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Microbial Degradation of Cellular Kinases Impairs Innate Immune Signaling and Paracrine TNFα Responses

Kenneth Barth1, Caroline Attardo Genco1

  • 1Department of Integrative Physiology and Pathobiology, Tufts University School of Medicine, 136 Harrison Avenue, Boston, MA 02111, USA.

Scientific Reports
|October 5, 2016
PubMed

Insights

Porphyromonas gingivalis uses a toxin called Kgp to degrade key immune signaling proteins, dampening the body's innate immune response and inflammatory processes during infection.

Area of Science:

  • Innate immunity
  • Molecular microbiology
  • Signaling pathways

Background:

  • NFκB and MAPK pathways are vital for innate immunity, orchestrating responses to pathogens.
  • Activation leads to proinflammatory mediators like TNFα, crucial for paracrine signaling at infection sites.

Purpose of the Study:

  • To identify mechanisms by which Porphyromonas gingivalis disrupts innate immune responses.
  • To investigate the role of P. gingivalis lysine-specific gingipain (Kgp) in immune signaling.

Main Methods:

  • Investigated the effect of P. gingivalis Kgp on intracellular immune kinases (RIPK1, TAK1, AKT) in human endothelial cells.
  • Assessed endothelial cell responsiveness to TNFα and downstream signaling pathways (AKT, ERK, NFκB).
  • Analyzed the induction of proinflammatory mRNA, including cytokines, chemokines, and adhesion molecules.

Main Results:

  • P. gingivalis Kgp selectively degraded RIPK1, TAK1, and AKT, leading to dysregulated innate immune signaling.
  • Kgp attenuated endothelial response to TNFα, reducing signal flux and downstream proinflammatory mRNA induction.
  • Absence of Kgp activity prevented kinase degradation and maintained endothelial responsiveness to TNFα.

Conclusions:

  • P. gingivalis employs a novel mechanism to suppress innate immunity by disrupting kinase signaling and degrading inflammatory mediators.
  • Kgp inhibition of cell activation, paracrine signaling, and proinflammatory responses represents a unique pathogen-induced immune dysregulation.
  • Targeting Kgp may offer therapeutic strategies against P. gingivalis-mediated immune suppression.

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