title: The Tick Protein Sialostatin L2 Binds to Annexin A2 and Inhibits NLRC4-Mediated Inflammasome Activation.
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.
authors.affiliation: Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, Maryland, USA.
authors.forename: Xiaowei
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, Maryland, USA.
authors.forename: Dana K
authors.initials: DK
authors.lastname: Shaw
authors.affiliation: Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, Maryland, USA.
authors.forename: Olivia S
authors.initials: OS
authors.lastname: Sakhon
authors.affiliation: Institute of Human Virology, Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland, USA.
authors.forename: Greg A
authors.initials: GA
authors.lastname: Snyder
authors.affiliation: Institute of Human Virology, Departments of Medicine and Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, Maryland, USA.
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Sundberg
authors.affiliation: Departments of Pathology, Microbiology and Immunology and Orthopedic Surgery, Albert Einstein College of Medicine, Yeshiva University, Bronx, New York, USA.
authors.forename: Laura
authors.initials: L
authors.lastname: Santambrogio
authors.affiliation: Inflammation Program and Division of Infectious Diseases, Department of Internal Medicine, University of Iowa, Iowa City, Iowa, USA.
authors.forename: Fayyaz S
authors.initials: FS
authors.lastname: Sutterwala
authors.affiliation: Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, Maryland, USA.|Department of Pathology, University of Maryland School of Medicine, Baltimore, Maryland, USA.
authors.forename: J Stephen
authors.initials: JS
authors.lastname: Dumler
authors.affiliation: Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, Maryland, USA.
authors.forename: Kari Ann
authors.initials: KA
authors.lastname: Shirey
authors.affiliation: Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, Maryland, USA.
authors.forename: Darren J
authors.initials: DJ
authors.lastname: Perkins
authors.affiliation: Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, Maryland, USA.
authors.forename: Katharina
authors.initials: K
authors.lastname: Richard
authors.affiliation: Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Maryland, USA.
authors.forename: Andrezza C
authors.initials: AC
authors.lastname: Chagas
authors.affiliation: Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Maryland, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Calvo
authors.affiliation: Faculty of Science, University of South Bohemia in České Budějovice, Budweis, Czech Republic.
authors.forename: Jan
authors.initials: J
authors.lastname: Kopecký
authors.affiliation: Institute of Parasitology, Biology Centre, Czech Academy of Sciences, Budweis, Czech Republic.
authors.forename: Michail
authors.initials: M
authors.lastname: Kotsyfakis
authors.affiliation: Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, Maryland, USA jpedra@som.umaryland.edu.
authors.forename: Joao H F
authors.initials: JHF
authors.lastname: Pedra
mesh_terms: D000595:Amino Acid Sequence; D041081:Anaplasma phagocytophilum / Q000235:genetics / Q000276:immunology*; D000818:Animals; D017306:Annexin A2 / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D051017:Apoptosis Regulatory Proteins / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D001096:Arachnid Vectors / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D002135:Calcium-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D020170:Caspase 1 / Q000235:genetics / Q000276:immunology; D020169:Caspases / Q000235:genetics / Q000276:immunology; D053471:Caspases, Initiator; D015891:Cystatins / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D016873:Ehrlichiosis / Q000276:immunology / Q000382:microbiology* / Q000473:pathology; D004926:Escherichia coli / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D057131:Immune Evasion; D058847:Inflammasomes / Q000235:genetics / Q000276:immunology; D020382:Interleukin-18 / Q000235:genetics / Q000276:immunology; D053583:Interleukin-1beta / Q000235:genetics / Q000276:immunology; D018884:Ixodes / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D008264:Macrophages / Q000276:immunology / Q000382:microbiology; D051379:Mice; D008958:Models, Molecular; D011485:Protein Binding; D020033:Protein Isoforms / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction
chemical_list: D017306:Annexin A2; D051017:Apoptosis Regulatory Proteins; D002135:Calcium-Binding Proteins; D015891:Cystatins; C587672:IL1B protein, mouse; D058847:Inflammasomes; D020382:Interleukin-18; D053583:Interleukin-1beta; C512299:Ipaf protein, mouse; D020033:Protein Isoforms; D011994:Recombinant Proteins; C515505:sialostatin L, Ixodes scapularis; C101136:Casp4 protein, mouse; D020169:Caspases; D053471:Caspases, Initiator; D020170:Caspase 1