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bioRxiv · 10.1101/2023.01.05.522967

Zika virus infection induces IL-1β-mediated inflammatory responses by macrophages in the brain of an adult mouse model

Jeong, G. U.·Lee, S.·Kim, D. Y.·Lyu, J.·Yoon, G. Y.·Ko, J.·Kwon, Y.-C.
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Abstract

During the 2015/16 Zika virus (ZIKV) epidemic, ZIKV associated neurological diseases were reported in adults, including microcephaly, Guillain-Barre syndrome, myelitis, meningoencephalitis, and fatal encephalitis. However, the mechanisms underlying the neuropathogenesis of ZIKV infection are not yet fully understood. In this study, we used an adult ZIKV-infection mouse model (Ifnar1-/-) to investigate the mechanisms underlying neuroinflammation and neuropathogenesis. ZIKV infection induced the expression of proinflammatory cytokines, including IL-1{beta}, IL-6, IFN-{gamma}, and TNF-, in the brains of Ifnar1-/- mice. RNA-seq analysis of the infected mouse brain also revealed that genes involved in innate immune responses and cytokine-mediated signaling pathways were significantly upregulated at 6 days post infection. Furthermore, ZIKV infection induced macrophage infiltration and activation, and augmented IL-1{beta} expression, whereas microgliosis was not observed in the brain. Using human monocyte THP-1 cells, we confirmed that ZIKV infection promotes inflammatory cell death and increases IL-1{beta} secretion. In addition, the expression of complement component C3, which is associated with neurodegenerative diseases and known to be upregulated by proinflammatory cytokines, was induced by ZIKV infection through the IL-1{beta}-mediated pathway. An increase in C5a produced by complement activation in the brains of ZIKV-infected mice was also confirmed. Taken together, our results suggest that ZIKV infection of the brain in this animal model augments IL-1{beta} expression in infiltrating macrophages and elicits IL-1{beta}-mediated inflammation, which can lead to the destructive consequences of neuroinflammation. ImportanceZika virus (ZIKV) associated neurological impairments are an important global health problem. Our results suggest that ZIKV infection of the mouse brain can induce IL-1{beta}-mediated inflammation and complement activation, contributing to the development of neurological disorders. Thus, our findings reveal a mechanism by which ZIKV induces neuroinflammation in the mouse brain. Although we used adult type I IFN receptor IFNAR knockout (Ifnar1-/-) mice owing to the limited mouse model of ZIKV pathogenesis, our conclusion could contribute to understanding ZIKV associated neurological diseases to develop treatment strategies based on these findings for the patients with ZIKV infection.

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Jeong, G. U., Lee, S., Kim, D. Y., Lyu, J., Yoon, G. Y., Ko, J., Kwon, Y.-C.. 2023-01-06. Zika virus infection induces IL-1β-mediated inflammatory responses by macrophages in the brain of an adult mouse model. https://doi.org/10.1101/2023.01.05.522967

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