An IKBKE variant conferring functional cGAS/STING pathway deficiency and susceptibility to recurrent HSV-2 meningitis.

The mechanisms underlying susceptibility to recurrent herpes simplex virus type 2 (HSV-2) meningitis remain incompletely understood. In a patient experiencing multiple episodes of HSV-2 meningitis, we identified a monoallelic variant in the IKBKE gene, which encodes the IKKε kinase involved in induction of antiviral IFN genes. Patient cells displayed impaired induction of IFN-β1 (IFNB1) expression upon infection with HSV-2 or stimulation with double-stranded DNA (dsDNA) and failed to induce phosphorylation of STING, an activation marker of the DNA-sensing cyclic GMP-AMP synthase/stimulator of IFN genes (cGAS/STING) pathway.

CD8 T cells in the central nervous system of mice with herpes simplex infection are highly activated and express high levels of CCR5 and CXCR3.

Herpes simplex virus type 2 (HSV-2) is a neurotropic virus that can cause meningitis, an inflammation of the meninges in the central nervous system. T cells are key players in viral clearance, and these cells migrate from peripheral blood into the central nervous system upon infection. Several factors contribute to T cell migration, including the expression of chemokines in the inflamed tissue that attract T cells through their expression of chemokine receptors.

Cutting Edge: Genetic Association between IFI16 Single Nucleotide Polymorphisms and Resistance to Genital Herpes Correlates with IFI16 Expression Levels and HSV-2-Induced IFN-β Expression.

IFN-γ-inducible protein 16 (IFI16) is an immunological DNA sensor proposed to act in the cyclic GMP-AMP synthase-stimulator of IFN genes pathway. Because mice do not have a clear ortholog of IFI16, this system is not suitable for genetic studies of IFI16. In this study, we have compared the dependency on IFI16, cyclic GMP-AMP synthase, and stimulator of IFN genes for type I IFN induction by a panel of pathogenic bacteria and DNA viruses.

Maturation-dependent expression of AIM2 in human B-cells.

Intracellular DNA- and RNA-sensing receptors, such as the IFN-inducible protein Absent in Melanoma 2 (AIM2), serve as host sensors against a wide range of infections. Immune sensing and inflammasome activation by AIM2 has been implicated in innate antiviral recognition in many experimental systems using cell-lines and animal models. However, little is known about the expression and function of AIM2 in freshly isolated human cells.

Extracts of Equisetum giganteum L and Copaifera reticulate Ducke show strong antiviral activity against the sexually transmitted pathogen herpes simplex virus type 2.

Ethnopharmacological Relevance: Equisetum giganteum L and Copaifera reticulate Ducke have been traditionally used by women of the Tacana tribe in the Bolivian Amazonas for genital hygiene and for treatment of genital infection/inflammation.

Aim Of The Study: To assess the ability of extracts from Equisetum giganteum L and Copaifera reticulate Ducke to block genital viral infection by herpes simplex virus type 2.

Materials And Methods: Equisetum giganteum L and Copaifera reticulate Ducke were collected from the Amazon region of La Paz, Bolivia.

Identification of adult septic patients in the prehospital setting: a comparison of two screening tools and clinical judgment.

Background: Timely identification and treatment of sepsis is crucial for patient outcome. The aim of this study was to compare two previously unvalidated prehospital sepsis screening tools with clinical judgment by emergency medical services (EMS) personnel with respect to identification of septic patients.

Patients And Methods: We carried out a retrospective cross-sectional study of 353 adult patients, transported by the EMS, with a hospital discharge International Classification of Diseases code consistent with sepsis.

STAT4 regulates antiviral gamma interferon responses and recurrent disease during herpes simplex virus 2 infection.

STAT4 is an important transcription factor that contributes to the incidence and severity of different autoimmune diseases and is implicated in the antiviral immune responses in mice. In this study, we evaluated the role of STAT4 in human and murine herpes simplex virus 2 (HSV-2) infections. We show that STAT4 regulates antiviral gamma interferon (IFN-γ) responses and disease severity during chronic HSV-2 infections in humans and vaccine-induced IFN-γ-mediated protection against HSV-2 infection in mice.

Polymorphisms in Toll-like receptor 3 confer natural resistance to human herpes simplex virus type 2 infection.

