Prime Editor Gene Therapy and TREX1 Mosaicism in Retinal Vasculopathy with Cerebral Leukoencephalopathy.

TREX1 mutations underlie a variety of human diseases, including retinal vasculopathy with cerebral leukoencephalopathy (RVCL or RVCL-S), a catastrophic adult-onset vasculopathy that is often confused with multiple sclerosis, systemic vasculitis, or systemic lupus erythematosus. Patients with RVCL develop brain, retinal, liver, and kidney disease around age 35-55, leading to premature death in 100% of patients expressing an autosomal dominant C-terminally truncated form of TREX1. We previously demonstrated that RVCL is characterized by high levels of DNA damage, premature cellular senescence, and risk of early-onset breast cancer before age 45.

Regulation of cGAS and STING signaling during inflammation and infection.

Stimulator of interferon genes (STING) is a sensor of cyclic dinucleotides including cyclic GMP-AMP, which is produced by cyclic GMP-AMP synthase (cGAS) in response to cytosolic DNA. The cGAS-STING signaling pathway regulates both innate and adaptive immune responses, as well as fundamental cellular functions such as autophagy, senescence, and apoptosis. Mutations leading to constitutive activation of STING cause devastating human diseases.

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.

Mutual inhibition between Prkd2 and Bcl6 controls T follicular helper cell differentiation.

T follicular helper cells (T) participate in germinal center (GC) development and are necessary for B cell production of high-affinity, isotype-switched antibodies. In a forward genetic screen, we identified a missense mutation in , encoding the serine/threonine kinase protein kinase D2, which caused elevated titers of immunoglobulin E (IgE) in the serum. Subsequent analysis of serum antibodies in mice with a targeted null mutation of demonstrated polyclonal hypergammaglobulinemia of IgE, IgG1, and IgA isotypes, which was exacerbated by the T cell-dependent humoral response to immunization.

Zika Virus Causes Acute Infection and Inflammation in the Ovary of Mice Without Apparent Defects in Fertility.

Background: Zika virus (ZIKV) has become a global concern because infection of pregnant mothers was linked to congenital birth defects. Zika virus is unique from other flaviviruses, because it is transmitted vertically and sexually in addition to by mosquito vectors. Prior studies in mice, nonhuman primates, and humans have shown that ZIKV targets the testis in males, resulting in persistent infection and oligospermia.

Mxra8 is a receptor for multiple arthritogenic alphaviruses.

Arthritogenic alphaviruses comprise a group of enveloped RNA viruses that are transmitted to humans by mosquitoes and cause debilitating acute and chronic musculoskeletal disease . The host factors required for alphavirus entry remain poorly characterized . Here we use a genome-wide CRISPR-Cas9-based screen to identify the cell adhesion molecule Mxra8 as an entry mediator for multiple emerging arthritogenic alphaviruses, including chikungunya, Ross River, Mayaro and O'nyong nyong viruses.

Oral Antibiotic Treatment of Mice Exacerbates the Disease Severity of Multiple Flavivirus Infections.

Although the outcome of flavivirus infection can vary from asymptomatic to lethal, environmental factors modulating disease severity are poorly defined. Here, we observed increased susceptibility of mice to severe West Nile (WNV), Dengue, and Zika virus infections after treatment with oral antibiotics (Abx) that depleted the gut microbiota. Abx treatment impaired the development of optimal T cell responses, with decreased levels of WNV-specific CD8 T cells associated with increased infection and immunopathology.

Interferon Regulatory Factor 1 Protects against Chikungunya Virus-Induced Immunopathology by Restricting Infection in Muscle Cells.

The innate immune system protects cells against viral pathogens in part through the autocrine and paracrine actions of alpha/beta interferon (IFN-α/β) (type I), IFN-γ (type II), and IFN-λ (type III). The transcription factor interferon regulatory factor 1 (IRF-1) has a demonstrated role in shaping innate and adaptive antiviral immunity by inducing the expression of IFN-stimulated genes (ISGs) and mediating signals downstream of IFN-γ. Although ectopic expression experiments have suggested an inhibitory function of IRF-1 against infection of alphaviruses in cell culture, its role remains unknown.

Therapy with CTLA4-Ig and an antiviral monoclonal antibody controls chikungunya virus arthritis.

In 2013, chikungunya virus (CHIKV) transmission was documented in the Western Hemisphere, and the virus has since spread throughout the Americas with more than 1.8 million people infected in more than 40 countries. CHIKV targets the joints, resulting in symmetric polyarthritis that clinically mimics rheumatoid arthritis and can endure for months to years.

The Interferon-Stimulated Gene IFITM3 Restricts Infection and Pathogenesis of Arthritogenic and Encephalitic Alphaviruses.

Unlabelled: Host cells respond to viral infections by producing type I interferon (IFN), which induces the expression of hundreds of interferon-stimulated genes (ISGs). Although ISGs mediate a protective state against many pathogens, the antiviral functions of the majority of these genes have not been identified. IFITM3 is a small transmembrane ISG that restricts a broad range of viruses, including orthomyxoviruses, flaviviruses, filoviruses, and coronaviruses.

The Interferon-Stimulated Gene Ifitm3 Restricts West Nile Virus Infection and Pathogenesis.

Unlabelled: The interferon-induced transmembrane protein (IFITM) family of proteins inhibit infection of several different enveloped viruses in cell culture by virtue of their ability to restrict entry and fusion from late endosomes. As few studies have evaluated the importance of Ifitm3 in vivo in restricting viral pathogenesis, we investigated its significance as an antiviral gene against West Nile virus (WNV), an encephalitic flavivirus, in cells and mice. Ifitm3(-/-) mice were more vulnerable to lethal WNV infection, and this was associated with greater virus accumulation in peripheral organs and central nervous system tissues.

Intragenic enhancers and suppressors of phytoene desaturase mutations in Chlamydomonas reinhardtii.

Photosynthetic organisms synthesize carotenoids for harvesting light energy, photoprotection, and maintaining the structure and function of photosynthetic membranes. A light-sensitive, phytoene-accumulating mutant, pds1-1, was isolated in Chlamydomonas reinhardtii and found to be genetically linked to the phytoene desaturase (PDS) gene. PDS catalyzes the second step in carotenoid biosynthesis--the conversion of phytoene to ζ-carotene.

Protonation of individual histidine residues is not required for the pH-dependent entry of west nile virus: evaluation of the "histidine switch" hypothesis.

Histidine residues have been hypothesized to function as sensors of environmental pH that can trigger the activity of viral fusion proteins. We investigated a requirement for histidine residues in the envelope (E) protein of West Nile virus during pH-dependent entry into cells. Each histidine was individually replaced with a nonionizable amino acid and tested functionally.