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

  • Nat Commun. 2022 Feb 16;13(1):890. doi: 10.1038/s41467-022-28533-z.
Saravanan Gunaseelan  1  2  3 ,  Mohammed Zacky Ariffin  1 ,  Sanjay Khanna  1  3 ,  Mong How Ooi  4  5 ,  David Perera  5 ,  Justin Jang Hann Chu  6  7  8 ,  John Jia En Chua  9  10  11  12
Affiliations
  • 1. Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
  • 2. Department of Microbiology and Immunology, National University of Singapore, Singapore, 117597, Singapore.
  • 3. LSI Neurobiology Programme, National University of Singapore, Singapore, 117456, Singapore.
  • 4. Department of Paediatrics, Sarawak General Hospital, Kuching, Sarawak, Malaysia.
  • 5. Institute of Health and Community Medicine, Universiti Malaysia Sarawak, Kota Samarahan, Sarawak, Malaysia.
  • 6. Department of Microbiology and Immunology, National University of Singapore, Singapore, 117597, Singapore. [email protected].
  • 7. Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), Singapore, 138673, Singapore. [email protected].
  • 8. Infectious Disease Translational Research Programme, National University of Singapore, Singapore, 117597, Singapore. [email protected].
  • 9. Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore. [email protected].
  • 10. LSI Neurobiology Programme, National University of Singapore, Singapore, 117456, Singapore. [email protected].
  • 11. Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), Singapore, 138673, Singapore. [email protected].
  • 12. Healthy Longevity Translational Research Program, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore. [email protected].
PMID: 35173169 DOI: 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.

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