instmctions): Our overall objective is to develop approaches for effective vaccination against pulmonary tularemia. During the previous funding period, we made considerable progress, including the demonstration that significant protection in C57BL/6 mice against the highly virulent type A strain of F. tularensis {Ft), SchuS4, can be induced by i.n. inoculation of FcR-targeted inactivated LVS { Ft). This is the first case to our knowledge in wliich an inactivated vaccine has provided protection against Ft SchuS4. In this renewal application, we will further optimize conditions for mucosal vaccination, characterize the effects of pulmonary vaccination, and define the cellular and humoral mechanisms responsible for protective immunity against the highly virulent type A strain, SchuS4. Specifically, we will: 1) Determine the ability of i.n. vaccination with FcR-targeted immunogens, in the absence or presence of exogenous IL-12, to enhance the immune response to, and levels of protection against, mucosal (i.n.) challenge with Ft SchuS4. Two separate approaches will be used to target Ft to FcR: a) administration of preformed mAb-IFf complexes, and b) simultaneous inoculation of uncomplexed Ft plus anti-Ff mAb;2) Establish the mechanisms responsible for enhanced induction of immunity by assessing the distribution of FcR targeted Ft to tissues and lymphoid organs to determine if enhanced localization of ' Ft to secondary lymphoid tissues, and APC within these tissues, occurs as a result of FcR targeting. It will also be determined if enhanced Ft processing and presentation results from targeting to FcR on APC;and 3) Establish the effector mechanisms responsible for enhanced protection after i.n. vaccination with FcR-targeted bacteria. The mechanisms responsible for protection after mucosal vaccination will be investigated by passive transfer of anti-F/ antibody or cells to naive mice with particular attention paid to examining a potential requirement for synergy between humoral and cellular immune mechanisms for induction of effective protection. The roles of TLR/NLRs and ROS/RNS in both inductive and effector phases will be examined by using genetically deficient mice and specific agonists/antagonists, in consultation with the PLs of subprojects 2 and 3. The results of subproject 1 will allow the design of new mucosal vaccination strategies for effective biodefense against infection with virulent Ft and will provide novel insight into the pulmonary immune mechanisms that are responsible for protection against respiratory tularemia.

Public Health Relevance

(See Instruct'ons): The results of this subproject will allow the design of new mucosal vaccination strategies for effective biodefense against infection with virulent Ft and will provide novel insight into the pulmonary immune mechanisms that are responsible for protection against respiratory tularemia.

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
Chen, Fei; Cui, Guolin; Wang, Shuxia et al. (2017) Outer membrane vesicle-associated lipase FtlA enhances cellular invasion and virulence in Francisella tularensis LVS. Emerg Microbes Infect 6:e66
Periasamy, Sivakumar; Porter, Kristen A; Atianand, Maninjay K et al. (2017) Pyrin-only protein 2 limits inflammation but improves protection against bacteria. Nat Commun 8:15564
Holland, Kristen M; Rosa, Sarah J; Kristjansdottir, Kolbrun et al. (2017) Differential Growth of Francisella tularensis, Which Alters Expression of Virulence Factors, Dominant Antigens, and Surface-Carbohydrate Synthases, Governs the Apparent Virulence of Ft SchuS4 to Immunized Animals. Front Microbiol 8:1158
Duffy, Ellen B; Periasamy, Sivakumar; Hunt, Danielle et al. (2016) Fc?R mediates TLR2- and Syk-dependent NLRP3 inflammasome activation by inactivated Francisella tularensis LVS immune complexes. J Leukoc Biol 100:1335-1347
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
He, Lihong; Nair, Manoj Kumar Mohan; Chen, Yuling et al. (2016) The Protease Locus of Francisella tularensis LVS Is Required for Stress Tolerance and Infection in the Mammalian Host. Infect Immun 84:1387-402
McCarthy, Donald A; Nazem, Ahmad A; McNeilan, James et al. (2016) Featured Article: Nanoenhanced matrix metalloproteinase-responsive delivery vehicles for disease resolution and imaging. Exp Biol Med (Maywood) 241:2023-2032
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
Kumar, Sudeep; Sunagar, Raju; Pham, Giang et al. (2016) Differential Cultivation of Francisella tularensis Induces Changes in the Immune Response to and Protective Efficacy of Whole Cell-Based Inactivated Vaccines. Front Immunol 7:677
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

Showing the most recent 10 out of 65 publications