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

• Main Authors: Saravanan, Gunaseelan, Mohammed Zacky, Ariffin, Sanjay, Khanna, Mong, How Ooi, Perera, David, Chu, Justin Jang Hann, Chua, John Jia En
• Format: Article
• Language: English
• Published: Springer Nature 2022
• Subjects: RA0421 Public health. Hygiene. Preventive Medicine
• Online Access: http://ir.unimas.my/id/eprint/38040/1/Pharmacological%20perturbation%20of%20CXCL1.pdf; http://ir.unimas.my/id/eprint/38040/; https://www.nature.com/articles/s41467-022-28533-z

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.