STING-mediated disruption of calcium homeostasis chronically activates ER stress and primes T cell death

STING gain-of-function mutations cause lung disease and T cell cytopenia through unknown mechanisms. Here, we found that these mutants induce chronic activation of ER stress and unfolded protein response (UPR), leading to T cell death by apoptosis in th

A human STAT1 gain-of-function mutation impairs CD8 + T cell responses against gammaherpesvirus 68

Autosomal dominant STAT1 mutations in humans have been associated with chronic mucocutaneous candidiasis (CMC), as well as with increased susceptibility to herpesvirus infections. Prior studies have focused on mucosal and Th17-mediated immunity agains

Protective and pathogenic effects of interferon signaling during pregnancy

Immune regulation at the maternal-fetal interface is complex due to conflicting immunological objectives: protection of the fetus from maternal pathogens and prevention of immune-mediated rejection of the semiallogeneic fetus and placenta. Interferon (IFN) signaling plays an important role in restricting congenital infections as well as in the physiology of healthy pregnancies. In this review, we discuss the antiviral and pathogenic effects of type I IFN (IFN-α, IFN-β), type II IFN (IFN-γ), and type III IFN (IFN-λ) during pregnancy, with an emphasis on mouse and non-human primate models of congenital Zika virus infection. In the context of these animal model systems, we examine the role of IFN signaling during healthy pregnancy. Finally, we review mechanisms by which dysregulated type I IFN responses contribute to poor pregnancy outcomes in humans with autoimmune disease, including interferonopathies and systemic lupus erythematosus

The IFN-γ receptor promotes immune dysregulation and disease in STING gain-of-function mice

STING gain-of-function mutations cause STING-associated vasculopathy with onset in infancy (SAVI) in humans, a disease characterized by spontaneous lung inflammation and fibrosis. Mice with STING gain-of-function mutations (SAVI mice) develop αβ T cell-dependent lung disease and also lack lymph nodes. Although SAVI has been regarded as a type I interferonopathy, the relative contributions of the three interferon receptors are incompletely understood. Here, we show that STING gain of function led to upregulation of IFN-γ-induced chemokines in the lungs of SAVI mice and that deletion of the type II IFN receptor (IFNGR1), but not the type I IFN receptor (IFNAR1) or type III IFN receptor (IFNλR1), ameliorated lung disease and restored lymph node development in SAVI mice. Furthermore, deletion of IFNGR1, but not IFNAR1 or IFNλR1, corrected the ratio of effector to Tregs in SAVI mice and in mixed bone marrow chimeric mice. Finally, cultured SAVI mouse macrophages were hyperresponsive to IFN-γ, but not IFN-β, in terms of Cxcl9 upregulation and cell activation. These results demonstrate that IFNGR1 plays a major role in autoinflammation and immune dysregulation mediated by STING gain of function

TBK1 and IKKε act redundantly to mediate STING-induced NF-κB responses in myeloid cells

Stimulator of Interferon Genes (STING) is a critical component of host innate immune defense but can contribute to chronic autoimmune or autoinflammatory disease. Once activated, the cyclic guanosine monophosphate (GMP)-adenosine monophosphate (AMP) (cGAMP) synthase (cGAS)-STING pathway induces both type I interferon (IFN) expression and nuclear factor-κB (NF-κB)-mediated cytokine production. Currently, these two signaling arms are thought to be mediated by a single upstream kinase, TANK-binding kinase 1 (TBK1). Here, using genetic and pharmacological approaches, we show that TBK1 alone is dispensable for STING-induced NF-κB responses in human and mouse immune cells, as well as in vivo. We further demonstrate that TBK1 acts redundantly with IκB kinase ε (IKKε) to drive NF-κB upon STING activation. Interestingly, we show that activation of IFN regulatory factor 3 (IRF3) is highly dependent on TBK1 kinase activity, whereas NF-κB is significantly less sensitive to TBK1/IKKε kinase inhibition. Our work redefines signaling events downstream of cGAS-STING. Our findings further suggest that cGAS-STING will need to be targeted directly to effectively ameliorate the inflammation underpinning disorders associated with STING hyperactivity

Neurogenesis Deep Learning

Neural machine learning methods, such as deep neural networks (DNN), have achieved remarkable success in a number of complex data processing tasks. These methods have arguably had their strongest impact on tasks such as image and audio processing - data processing domains in which humans have long held clear advantages over conventional algorithms. In contrast to biological neural systems, which are capable of learning continuously, deep artificial networks have a limited ability for incorporating new information in an already trained network. As a result, methods for continuous learning are potentially highly impactful in enabling the application of deep networks to dynamic data sets. Here, inspired by the process of adult neurogenesis in the hippocampus, we explore the potential for adding new neurons to deep layers of artificial neural networks in order to facilitate their acquisition of novel information while preserving previously trained data representations. Our results on the MNIST handwritten digit dataset and the NIST SD 19 dataset, which includes lower and upper case letters and digits, demonstrate that neurogenesis is well suited for addressing the stability-plasticity dilemma that has long challenged adaptive machine learning algorithms.Comment: 8 pages, 8 figures, Accepted to 2017 International Joint Conference on Neural Networks (IJCNN 2017

A Mouse Model of Zika Virus Pathogenesis

SummaryThe ongoing Zika virus (ZIKV) epidemic and unexpected clinical outcomes, including Guillain-Barré syndrome and birth defects, has brought an urgent need for animal models. We evaluated infection and pathogenesis with contemporary and historical ZIKV strains in immunocompetent mice and mice lacking components of the antiviral response. Four- to six-week-old Irf3−/− Irf5−/− Irf7−/− triple knockout mice, which produce little interferon α/β, and mice lacking the interferon receptor (Ifnar1−/−) developed neurological disease and succumbed to ZIKV infection, whereas single Irf3−/−, Irf5−/−, and Mavs−/− knockout mice exhibited no overt illness. Ifnar1−/− mice sustained high viral loads in the brain and spinal cord, consistent with evidence that ZIKV causes neurodevelopmental defects in human fetuses. The testes of Ifnar1−/− mice had the highest viral loads, which is relevant to sexual transmission of ZIKV. This model of ZIKV pathogenesis will be valuable for evaluating vaccines and therapeutics as well as understanding disease pathogenesis

Barrier-to-autointegration factor 1 protects against a basal cGAS-STING response

Although the pathogen recognition receptor pathways that activate cell-intrinsic antiviral responses are well delineated, less is known about how the host regulates this response to prevent sustained signaling and possible immune-mediated damage. Using a genome-wide CRISPR-Cas9 screening approach to identify host factors that modulate interferon-stimulated gene (ISG) expression, we identified the DNA binding protein Barrier-to-autointegration factor 1 (Banf1), a previously described inhibitor of retrovirus integration, as a modulator of basal cell-intrinsic immunity. Ablation of Banf1 by gene editing resulted in chromatin activation near host defense genes with associated increased expression of ISGs, includin