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Title: Pharmacological perturbation of CXCL1 signaling alleviates neuropathogenesis in a model of HEVA71 infection
Mohammed Zacky Ariffin 
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.
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
ISSN: 2041-1723
DOI: 10.1038/s41467-022-28533-z
Appears in Collections:Staff Publications

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