Influenza infection triggers disease in a genetic model of experimental autoimmune encephalomyelitis

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 114; no. 30; pp. E6107 - E6116
• Main Authors: Blackmore, Stephen, Hernandez, Jessica, Juda, Michal, Ryder, Emily, Freund, Gregory G., Johnson, Rodney W., Steelman, Andrew J.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 25.07.2017
• Series: PNAS Plus
• Subjects: Alphainfluenzavirus; Animals; Autoimmune diseases; Biological Sciences; Brain; Brain diseases; Cell activation; Central nervous system; Cerebellum; Cerebellum - immunology; Cerebellum - metabolism; Cerebrospinal fluid; Chemokine CXCL5 - immunology; Chemokine CXCL5 - metabolism; Cytometry; Demyelination; Encephalomyelitis, Autoimmune, Experimental - complications; Encephalomyelitis, Autoimmune, Experimental - genetics; Experimental allergic encephalomyelitis; Experiments; Flow cytometry; Gene expression; Genetics; Health risks; Immunologic Surveillance; Infections; Inflammation; Influenza; Influenza A; Lymphocytes T; Mice; Mice, Inbred C57BL; Mice, Transgenic; Monocytes; Multiple sclerosis; Neurological diseases; Orthomyxoviridae Infections - complications; Patients; PNAS Plus; Remission; Spinal cord; Spinal Cord - immunology; Spinal Cord - metabolism; T cell receptors; Transcriptome; Transgenic mice; Viruses; experimental autoimmune encephalomyelitis; upper-respiratory viral infection; neuroinflammation; immune cell surveillance; multiple sclerosis
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1620415114

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system. Most MS patients experience periods of symptom exacerbation (relapses) followed by periods of partial recovery (remission). Interestingly, upper-respiratory viral infections increase the risk for relapse. Here, we used an autoimmune-prone T-cell receptor transgenic mouse (2D2) and a mouse-adapted human influenza virus to test the hypothesis that upper-respiratory viral infection can cause glial activation, promote immune cell trafficking to the CNS, and trigger disease. Specifically, we inoculated 2D2 mice with influenza A virus (Puerto Rico/8/34; PR8) and then monitored them for symptoms of inflammatory demyelination. Clinical and histological experimental autoimmune encephalomyelitis was observed in ∼29% of infected 2D2 mice. To further understand how peripheral infection could contribute to disease onset, we inoculated wild-type C57BL/6 mice and measured transcriptomic alterations occurring in the cerebellum and spinal cord and monitored immune cell surveillance of the CNS by flow cytometry. Infection caused temporal alterations in the transcriptome of both the cerebellum and spinal cord that was consistent with glial activation and increased T-cell, monocyte, and neutrophil trafficking to the brain at day 8 post infection. Finally, Cxcl5 expression was up-regulated in the brains of influenza-infected mice and was elevated in cerebrospinal fluid of MS patients during relapse compared with specimens acquired during remission. Collectively, these data identify a mechanism by which peripheral infection may exacerbate MS as well as other neurological diseases.