Prolonged feeding of ticks enables the transmission of several infectious agents to the mammalian host. Pathogen transmission by ticks is facilitated by the anti-inflammatory properties of tick saliva. While the extraordinary properties of tick saliva have been known for decades, the signaling mechanisms that lead to a more favorable environment for pathogen transmission remain elusive. The lack of such knowledge is problematic because it precludes the development of novel therapies for preventing infectious diseases. In this proposal, we will understand the complex interplay of a tick salivary protein, a pathogen and the vertebrate immune system. We hypothesize that sialostatin L2 - a tick salivary protein - modulates inflammasome activation and facilitates transmission of the rickettsial pathogen Anaplasma phagocytophilum to a mammalian host. The inflammasome promotes the maturation of inflammatory cytokines and is involved in host defense during infection. Our published and unpublished data show that the inflammasome is important for innate immunity against A. phagocytophilum. We also show that sialostatin L2 inhibits inflammasome activation. We will test our central hypothesis that sialostatin L2 facilitates transmission of the rickettsial pathogen A. phagocytophilum to a mammalian host by pursuing the following aims: (1) we will define signaling pathways that lead to inflammasome activation during A. phagocytophilum infection;and (2) we will characterize how sialostatin L2 inhibits inflammasome activation during tick transmission of A. phagocytophilum. The outcome of this proposal is significantly wide in scope. Ticks, mosquitoes, biting flies, fleas and blood feeding bugs have evolved salivary proteins to modulate host defense. Therefore, our findings may stimulate research into a diverse array of vector-host-pathogen associations resulting in new understandings of pathogenesis and immunity of vector-borne diseases. We envisage that deciphering how arthropod-borne pathogens colonize the mammalian host may lead to novel therapeutics against many arthropod borne diseases.

Public Health Relevance

Our application will define mechanistically how a tick salivary protein inhibits the host immune response during pathogen infection. The information gained from this application will provide a novel immunological concept that may be applied to the development of vaccines against rickettsial diseases.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
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Vector Biology Study Section (VB)
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Mukhopadhyay, Suman
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University of California Riverside
Schools of Earth Sciences/Natur
United States
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Chmelař, Jindřich; Kotál, Jan; Karim, Shahid et al. (2016) Sialomes and Mialomes: A Systems-Biology View of Tick Tissues and Tick-Host Interactions. Trends Parasitol 32:242-54
Chmelař, Jindřich; Kotál, Jan; Kopecký, Jan et al. (2016) All For One and One For All on the Tick-Host Battlefield. Trends Parasitol 32:368-77
Shaw, Dana K; Kotsyfakis, Michail; Pedra, Joao H F (2016) For Whom the Bell Tolls (and Nods): Spit-acular Saliva. Curr Trop Med Rep 3:40-50
Kotál, Jan; Langhansová, Helena; Lieskovská, Jaroslava et al. (2015) Modulation of host immunity by tick saliva. J Proteomics 128:58-68
Kotsyfakis, Michalis; Kopáček, Petr; Franta, Zdeněk et al. (2015) Deep Sequencing Analysis of the Ixodes ricinus Haemocytome. PLoS Negl Trop Dis 9:e0003754
Kotsyfakis, Michalis; Kopáček, Petr; Franta, Zdeněk et al. (2015) Correction: Deep Sequencing Analysis of the Ixodes ricinus Haemocytome. PLoS Negl Trop Dis 9:e0003909
Chen, Gang; Wang, Xiaowei; Severo, Maiara S et al. (2014) The tick salivary protein sialostatin L2 inhibits caspase-1-mediated inflammation during Anaplasma phagocytophilum infection. Infect Immun 82:2553-64
Xiao, Han; Lu, Min; Lin, Ting Yang et al. (2013) Sterol regulatory element binding protein 2 activation of NLRP3 inflammasome in endothelium mediates hemodynamic-induced atherosclerosis susceptibility. Circulation 128:632-42
Severo, Maiara S; Choy, Anthony; Stephens, Kimberly D et al. (2013) The E3 ubiquitin ligase XIAP restricts Anaplasma phagocytophilum colonization of Ixodes scapularis ticks. J Infect Dis 208:1830-40
Sakhon, Olivia S; Severo, Maiara S; Kotsyfakis, Michail et al. (2013) A Nod to disease vectors: mitigation of pathogen sensing by arthropod saliva. Front Microbiol 4:308

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