The Tick Protein Sialostatin L2 Binds to Annexin A2 and Inhibits NLRC4-Mediated Inflammasome Activation

Infect Immun. 2016 May 24;84(6):1796-1805. doi: 10.1128/IAI.01526-15. Print 2016 Jun.

Abstract

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 terms

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

Substances

  • Annexin A2
  • Apoptosis Regulatory Proteins
  • Calcium-Binding Proteins
  • Cystatins
  • IL1B protein, mouse
  • Inflammasomes
  • Interleukin-18
  • Interleukin-1beta
  • Ipaf protein, mouse
  • Protein Isoforms
  • Recombinant Proteins
  • sialostatin L, Ixodes scapularis
  • Casp4 protein, mouse
  • Caspases
  • Caspase 1