RETRACTED ARTICLE: Pharmacological perturbation of CXCL1 signaling alleviates neuropathogenesis in a model of HEVA71 infection

Saravanan Gunaseelan, Mohammed Zacky Ariffin, Sanjay Khanna, Mong How Ooi, David Perera, Justin Jang Hann Chu () and John Jia En Chua ()
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Saravanan Gunaseelan: National University of Singapore
Mohammed Zacky Ariffin: National University of Singapore
Sanjay Khanna: National University of Singapore
Mong How Ooi: Sarawak General Hospital, Kuching
David Perera: Universiti Malaysia Sarawak, Kota Samarahan
Justin Jang Hann Chu: National University of Singapore
John Jia En Chua: National University of Singapore

Nature Communications, 2022, vol. 13, issue 1, 1-21

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-28533-z

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