ABSTRACT
Autoinflammatory disease can result from monogenic errors of immunity. We describe a patient with early-onset multi-organ immune dysregulation resulting from a mosaic, gain-of-function mutation (S703I) in JAK1, encoding a kinase essential for signaling downstream of >25 cytokines. By custom single-cell RNA sequencing, we examine mosaicism with single-cell resolution. We find that JAK1 transcription was predominantly restricted to a single allele across different cells, introducing the concept of a mutational "transcriptotype" that differs from the genotype. Functionally, the mutation increases JAK1 activity and transactivates partnering JAKs, independent of its catalytic domain. S703I JAK1 is not only hypermorphic for cytokine signaling but also neomorphic, as it enables signaling cascades not canonically mediated by JAK1. Given these results, the patient was treated with tofacitinib, a JAK inhibitor, leading to the rapid resolution of clinical disease. These findings offer a platform for personalized medicine with the concurrent discovery of fundamental biological principles.
Subject(s)
Hereditary Autoinflammatory Diseases/genetics , Hereditary Autoinflammatory Diseases/pathology , Janus Kinase 1/genetics , Systemic Inflammatory Response Syndrome/genetics , Systemic Inflammatory Response Syndrome/pathology , Adolescent , COVID-19/mortality , Catalytic Domain/genetics , Cell Line , Cytokines/metabolism , Female , Gain of Function Mutation/genetics , Genotype , HEK293 Cells , Hereditary Autoinflammatory Diseases/drug therapy , Humans , Janus Kinase 1/antagonists & inhibitors , Mosaicism , Piperidines/therapeutic use , Precision Medicine/methods , Pyrimidines/therapeutic use , Signal Transduction/immunology , Systemic Inflammatory Response Syndrome/drug therapyABSTRACT
Consistent observations report increased severity of SARS-CoV-2 infection in overweight men with cardiovascular factors. As the visceral fat possesses an intense immune activity, is involved in metabolic syndrome and is at the crossroad between the intestines, the systemic circulation and the lung, we hypothesized that it plays a major role in severe forms of SARS-CoV-2 infection. SARS-CoV2 presents the ability to infect epithelial cells of the respiratory tract as well as the intestinal tract. Several factors may increase intestinal permeability including direct enterocyte damage by SARS-CoV2, systemic inflammatory response syndrome (SIRS) and epithelial ischemia secondary to SARS-CoV2- associated endothelial dysfunction. This increase permeability further leads to translocation of microbial components such as MAMPs (microbial-associated molecular pattern), triggering an inflammatory immune response by TLR-expressing cells of the mesentery fat (mostly macrophages and adipocytes). The pro-inflammatory cytokines produced by the mesentery fat mediates systemic inflammation and aggravate acute respiratory distress syndrome (ARDS) through the mesenteric lymph drainage.
Subject(s)
COVID-19/physiopathology , Lung/physiopathology , Lymphatic System/physiopathology , Obesity/physiopathology , COVID-19/complications , Critical Care , Cytokines/metabolism , Gastrointestinal Microbiome , Humans , Immune System , Inflammation , Intensive Care Units , Intra-Abdominal Fat/pathology , Ischemia/pathology , Male , Metabolic Syndrome/immunology , Models, Theoretical , Obesity/complications , Overweight/complications , Permeability , Risk Factors , Systemic Inflammatory Response Syndrome/immunologyABSTRACT
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
ABSTRACT
The COVID-19 pandemic caused by infection with SARS-CoV-2 has led to more than 200,000 deaths worldwide. Several studies have now established that the hyperinflammatory response induced by SARS-CoV-2 is a major cause of disease severity and death in infected patients. Macrophages are a population of innate immune cells that sense and respond to microbial threats by producing inflammatory molecules that eliminate pathogens and promote tissue repair. However, a dysregulated macrophage response can be damaging to the host, as is seen in the macrophage activation syndrome induced by severe infections, including in infections with the related virus SARS-CoV. Here we describe the potentially pathological roles of macrophages during SARS-CoV-2 infection and discuss ongoing and prospective therapeutic strategies to modulate macrophage activation in patients with COVID-19.