Dissecting the signaling pathways controlling inflammation during Gram-negative bacterial infections : the role of ALPK1, TIFA and TRAF6 during Shigella flexneri infection

Abstract : Epithelial cells represent the first line of defense against pathogens and play an active role in innate immunity. Via local secretion of cytokines, they are able to orchestrate the immune response against invading pathogens. The activation of both intracellular and extracellular pathogen recognition receptors leads to a complex signaling cascade, resulting in the activation of the transcription factor nuclear factor kB(NF-kB)and the subsequent production of pro-inflammatory cytokines. However, the molecular mechanisms governing this process have not been fully elucidated. The Gram-negative bacterium Shigella flexneriis an important human pathogen and the causative agent of bacillary dysentery. This disease is characterized by acute inflammation of the colon resulting in the destruction of the intestinal tissue and, in severe cases, death. S. flexneri can invade and replicate within colonic epithelial cells. Following detection of the bacteria, both infected and uninfected bystander cells initiate inflammatory signaling pathways, which result in massive interleukin-8 (IL-8) production by the latter. Using S. flexneri as a model of infection, we have identified a novel signaling pathway, which is central to the activation of NF-kB and the subsequent production of IL-8 during Gram-negative bacterial infections. Following the cytosolic detection of bacteria, the protein TRAF-interacting factor with forkhead-associated domain (TIFA) forms oligomers, a process dependent on its threonine at position 9 and theforkhead-associated domain. These oligomers interact withTNF receptor associated factor (TRAF)6, leading to its oligomerization and the subsequent activation of NF-kB. In addition, we show that oligomerization of TIFA is dependent on the kinase alpha-kinase(ALPK)1 and that this pathway is activated in response to the detection of the bacterial metabolite heptose-1, 7-bisphosphate (HBP). These observations could be extended to the enteroinvasive pathogen Salmonella typhimurium as well as the extracellular bacteria Neisseria meningitidis. Our results therefore demonstrate the central role of the ALPK1-TIFA-TRAF6 signaling pathway in response to HBP of both intracellular and extracellular Gram-negative bacterial pathogens, and offer a better understanding of the molecular mechanisms governing the epithelial cell immune response to pathogenic bacteria.
Complete list of metadatas

Cited literature [384 references]  Display  Hide  Download

https://tel.archives-ouvertes.fr/tel-02180591
Contributor : Abes Star <>
Submitted on : Thursday, July 11, 2019 - 3:30:09 PM
Last modification on : Saturday, July 13, 2019 - 1:14:30 AM

File

va_Milivojevic_Milica.pdf
Version validated by the jury (STAR)

Identifiers

  • HAL Id : tel-02180591, version 1

Collections

Citation

Milica Milivojevic. Dissecting the signaling pathways controlling inflammation during Gram-negative bacterial infections : the role of ALPK1, TIFA and TRAF6 during Shigella flexneri infection. Bacteriology. Université Sorbonne Paris Cité, 2017. English. ⟨NNT : 2017USPCB061⟩. ⟨tel-02180591⟩

Share

Metrics

Record views

53

Files downloads

11