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https://doi.org/10.1038/s41467-022-28533-z
Title: | Pharmacological perturbation of CXCL1 signaling alleviates neuropathogenesis in a model of HEVA71 infection | Authors: | SARAVANAN S/O GUNASEELAN Mohammed Zacky Ariffin SANJAY KHANNA Ooi, MH Perera, D Chu, J.J.H. Chua J.J.E. |
Issue Date: | 16-Feb-2022 | Publisher: | Springer Science and Business Media LLC | Citation: | SARAVANAN S/O GUNASEELAN, Mohammed Zacky Ariffin, SANJAY KHANNA, Ooi, MH, Perera, D, Chu, J.J.H., Chua J.J.E. (2022-02-16). Pharmacological perturbation of CXCL1 signaling alleviates neuropathogenesis in a model of HEVA71 infection. Nature communications 13 (1) : 890-. ScholarBank@NUS Repository. https://doi.org/10.1038/s41467-022-28533-z | Abstract: | Hand, foot and mouth disease (HFMD) caused by Human Enterovirus A71 (HEVA71) infection is typically a benign infection. However, in minority of cases, children can develop severe neuropathology that culminate in fatality. Approximately 36.9% of HEVA71-related hospitalizations develop neurological complications, of which 10.5% are fatal. Yet, the mechanism by which HEVA71 induces these neurological deficits remain unclear. Here, we show that HEVA71-infected astrocytes release CXCL1 which supports viral replication in neurons by activating the CXCR2 receptor-associated ERK1/2 signaling pathway. Elevated CXCL1 levels correlates with disease severity in a HEVA71-infected mice model. In humans infected with HEVA71, high CXCL1 levels are only present in patients presenting neurological complications. CXCL1 release is specifically triggered by VP4 synthesis in HEVA71-infected astrocytes, which then acts via its receptor CXCR2 to enhance viral replication in neurons. Perturbing CXCL1 signaling or VP4 myristylation strongly attenuates viral replication. Treatment with AZD5069, a CXCL1-specific competitor, improves survival and lessens disease severity in infected animals. Collectively, these results highlight the CXCL1-CXCR2 signaling pathway as a potential target against HFMD neuropathogenesis. | Source Title: | Nature communications | URI: | https://scholarbank.nus.edu.sg/handle/10635/216616 | ISSN: | 2041-1723 | DOI: | 10.1038/s41467-022-28533-z |
Appears in Collections: | Staff Publications Elements |
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