Transcriptome analysis of SARS-CoV-2 infected A549-ACE2 cells depleted for IKKa, RelA, RelB or Ctrl (NTC)
Inflammatory processes serve as critical defense mechanisms against microbial pathogens, yet their dysregulation can lead to collateral damage, including multi-organ failure and exacerbated disease pathogenesis. How inflammation influences microbial propagation and disease progression remains incompletely understood. Here, we show that the central NF-?B kinase IKKa contributes to the endosomal uptake and maturation pathway that is commonly used by viruses and bacteria. Chemical inhibition or genetic deletion of IKKa impaired uptake of coronaviruses, poxviruses, Shigella and Salmonella in vitro and reduced viral RNA abundance in lungs in a SARS-CoV-2 in vivo mouse model. Functionally, IKKa depletion or inhibition trapped viral particles in the endolysosomal compartment, while viruses that enter cells by plasma membrane fusion were not affected. The here described activity of IKKa is independent of NF-?B transcription factors but involves IKKa-dependent phosphorylation of ß-catenin, a critical regulator of endocytosis. We here propose a mechanistic link between inflammation and the endosomal uptake machinery. The aggravated inflammatory response, commonly associated with inflammation-driven diseases, may represent a pathogen-driven mechanism that favors IKKa activity and might thereby contribute to pathogen uptake in inflamed tissue.
Inflammatory processes serve as critical defense mechanisms against microbial pathogens, yet their dysregulation can lead to collateral damage, including multi-organ failure and exacerbated disease pathogenesis. How inflammation influences microbial propagation and disease progression remains incompletely understood. Here, we show that the central NF-?B kinase IKKa contributes to the endosomal uptake and maturation pathway that is commonly used by viruses and bacteria. Chemical inhibition or genetic deletion of IKKa impaired uptake of coronaviruses, poxviruses, Shigella and Salmonella in vitro and reduced viral RNA abundance in lungs in a SARS-CoV-2 in vivo mouse model. Functionally, IKKa depletion or inhibition trapped viral particles in the endolysosomal compartment, while viruses that enter cells by plasma membrane fusion were not affected. The here described activity of IKKa is independent of NF-?B transcription factors but involves IKKa-dependent phosphorylation of ß-catenin, a critical regulator of endocytosis. We here propose a mechanistic link between inflammation and the endosomal uptake machinery. The aggravated inflammatory response, commonly associated with inflammation-driven diseases, may represent a pathogen-driven mechanism that favors IKKa activity and might thereby contribute to pathogen uptake in inflamed tissue.