Encephalitis and poor neuronal death-mediated control of herpes simplex virus in human inherited RIPK3 deficiency.

Inborn errors of TLR3-dependent type I IFN immunity in cortical neurons underlie forebrain herpes simplex virus-1 (HSV-1) encephalitis (HSE) due to uncontrolled viral growth and subsequent cell death. We report an otherwise healthy patient with HSE who was compound heterozygous for nonsense (R422*) and frameshift (P493fs9*) variants. Receptor-interacting protein kinase 3 (RIPK3) is a ubiquitous cytoplasmic kinase regulating cell death outcomes, including apoptosis and necroptosis.

Inborn errors of TLR3- or MDA5-dependent type I IFN immunity in children with enterovirus rhombencephalitis.

Enterovirus (EV) infection rarely results in life-threatening infection of the central nervous system. We report two unrelated children with EV30 and EV71 rhombencephalitis. One patient carries compound heterozygous TLR3 variants (loss-of-function F322fs2* and hypomorphic D280N), and the other is homozygous for an IFIH1 variant (loss-of-function c.

TLR3 controls constitutive IFN-β antiviral immunity in human fibroblasts and cortical neurons.

Human herpes simplex virus 1 (HSV-1) encephalitis can be caused by inborn errors of the TLR3 pathway, resulting in impairment of CNS cell-intrinsic antiviral immunity. Deficiencies of the TLR3 pathway impair cell-intrinsic immunity to vesicular stomatitis virus (VSV) and HSV-1 in fibroblasts, and to HSV-1 in cortical but not trigeminal neurons. The underlying molecular mechanism is thought to involve impaired IFN-α/β induction by the TLR3 recognition of dsRNA viral intermediates or by-products.

Herpes simplex encephalitis in a patient with a distinctive form of inherited IFNAR1 deficiency.

Inborn errors of TLR3-dependent IFN-α/β- and IFN-λ-mediated immunity in the CNS can underlie herpes simplex virus 1 (HSV-1) encephalitis (HSE). The respective contributions of IFN-α/β and IFN-λ are unknown. We report a child homozygous for a genomic deletion of the entire coding sequence and part of the 3'-UTR of the last exon of IFNAR1, who died of HSE at the age of 2 years.

Human SNORA31 variations impair cortical neuron-intrinsic immunity to HSV-1 and underlie herpes simplex encephalitis.

Herpes simplex virus-1 (HSV-1) encephalitis (HSE) is typically sporadic. Inborn errors of TLR3- and DBR1-mediated central nervous system cell-intrinsic immunity can account for forebrain and brainstem HSE, respectively. We report five unrelated patients with forebrain HSE, each heterozygous for one of four rare variants of SNORA31, encoding a small nucleolar RNA of the H/ACA class that are predicted to direct the isomerization of uridine residues to pseudouridine in small nuclear RNA and ribosomal RNA.

Severe influenza pneumonitis in children with inherited TLR3 deficiency.

Autosomal recessive IRF7 and IRF9 deficiencies impair type I and III IFN immunity and underlie severe influenza pneumonitis. We report three unrelated children with influenza A virus (IAV) infection manifesting as acute respiratory distress syndrome (IAV-ARDS), heterozygous for rare variants (P554S in two patients and P680L in the third) causing autosomal dominant (AD) TLR3 deficiency. AD TLR3 deficiency can underlie herpes simplex virus-1 (HSV-1) encephalitis (HSE) by impairing cortical neuron-intrinsic type I IFN immunity to HSV-1.

Inborn Errors of RNA Lariat Metabolism in Humans with Brainstem Viral Infection.

Viruses that are typically benign sometimes invade the brainstem in otherwise healthy children. We report bi-allelic DBR1 mutations in unrelated patients from different ethnicities, each of whom had brainstem infection due to herpes simplex virus 1 (HSV1), influenza virus, or norovirus. DBR1 encodes the only known RNA lariat debranching enzyme.

Flexible Connectors between Capsomer Subunits that Regulate Capsid Assembly.

Viruses build icosahedral capsids of specific size and shape by regulating the spatial arrangement of the hexameric and pentameric protein capsomers in the growing shell during assembly. In the T=7 capsids of Escherichia coli bacteriophage HK97 and other phages, 60 capsomers are hexons, while the rest are pentons that are correctly positioned during assembly. Assembly of the HK97 capsid to the correct size and shape has been shown to depend on specific ionic contacts between capsomers.

Comparative functional properties of engineered cationic antimicrobial peptides consisting exclusively of tryptophan and either lysine or arginine.

