Rickettsial agents are sensed by pattern recognition receptors but lack pathogen-associated molecular patterns commonly observed in facultative intracellular bacteria. Due to these molecular features, the order Rickettsiales can be used to uncover broader principles of bacterial immunity. Here, we used the bacterium Anaplasma phagocytophilum, the agent of human granulocytic anaplasmosis, to reveal a novel microbial surveillance system. Mechanistically, we discovered that upon A. phagocytophilum infection, cytosolic phospholipase A2 cleaves arachidonic acid from phospholipids, which is converted to the eicosanoid prostaglandin E2 (PGE2) via cyclooxygenase 2 (COX2) and the membrane associated prostaglandin E synthase-1 (mPGES-1). PGE2-EP3 receptor signaling leads to activation of the NLRC4 inflammasome and secretion of interleukin (IL)-1β and IL-18. Importantly, the receptor-interacting serine/threonine-protein kinase 2 (RIPK2) was identified as a major regulator of the immune response against A. phagocytophilum. Accordingly, mice lacking COX2 were more susceptible to A. phagocytophilum, had a defect in IL-18 secretion and exhibited splenomegaly and damage to the splenic architecture. Remarkably, Salmonella-induced NLRC4 inflammasome activation was not affected by either chemical inhibition or genetic ablation of genes associated with PGE2 biosynthesis and signaling. This divergence in immune circuitry was due to reduced levels of the PGE2-EP3 receptor during Salmonella infection when compared to A. phagocytophilum. Collectively, we reveal the existence of a functionally distinct NLRC4 inflammasome illustrated by the rickettsial agent A. phagocytophilum.
- MeSH
- Anaplasma phagocytophilum imunologie MeSH
- dinoproston imunologie MeSH
- ehrlichióza imunologie MeSH
- ELISA MeSH
- imunoblotting MeSH
- inflamasomy imunologie MeSH
- kvantitativní polymerázová řetězová reakce MeSH
- modely nemocí na zvířatech MeSH
- myši inbrední C57BL MeSH
- myši knockoutované MeSH
- myši MeSH
- proteiny regulující apoptózu imunologie MeSH
- proteiny vázající vápník imunologie MeSH
- receptory prostaglandinů E - podtyp EP3 imunologie MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Tick saliva contains a number of effector molecules that inhibit host immunity and facilitate pathogen transmission. How tick proteins regulate immune signaling, however, is incompletely understood. Here, we describe that loop 2 of sialostatin L2, an anti-inflammatory tick protein, binds to annexin A2 and impairs the formation of the NLRC4 inflammasome during infection with the rickettsial agent Anaplasma phagocytophilum Macrophages deficient in annexin A2 secreted significantly smaller amounts of interleukin-1β (IL-1β) and IL-18 and had a defect in NLRC4 inflammasome oligomerization and caspase-1 activation. Accordingly, Annexin a2-deficient mice were more susceptible to A. phagocytophilum infection and showed splenomegaly, thrombocytopenia, and monocytopenia. Providing translational support to our findings, better binding of annexin A2 to sialostatin L2 in sera from 21 out of 23 infected patients than in sera from control individuals was also demonstrated. Overall, we establish a unique mode of inflammasome evasion by a pathogen, centered on a blood-feeding arthropod.
- MeSH
- Anaplasma phagocytophilum genetika imunologie MeSH
- annexin A2 chemie genetika imunologie MeSH
- arachnida jako vektory chemie genetika imunologie MeSH
- cystatiny chemie genetika imunologie MeSH
- ehrlichióza imunologie mikrobiologie patologie MeSH
- Escherichia coli genetika metabolismus MeSH
- imunitní únik * MeSH
- inflamasomy genetika imunologie MeSH
- interleukin-18 genetika imunologie MeSH
- interleukin-1beta genetika imunologie MeSH
- kaspasa 1 genetika imunologie MeSH
- kaspasy genetika imunologie MeSH
- klíště chemie genetika imunologie MeSH
- lidé MeSH
- makrofágy imunologie mikrobiologie MeSH
- molekulární modely MeSH
- myši MeSH
- protein - isoformy chemie genetika imunologie MeSH
- proteiny regulující apoptózu chemie genetika imunologie MeSH
- proteiny vázající vápník chemie genetika imunologie MeSH
- regulace genové exprese MeSH
- rekombinantní proteiny chemie genetika imunologie MeSH
- sekvence aminokyselin MeSH
- signální transdukce MeSH
- vazba proteinů MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH