Extracellular vesicles are thought to facilitate pathogen transmission from arthropods to humans and other animals. Here, we reveal that pathogen spreading from arthropods to the mammalian host is multifaceted. Extracellular vesicles from Ixodes scapularis enable tick feeding and promote infection of the mildly virulent rickettsial agent Anaplasma phagocytophilum through the SNARE proteins Vamp33 and Synaptobrevin 2 and dendritic epidermal T cells. However, extracellular vesicles from the tick Dermacentor andersoni mitigate microbial spreading caused by the lethal pathogen Francisella tularensis. Collectively, we establish that tick extracellular vesicles foster distinct outcomes of bacterial infection and assist in vector feeding by acting on skin immunity. Thus, the biology of arthropods should be taken into consideration when developing strategies to control vector-borne diseases.

• MeSH
• Anaplasma phagocytophilum patogenita   MeSH
• bakteriální infekce imunologie   metabolismus   MeSH
• buněčné linie MeSH
• členovci metabolismus   mikrobiologie   fyziologie   MeSH
• Dermacentor metabolismus   mikrobiologie   fyziologie   MeSH
• extracelulární vezikuly metabolismus   ultrastruktura   MeSH
• Francisella tularensis patogenita   MeSH
• genová ontologie MeSH
• intravitální mikroskopie MeSH
• klíšťata metabolismus   mikrobiologie   MeSH
• klíště metabolismus   mikrobiologie   fyziologie   MeSH
• kůže imunologie   mikrobiologie   parazitologie   MeSH
• lidé MeSH
• membránový protein 2 asociovaný s vezikuly metabolismus   MeSH
• myši inbrední C57BL MeSH
• myši knockoutované MeSH
• myši MeSH
• proteiny R-SNARE metabolismus   MeSH
• proteomika MeSH
• T-lymfocyty metabolismus   MeSH
• tandemová hmotnostní spektrometrie MeSH
• transmisní elektronová mikroskopie MeSH
• zánět imunologie   metabolismus   parazitologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Research Support, N.I.H., Extramural MeSH
• Research Support, U.S. Gov't, Non-P.H.S. MeSH

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