The NF-κB/leukemia inhibitory factor/STAT3 signaling pathway in antibody-mediated suppression of Sindbis virus replication in neurons
- 3 November 2020
- journal article
- research article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences of the United States of America
- Vol. 117 (46), 29035-29045
- https://doi.org/10.1073/pnas.2016691117
Abstract
Alphaviruses are positive-sense, enveloped RNA viruses that are important causes of viral encephalomyelitis. Sindbis virus (SINV) is the prototype alphavirus and preferentially infects neurons in rodents to induce an encephalomyelitis similar to the human disease. Using a mouse model of SINV infection of the nervous system, many of the immune processes involved in recovery from viral encephalomyelitis have been identified. Antibody specific to the SINV E2 glycoprotein plays an important role in recovery and is sufficient for noncytolytic suppression of virus replication in vivo and in vitro. To investigate the mechanism of anti-E2 antibody-mediated viral suppression, a reverse-phase protein array was used to broadly survey cellular signaling pathway activation following antibody treatment of SINV-infected differentiated AP-7 neuronal cells. Anti-E2 antibody induced rapid transient NF-κB and later sustained Y705 STAT3 phosphorylation, outlining an intracellular signaling cascade activated by antiviral antibody. Because NF-κB target genes include the STAT3-activating IL-6 family cytokines, expression of these messenger RNAS (mRNAs) was assessed. Expression of leukemia inhibitory factor (LIF) cytokine mRNA, but not other IL-6 family member mRNAs, was up-regulated by anti-E2 antibody. LIF induced STAT3 Y705 phosphorylation in infected differentiated AP-7 cells but did not inhibit virus replication. However, anti-E2 antibody localized the LIF receptor to areas of E2 expression on the infected cell surface, and LIF enhanced the antiviral effects of antibody. These findings identify activation of the NF-κB/LIF/STAT3 signaling cascade as involved in inducing antibody-mediated viral suppression and highlight the importance of nonneutralizing antibody functions in viral clearance from neurons.Funding Information
- HHS | National Institutes of Health (R01 NS087539)
- HHS | National Institutes of Health (R01 NS038932)
- HHS | National Institutes of Health (T32 AI007247)
- HHS | National Institutes of Health (T32 AI 007417)
- HHS | National Institutes of Health (F31 NS 101824)
- Mason | College of Science, George Mason University (1000)
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