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RETRACTED ARTICLE: Pharmacological perturbation of CXCL1 signaling alleviates neuropathogenesis in a model of HEVA71 infection

Author

Listed:
  • Saravanan Gunaseelan

    (National University of Singapore
    National University of Singapore
    National University of Singapore)

  • Mohammed Zacky Ariffin

    (National University of Singapore)

  • Sanjay Khanna

    (National University of Singapore
    National University of Singapore)

  • Mong How Ooi

    (Sarawak General Hospital, Kuching
    Universiti Malaysia Sarawak, Kota Samarahan)

  • David Perera

    (Universiti Malaysia Sarawak, Kota Samarahan)

  • Justin Jang Hann Chu

    (National University of Singapore
    Technology and Research (A*STAR)
    National University of Singapore)

  • John Jia En Chua

    (National University of Singapore
    National University of Singapore
    Technology and Research (A*STAR)
    National University of Singapore)

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.

Suggested Citation

  • Saravanan Gunaseelan & Mohammed Zacky Ariffin & Sanjay Khanna & Mong How Ooi & David Perera & Justin Jang Hann Chu & John Jia En Chua, 2022. "RETRACTED ARTICLE: Pharmacological perturbation of CXCL1 signaling alleviates neuropathogenesis in a model of HEVA71 infection," Nature Communications, Nature, vol. 13(1), pages 1-21, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-28533-z
    DOI: 10.1038/s41467-022-28533-z
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    References listed on IDEAS

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    1. Gael Boivin & Julien Faget & Pierre-Benoit Ancey & Aspasia Gkasti & Julie Mussard & Camilla Engblom & Christina Pfirschke & Caroline Contat & Justine Pascual & Jessica Vazquez & Nathalie Bendriss-Verm, 2020. "Durable and controlled depletion of neutrophils in mice," Nature Communications, Nature, vol. 11(1), pages 1-9, December.
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