Particles from the Echinococcus granulosus Laminated Layer Inhibit CD40 Upregulation in Dendritic Cells by Interfering with Akt Activation

Infect Immun. 2019 Nov 18;87(12):e00641-19. doi: 10.1128/IAI.00641-19. Print 2019 Dec.

Abstract

The larval stage of the cestode Echinococcus granulosus causes cystic echinococcosis in humans and livestock. This larva is protected by the millimeter-thick, mucin-based laminated layer (LL), from which materials have to be shed to allow parasite growth. We previously reported that dendritic cells (DCs) respond to microscopic pieces of the mucin gel of the LL (pLL) with unconventional maturation phenotypes, in the absence or presence of Toll-like receptor (TLR) agonists, including lipopolysaccharide (LPS). We also reported that the presence of pLL inhibited the activating phosphorylation of the phosphatidylinositol 3-kinase (PI3K) effector Akt induced by granulocyte-macrophage colony-stimulating factor or interleukin-4. We now show that the inhibitory effect of pLL extends to LPS as a PI3K activator, and results in diminished phosphorylation of GSK3 downstream from Akt. Functionally, the inhibition of Akt and GSK3 phosphorylation are linked to the blunted upregulation of CD40, a major feature of the unconventional maturation phenotype. Paradoxically, all aspects of unconventional maturation induced by pLL depend on PI3K class I. Additional components of the phagocytic machinery are needed, but phagocytosis of pLL particles is not required. These observations hint at a DC response mechanism related to receptor-independent mechanisms proposed for certain crystalline and synthetic polymer-based particles; this would fit the previously reported lack of detection of molecular-level motifs necessary of the effects of pLL on DCs. Finally, we report that DCs exposed to pLL are able to condition DCs not exposed to the material so that these cannot upregulate CD40 in full in response to LPS.

Keywords: AKT signaling; CD40; Echinococcus; PI3K; dendritic cells; helminths; membrane affinity-triggered signaling.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD40 Antigens / biosynthesis*
  • Cells, Cultured
  • Dendritic Cells / immunology*
  • Echinococcosis / immunology
  • Echinococcosis / parasitology
  • Echinococcosis / pathology
  • Echinococcus granulosus / immunology*
  • Enzyme Activation / immunology
  • Glycogen Synthase Kinase 3 / metabolism
  • Granulocyte-Macrophage Colony-Stimulating Factor / metabolism
  • Interleukin-4 / metabolism
  • Lipopolysaccharides
  • Mice
  • Mice, Inbred C57BL
  • Phagocytosis / physiology
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Phosphorylation
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Signal Transduction / immunology

Substances

  • CD40 Antigens
  • Il4 protein, mouse
  • Lipopolysaccharides
  • Interleukin-4
  • Granulocyte-Macrophage Colony-Stimulating Factor
  • Proto-Oncogene Proteins c-akt
  • Glycogen Synthase Kinase 3