4.7 Article

Influenza A induces lactate formation to inhibit type I IFN in primary human airway epithelium

Journal

ISCIENCE
Volume 24, Issue 11, Pages -

Publisher

CELL PRESS
DOI: 10.1016/j.isci.2021.103300

Keywords

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Funding

  1. Graduate School of Health Aarhus University
  2. Fhv. Dir. Leo Nielsen & Hustru Karen Margrethe Nielsens Legat for Laegevidenskabelig Grundforskning
  3. Ester M. & Konrad Kristian Sigurdssons Dyrevaernsfond
  4. Beckett-fonden
  5. Kong Christian IX & Dronning Louises Jubilaeumslegat
  6. Christian Larsen & Dommer Ellen Larsens Legat
  7. Direktor Emil C. Hertz & hustru Inger Hertz' fond og A.P. Moller Fonden
  8. Francis Crick Institute from Cancer Research UK [FC001206]
  9. UK Medical Council [FC001206]
  10. Wellcome Trust [FC001206]

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In this study, the researchers demonstrated that both Influenza A virus (IAV) and severe acute respiratory syndrome corona virus 2 (SARS-CoV-2) induce distinct metabolic changes in human airway epithelium, with lactate dehydrogenase A (LDHA) playing a key role in regulating type I interferon responses and promoting IAV replication. The findings suggest that LDHA and lactate promote IAV replication by inhibiting MAVS-dependent induction of type I IFN in primary human airway epithelium, highlighting a potential target for future antiviral strategies.
Pathogenic viruses induce metabolic changes in host cells to secure the availability of biomolecules and energy to propagate. Influenza A virus (IAV) and severe acute respiratory syndrome corona virus 2 (SARS-CoV-2) both infect the human airway epithelium and are important human pathogens. The metabolic changes induced by these viruses in a physiologically relevant human model and how this affects innate immune responses to limit viral propagation are not wellknown. Using an ex vivo model of pseudostratified primary human airway epithelium,we here demonstrate that infection with both IAV and SARS-CoV-2 resulted in distinct metabolic changes including increases in lactate dehydrogenase A(LDHA) expression and LDHA-mediated lactate formation. Interestingly, LDHA regulated both basal and induced mitochondrial anti-viral signaling protein(MAVS)-dependent type I interferon (IFN) responses to promote IAV, but notSARS-CoV-2, replication. Our data demonstrate that LDHA and lactate promote IAV but not SARS-CoV-2 replication by inhibiting MAVS-dependent induction of type I IFN in primary human airway epithelium.

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