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 Our published and unpublished data show that the inflammasome is important for innate immunity against A. phagocytophilum.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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI093653-02
Application #
8298143
Study Section
Vector Biology Study Section (VB)
Program Officer
Mukhopadhyay, Suman
Project Start
2011-07-06
Project End
2013-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
2
Fiscal Year
2012
Total Cost
$352,446
Indirect Cost
$100,442
Name
University of California Riverside
Department
Zoology
Type
Schools of Earth Sciences/Natur
DUNS #
627797426
City
Riverside
State
CA
Country
United States
Zip Code
92521
Shaw, Dana K; Wang, Xiaowei; Brown, Lindsey J et al. (2017) Infection-derived lipids elicit an immune deficiency circuit in arthropods. Nat Commun 8:14401
McClure, Erin E; Chávez, Adela S Oliva; Shaw, Dana K et al. (2017) Engineering of obligate intracellular bacteria: progress, challenges and paradigms. Nat Rev Microbiol 15:544-558
Wang, Xiaowei; Shaw, Dana K; Sakhon, Olivia S et al. (2016) The Tick Protein Sialostatin L2 Binds to Annexin A2 and Inhibits NLRC4-Mediated Inflammasome Activation. Infect Immun 84:1796-805
Wang, Xiaowei; Shaw, Dana K; Hammond, Holly L et al. (2016) The Prostaglandin E2-EP3 Receptor Axis Regulates Anaplasma phagocytophilum-Mediated NLRC4 Inflammasome Activation. PLoS Pathog 12:e1005803
Chmela?, Jind?ich; 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
Chmela?, Jind?ich; 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; McClure, Erin E; Wang, Xiaowei et al. (2016) Deviant Behavior: Tick-Borne Pathogens and Inflammasome Signaling. Vet Sci 3:
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; Kopá?ek, Petr; Franta, Zden?k et al. (2015) Correction: Deep Sequencing Analysis of the Ixodes ricinus Haemocytome. PLoS Negl Trop Dis 9:e0003909

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