In the absence of T cells, natural killer cells protect from mortality due to HSV-1 encephalitis

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...

Section: Resultsmentioning

confidence: 99%

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

Lundberg¹,

Welander²,

Edwards

et al. 2007

“…2A). Previous studies have observed that NK cells play crucial roles in the elimination of virus at the early stage of infection but also that they are an important contributor to virus-induced lung immune injury (1,8). We found that during RSV infection, the percentages of NK (CD3 Ϫ DX5 ϩ ) and T (CD3 ϩ DX5 Ϫ ) cells in the lungs were increased, and the percentage of NK cells reached a peak at day 3, but the percentage of T cells reached a peak at day 7 ( Fig.…”

Section: Rsv Infection Induces Acute Lung Immune Injury In Micementioning

confidence: 99%

Natural Killer Cells Are Involved in Acute Lung Immune Injury Caused by Respiratory Syncytial Virus Infection

Zhu

Sun

et al. 2012

“…This is especially true for sexually transmitted viruses, such as herpes simplex virus type 2 (HSV-2) and human immunodeficiency virus type 1 (HIV-1), that initiate infection at the genital mucosa. Previous studies (1,4,7,12,13,26,28) have shown that innate mechanisms, such as NK cells, neutrophils, macrophages, complement, and natural antibodies, are involved in innate defense against HSV infections. In addition, a mouse model employing intravaginal (IVAG) immunization with attenuated HSV-2 has been used to demonstrate the importance of T-cell-mediated adaptive immune responses, gamma interferon (IFN-␥), and local antibodies in protection of immunized mice against vaginal HSV-2 infection (22,23,28,(30)(31)(32).…”

mentioning

confidence: 98%

Local Delivery of CpG Oligodeoxynucleotides Induces Rapid Changes in the Genital Mucosa and Inhibits Replication, but Not Entry, of Herpes Simplex Virus Type 2

Ashkar

Bauer

Mitchell

et al. 2003

138

101

Mucosal surfaces are the entry sites for the vast majority of infectious pathogens and provide the first line of defense against infection. In addition to the epithelial barrier, the innate immune system plays a key role in recognizing and rapidly responding to invading pathogens via innate receptors, such as Toll-like receptors (TLR). Bacterial CpG DNA, a potent activator of innate immunity, is recognized by TLR9. Here, we confirm that local mucosal, but not systemic, delivery of CpG oligodeoxynucleotides (ODN) to the genital tract protects mice from a subsequent lethal vaginal herpes simplex virus type 2 (HSV-2) challenge. Since these effects were so local in action, we examined the genital mucosa. Local delivery of CpG ODN induced rapid proliferation and thickening of the genital epithelium and caused significant recruitment of inflammatory cells to the submucosa. Local CpG ODN treatment also resulted in inhibition of HSV-2 replication but had no effect on HSV-2 entry into the genital mucosa. CpG ODN-induced protection against HSV-2 was not associated with early increases in gamma interferon (IFN-␥) secretion in the genital tract, and CpG ODN-treated IFN-␥ ؊/؊ mice were protected from subsequent challenge with a lethal dose of HSV-2. Treatment of human HEK-293 cells transfected with murine TLR9 showed that the antiviral activity of CpG ODN was mediated through TLR9. These studies suggest that local induction of mucosal innate immunity can provide protection against sexually transmitted infections, such as HSV-2 or possibly human immunodeficiency virus, at the mucosal surfaces.