.…”