We previously reported a series of de novo engineered cationic antibiotic peptides (eCAPs) consisting exclusively of arginine and tryptophan (WR) that display potent activity against diverse multidrug-resistant (MDR) bacterial strains. In this study, we sought to examine the influence of arginine compared to lysine on antibacterial properties by direct comparison of the WR peptides (8-18 residues) with a parallel series of engineered peptides containing only lysine and tryptophan. WR and WK series were compared for antibacterial activity by bacterial killing and growth inhibition assays and for mechanism of peptide-bacteria interactions by surface plasmon resonance and flow cytometry.

Tolerance of skin allografts incompatible at the entire H-2 complex induced in adult mice by the post-transplant treatment.

Permanent tolerance of the entire H-2 complex incompatible B10 skin allografts was induced in adult B10.A mice by post-transplant treatment. Recipient mice were treated with heterologous antithymocyte serum (ATS) and specific tissue extracts or monoclonal antibodies anti-Thy-1.

The presence of retroviral particles in hybridoma cell lines.

The presence of very high numbers of type C and type A retroviral particles was repeatedly confirmed not only in myeloma cells NSI, Ag 8 and in thymoma cells BW5147, EL 4 but also in B and T cell hybridomas constructed from the myeloma and thymoma cells used. Retroviral particles were demonstrated by current electron-microscopic and physicochemical methods. Biological tests for the induction of possible malignant or any pathological changes in the artificially infected sensitive cells during long-term cultivations in vitro or in vivo gave negative results.

Establishment and characterization of a permanent T-cell line producing an antigen non-specific suppressor factor.

A permanent cell line designated SL4c has been established from a primary culture of murine BALB/c spleen cells regularly stimulated with large doses of irradiated allogeneic cells plus exogenous interleukin-2(IL-2). After 8 months of cultivation, the cells of the SL4c line proliferate spontaneously and do not respond with an increase in proliferation to alloantigenic stimulation. The cells have the Lyt 1.

A contribution to the question of genetic transmission of immunological tolerance.

In view of the discrepancy in the results concerning the question of inheritance of immunological tolerance, we tried to enhance the genetic effect of tolerization by tolerizing male mice over three succeeding generations and by testing the ability of their progeny to reject an allogeneic tumour graft. This highly sensitive in vivo test, even of partial tolerance, did not reveal any difference in allogeneic tumour growth between progeny of control and tolerized males. Thus, the results again did not confirm genetic transmission of induced tolerance.

Suppressor factor from a permanent T cell line inhibits allotransplantation reactions in vivo.

A permanent T cell line producing an antigen-non-specific suppressor factor was established. This factor inhibits the proliferation of lymphoid cells in vitro and, when injected in vivo, it suppresses the allotransplantation reaction. The line established may represent one of the cell populations playing an active role in the induction and maintenance of immunological tolerance.

Prolonged or permanent survival of skin allografts induced by monoclonal antibodies against lymphocyte subpopulations.

The effect of cytotoxic monoclonal antibodies against T lymphocyte subpopulations on skin allograft survival in mice was compared. Antibodies against cytotoxic lymphocytes (anti-Lyt-2.2) suppressed the allotransplantation reaction more effectively than antibodies against helper/inducer T lymphocytes (monoab anti-Lyt-1.

Prolongation of skin allograft survival in ATS-treated mice by post-transplant injections of species antigenic extracts.

B10.A male mice were grafted with H-2-incompatible murine B10.A(2R) skin allografts and treated with antithymocyte serum on days 2, 4, and 7 after transplantation.

Establishment of a macrophage hybrid population by the fusion of mouse peritoneal macrophages with thymoma cells BW5147.

A continuous macrophage hybrid population, designated MBW-1, was produced by the fusion of peritoneal macrophages from a normal AKR mouse with thymoma cells BW5147. The hybrid cells are resistant to HA selection medium. In their nearly triploid chromosome complement they carry metacentric chromosomes typical of BW5147 cells and express the typical macrophage-like characteristics (morphology of macrophages, adherence properties, phagocytosis, expression of macrophage-specific antigen and receptor for the C3b component of complement).

Recognition of syngeneic and allogeneic histocompatibility antigens by peripheral blood leucocytes from non-immunized rats.

Peripheral blood leucocytes from normal, non-immunized adult rats recognize syngeneic and allogeneic tissue antigens, and this recognition can be detected by the tube leucocyte adherence inhibition assay. We show that PBL from newborn rats have the same and even a stronger ability for recognition and that the recognition is preserved in rats bearing tolerated skin allografts after neonatal induction of transplantation tolerance. Testing of tissue extracts prepared from the congenic strain of rats suggested that PBL from normal animals recognize histocompatibility antigens.