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

Abstract

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.upper-respiratory viral infection | multiple sclerosis | neuroinflammation | immune cell surveillance | experimental autoimmune encephalomyelitis

TAK1 inhibition in mouse astrocyte cultures ameliorates cytokine‐induced chemokine production and neutrophil migration

“…The ability for astrocytes to produce various chemokines in abundance is significant when considering the pathogenesis of neuroimmunologic diseases. For instance, CXCL5, a neutrophil chemotactic protein and one of the most up‐regulated chemokines secreted by activated astrocytes in this study, was recently reported to be a serum biomarker associated with multiple sclerosis relapse (Rumble et al, ), and was elevated in cerebrospinal fluid samples of patients experiencing relapse compared to those in remission (Blackmore et al, ). Neutrophils have garnered attention for their involvement in EAE (Pierson, Wagner, & Goverman, ), ability to facilitate demyelination(Bell et al, ; Ferrari et al, ; Liu et al, ) Ferrari et al, ; Bell et al, ) and promote neurodegeneration (Zenaro et al, ).…”

“…For instance, it is well established that immune cells traffic to the brain during infection, and that adaptive immune responses occurring within the CNS can be beneficial as they serve to rid the tissue of infectious pathogens (Aguilar-Valenzuela et al, 2018;Borrow, Tonks, Welsh, & Nash, 1992;Ciurkiewicz et al, 2018;Welsh, Tonks, Nash, & Blakemore, 1987). However, a substantial amount of evidence also suggests that resident cells of the CNS alter their transcriptional responses and up-regulate cytokine and chemokine expression in response to systemic inflammation brought on by pathogenic infection outside the CNS (Blackmore et al, 2017;Ji, Schachtschneider, Schook, Walker, & Johnson, 2016). As such, it is not surprising that systemic inflammation can trigger immune cell surveillance of the CNS (Blackmore et al, 2017;Liu, Nemeth, & McKim, 2019;Rummel, Inoue, Poole, & Luheshi, 2010).…”

“…However, a substantial amount of evidence also suggests that resident cells of the CNS alter their transcriptional responses and up-regulate cytokine and chemokine expression in response to systemic inflammation brought on by pathogenic infection outside the CNS (Blackmore et al, 2017;Ji, Schachtschneider, Schook, Walker, & Johnson, 2016). As such, it is not surprising that systemic inflammation can trigger immune cell surveillance of the CNS (Blackmore et al, 2017;Liu, Nemeth, & McKim, 2019;Rummel, Inoue, Poole, & Luheshi, 2010). Although the mechanisms underlying this occurrence have not been entirely elucidated, neutrophil and monocyte trafficking to the brain during peripheral infection promotes sickness behavior and in the case of chronic inflammation may exacerbate neurological disorders.…”

Respiratory virus-induced heterologous immunity

“…HMPV [96], parainfluenza [97] and IV infection [98] or IV vaccination [94] preceding ADEM, have all been reported. Influenza infection has been shown to trigger [99] or exacerbate [100] disease in experimental autoimmune encephalomyelitis (EAE) models, which might be a useful to study ADEM [101].…”

Respiratory virus-induced heterologous immunity

“…HMPV [96], parain uenza [97] and IV infection [98] or IV vaccination [94] preceding ADEM, have all been reported. In uenza infection has been shown to trigger [99] or exacerbate [100] disease in experimental autoimmune encephalomyelitis (EAE) models, which might be a useful to study ADEM [101].…”