Lack of Toll-like receptor 3 (TLR3) functional activity predisposes children to human herpesvirus 1 (HSV-1) encephalitis. In this study, we have investigated whether there is any link between TLR3 and adult HSV-2 infection by studying genetic variations in TLR3. The frequency of four single-nucleotide polymorphisms (SNPs) in the TLR3 gene in 239 patients with genital HSV-2 infection and 162 healthy controls, as well as the impact of these variants on TLR3 gene-expression levels, were compared.

Characterization of natural killer cell phenotype and function during recurrent human HSV-2 infection.

Human natural killer (NK) cell differentiation, characterized by a loss of NKG2A in parallel with the acquisition of NKG2C, KIRs, and CD57 is stimulated by a number of virus infections, including infection with human cytomegalovirus (CMV), hantavirus, chikungunya virus, and HIV-1. Here, we addressed if HSV-2 infection in a similar way drives NK cell differentiation towards an NKG2A(-)NKG2C(+)KIR(+)CD57(+) phenotype. In contrast to infection with CMV, hantavirus, chikungunya virus, and HIV-1, recurrent HSV-2 infection did not yield an accumulation of highly differentiated NK cells in human peripheral blood.

Inhibition of γ-secretase cleavage in the notch signaling pathway blocks HSV-2-induced type I and type II interferon production.

We have evaluated the role of γ-secretase, which is a crucial component in the Notch-induced signaling cascade, on herpes simplex virus type 2 (HSV-2)-induced innate and acquired interferon responses in human CD4(+) T cells and plasmacytoid dendritic cells (pDC). We found that blockade of the Notch signaling pathway with a pharmacological γ-secretase inhibitor blocked both HSV-2-induced interferon-γ (IFN-γ) production in CD4(+) T cells, and HSV-2-induced IFN-α production in pDC in a dose-dependent fashion. These effects were not due to an overall suppressive capacity of the γ-secretase inhibitor, as it affected neither phytohemagglutinin (PHA)-induced IFN-γ production in CD4(+) T cells, nor CpG-induced IFN-α production in pDC.

A 3'-untranslated region polymorphism in the TBX21 gene encoding T-bet is a risk factor for genital herpes simplex virus type 2 infection in humans.

It was recently shown that the transcription factor T-bet is crucial for adequate innate and acquired immune responses to genital herpes simplex virus type 2 (HSV-2) infection in mice. To test the possible genetic influence of variations in the TBX21 gene encoding T-bet on susceptibility to infection, this study evaluated the frequencies of five different single-nucleotide polymorphisms (SNPs) in the human TBX21 gene in 159 HSV-2-infected individuals and compared them with those in 186 healthy HSV-2-seronegative controls. The data showed that one variation (rs17244587) in the 3'-untranslated region of TBX21 was strongly associated with the incidence of genital HSV-2 infection.

Role of IFN-alpha/beta signaling in the prevention of genital herpes virus type 2 infection.

This study has shown that IFN-alpha/beta signaling is crucial for combating primary herpes simplex virus type 2 (HSV-2) infection and for responding to immunotherapy using ligands to TLR3, 7 and 9, but not for vaccine-induced immunity. Both genital viral replication and the disease progression were enhanced in HSV-2-infected mice lacking the IFN-alpha/beta receptor (IFN-alpha/betaR-/-). IFN-alpha/betaR-/- mice were, however, able to mount a normal HSV-2-specific Th1 response and acquired sterilizing immunity following vaccination.

Neurokinin 1 receptor signaling affects the local innate immune defense against genital herpes virus infection.

We show that genital infection with neurotropic HSV type 2 (HSV-2) induced a significant increase of the neuropeptide substance P (SP) within the genital tract of mice. SP was shown to weakly interfere with the HSV-2 replication. Furthermore, lack of SP signaling through the use of mice deficient in the SP receptor, neurokinin 1 receptor (NK1R), revealed an important role for SP in the innate defense against HSV-2.

Protective immunity to genital herpes simplex [correction of simpex] virus type 2 infection is mediated by T-bet.

We show, for the first time, that the transcription factor T-bet, which is implicated in IFN-gamma production, is required for the induction of vaccine-induced antiviral immune protection. T-bet was found to be important in both the innate and acquired immune protection against genital HSV-2 infection. T-bet(-/-) and T-bet(+/+) mice were infected vaginally with HSV-2 and examined daily for disease and mortality.