; Toll-like receptor (TLR) and NOD-like receptor (NLR) signaling during the innate response to infection influences the host cell's permissiveness for cytosolic replication of bacteria and the development of protective immunity. However, it is not entirely clear how these signaling events initiated by engagement of TLRs and NLRs influences the capacity to confer protection against lethal bacterial infection through vaccination. It also is unclear how antibody bound to Francisella tularensis (Ft) in the form of an inactivated Ff-monoclonal antibody (IFf-mAb) complex, the vaccinogen (1,2) under evaluation in this proposal, alters innate signaling via TLR2 or NLRs and thereby the adaptive/protective immune response. Changes in a pathogen's capacity to resist redox-mediated host defenses or alter redox-based host cell signaling, as has been shown for the live vaccine strain (LVS) of Ft deficient for superoxide dismutase activity (3, 4), impacts both TLR and NLR-dependent inflammatory responses. Thus, pathogen-derived antioxidants likely influence the ability of different vaccinogens to engender adaptive/protective immunity. Therefore, we hypothesize that signals transduced via TLR2 and/or NLRs influence the efficacy of vaccination and these signals are impacted by antibody opsonization of Ft and/or the bacterium's proinflammatory capacity. This hypothesis will be tested by 1) Establishing the impact of mAb bound Ft and Ft antioxidant mutants on synergistic TLR2/NLR signaling during the innate immune (inductive) phase of the anti-Ft immune response at the molecular level and 2) Evaluating whether TLR2 and/or NLR signaling impacts induction of protective immunity after vaccination with various Ff formulations. Synergy: Results obtained in Subproject 2 will provide a new view of TLR and NLR-directed innate responses in the context of the ongoing vaccine strategies employed in Subproject 1, enabling refinement of these approaches. The signaling pathways involved in macrophage ROS/RNS production intersect those activated by FcR, TLR, and NLR stimulation, namely the PI3 kinase, NF-KB, and MAPK pathways; accordingly, the results of these Aims are significantly relevant to, and will help inform, experiments in Subproject 3. Further, this synergy will be facilitated by the provision of characterized antioxidant mutants from Subproject 3, thus enabling our Subproject to shed light on how Ft antioxidant pathways impact

Public Health Relevance

The overarching goal of this proposal is to understand the cellular and molecular features of TLR2/NLRmediated responses, how these signaling events contribute to the host's ability to restrain bacterial growth, protective immunity, and how mAb bound to Ft and AAO Ft influences these immunological processes.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Program Projects (P01)
Project #
Application #
Study Section
Special Emphasis Panel (ZAI1-LR-M (S1))
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Albany Medical College
United States
Zip Code
Periasamy, Sivakumar; Avram, Dorina; McCabe, Amanda et al. (2016) An Immature Myeloid/Myeloid-Suppressor Cell Response Associated with Necrotizing Inflammation Mediates Lethal Pulmonary Tularemia. PLoS Pathog 12:e1005517
Sunagar, Raju; Kumar, Sudeep; Franz, Brian J et al. (2016) Tularemia vaccine development: paralysis or progress? Vaccine (Auckl) 6:9-23
McCarthy, Donald A; Nazem, Ahmad A; McNeilan, James et al. (2016) Nanoenhanced matrix metalloproteinase-responsive delivery vehicles for disease resolution and imaging. Exp Biol Med (Maywood) :
Sunagar, Raju; Kumar, Sudeep; Franz, Brian J et al. (2016) Vaccination evokes gender-dependent protection against tularemia infection in C57BL/6Tac mice. Vaccine 34:3396-404
Rabadi, Seham M; Sanchez, Belkys C; Varanat, Mrudula et al. (2016) Antioxidant Defenses of Francisella tularensis Modulate Macrophage Function and Production of Proinflammatory Cytokines. J Biol Chem 291:5009-21
Duffy, Ellen B; Periasamy, Sivakumar; Hunt, Danielle et al. (2016) FcγR mediates TLR2- and Syk-dependent NLRP3 inflammasome activation by inactivated Francisella tularensis LVS immune complexes. J Leukoc Biol 100:1335-1347
Shakerley, Nicole L; Chandrasekaran, Akshaya; Trebak, Mohamed et al. (2016) Francisella tularensis Catalase Restricts Immune Function by Impairing TRPM2 Channel Activity. J Biol Chem 291:3871-81
Franz, Brian J; Li, Ying; Bitsaktsis, Constantine et al. (2015) Downmodulation of vaccine-induced immunity and protection against the intracellular bacterium Francisella tularensis by the inhibitory receptor FcγRIIB. J Immunol Res 2015:840842
Bitsaktsis, Constantine; Babadjanova, Zulfia; Gosselin, Edmund J (2015) In vivo mechanisms involved in enhanced protection utilizing an Fc receptor-targeted mucosal vaccine platform in a bacterial vaccine and challenge model. Infect Immun 83:77-89
Suresh, Ragavan Varadharajan; Ma, Zhuo; Sunagar, Raju et al. (2015) Preclinical testing of a vaccine candidate against tularemia. PLoS One 10:e0124326

Showing the most recent 10 out of 57 publications