Type I IFNs and CD8 T cells increase intestinal barrier permeability after chronic viral infection
| Autor: | Karenina Sanders, Steven P. Nilsen, Jerrold R. Turner, Elina I. Zuniga, Tara Schwartz, Gregory Humphrey, Austin D. Swafford, Rob Knight, Lara Labarta-Bajo |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
CD8-Positive T-Lymphocytes Inbred C57BL Medical and Health Sciences Mesoderm Mice 0302 clinical medicine Intestinal mucosa 2.1 Biological and endogenous factors 2.2 Factors relating to the physical environment Lymphocytic choriomeningitis virus Immunology and Allergy Cytotoxic T cell Intestinal Mucosa Clostridiales Tight junction Mucosal Immunology Colitis Haematopoiesis Infectious Diseases 030220 oncology & carcinogenesis Paracellular transport Interferon Type I Female Infection Signal Transduction Immunology Firmicutes Lymphocytic Choriomeningitis Biology Lymphocytic choriomeningitis Autoimmune Disease Article Antibodies Permeability Virus Infectious Disease and Host Defense Vaccine Related 03 medical and health sciences Biodefense medicine Animals Tight Junction Proteins Prevention Epithelial Cells Hematopoietic Stem Cells medicine.disease Gastrointestinal Microbiome Mice Inbred C57BL Emerging Infectious Diseases 030104 developmental biology Gene Expression Regulation Viral replication Chronic Disease Digestive Diseases |
| Zdroj: | The Journal of experimental medicine, vol 217, iss 12 The Journal of Experimental Medicine |
| ISSN: | 1540-9538 0022-1007 |
| Popis: | Intestinal barrier dysfunction is a marker of disease progression during chronic viral infections, but its causes remain mostly unknown. This study demonstrates essential roles for type I IFN signaling and CD8 T cell responses in increasing intestinal permeability during chronic viral infection. Intestinal barrier leakage constitutes a potential therapeutic target for many inflammatory diseases and represents a disease progression marker during chronic viral infections. However, the causes of altered gut barrier remain mostly unknown. Using murine infection with lymphocytic choriomeningitis virus, we demonstrate that, in contrast to an acute viral strain, a persistent viral isolate leads to long-term viral replication in hematopoietic and mesenchymal cells, but not epithelial cells (IECs), in the intestine. Viral persistence drove sustained intestinal epithelial barrier leakage, which was characterized by increased paracellular flux of small molecules and was associated with enhanced colitis susceptibility. Type I IFN signaling caused tight junction dysregulation in IECs, promoted gut microbiome shifts and enhanced intestinal CD8 T cell responses. Notably, both type I IFN receptor blockade and CD8 T cell depletion prevented infection-induced barrier leakage. Our study demonstrates that infection with a virus that persistently replicates in the intestinal mucosa increases epithelial barrier permeability and reveals type I IFNs and CD8 T cells as causative factors of intestinal leakage during chronic infections. Graphical Abstract |
| Databáze: | OpenAIRE |
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