Journal
EMBO MOLECULAR MEDICINE
Volume 11, Issue 1, Pages -Publisher
WILEY
DOI: 10.15252/emmm.201809528
Keywords
antiviral response; genetic susceptibility; GLDC; severe influenza; viral replication
Categories
Funding
- Health and Medical Research Fund (HMRF) of Food and Health Bureau [RRG-05, 17161272]
- Collaborative Research Fund of the Research Grants Council [C7011-15R]
- Government of Hong Kong Special Administrative Region
- High Level Hospital-Summit Program in Guangdong
- University of Hong Kong-Shenzhen Hospital
- Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Ministry of Education of China
- National Project of Infectious Disease, Ministry of Science and Technology of China [2014ZX10004001004]
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Glycine decarboxylase (GLDC) was prioritized as a candidate susceptibility gene to severe influenza in humans. The higher expression of GLDC derived from genetic variations may confer a higher risk to H7N9 and severe H1N1 infection. We sought to characterize GLDC as functional susceptibility gene that GLDC may intrinsically regulate antiviral response, thereby impacting viral replication and disease outcome. We demonstrated that GLDC inhibitor AOAA and siRNA depletion boosted IFN beta- and IFN-stimulated genes (ISGs) in combination with PolyI:C stimulation. GLDC inhibition and depletion significantly amplified antiviral response of type I IFNs and ISGs upon viral infection and suppressed the replication of H1N1 and H7N9 viruses. Consistently, GLDC overexpression significantly promoted viral replication due to the attenuated antiviral responses. Moreover, GLDC inhibition in H1N1-infected BALB/c mice recapitulated the amplified antiviral response and suppressed viral growth. AOAA provided potent protection to the infected mice from lethal infection, comparable to a standard antiviral against influenza viruses. Collectively, GLDC regulates cellular antiviral response and orchestrates viral growth. GLDC is a functional susceptibility gene to severe influenza in humans.
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