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 genetics   immunology   MeSH
• Annexin A2 chemistry   genetics   immunology   MeSH
• Arachnid Vectors chemistry   genetics   immunology   MeSH
• Cystatins chemistry   genetics   immunology   MeSH
• Ehrlichiosis immunology   microbiology   pathology   MeSH
• Escherichia coli genetics   metabolism   MeSH
• Immune Evasion * MeSH
• Inflammasomes genetics   immunology   MeSH
• Interleukin-18 genetics   immunology   MeSH
• Interleukin-1beta genetics   immunology   MeSH
• Caspase 1 genetics   immunology   MeSH
• Caspases genetics   immunology   MeSH
• Ixodes chemistry   genetics   immunology   MeSH
• Humans MeSH
• Macrophages immunology   microbiology   MeSH
• Models, Molecular MeSH
• Mice MeSH
• Protein Isoforms chemistry   genetics   immunology   MeSH
• Apoptosis Regulatory Proteins chemistry   genetics   immunology   MeSH
• Calcium-Binding Proteins chemistry   genetics   immunology   MeSH
• Gene Expression Regulation MeSH
• Recombinant Proteins chemistry   genetics   immunology   MeSH
• Amino Acid Sequence MeSH
• Signal Transduction MeSH
• Protein Binding MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH