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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
2P01AI056320-08A1
Application #
8226331
Study Section
Special Emphasis Panel (ZAI1-LR-M (S1))
Project Start
Project End
Budget Start
2011-12-01
Budget End
2012-11-30
Support Year
8
Fiscal Year
2012
Total Cost
$455,024
Indirect Cost
$151,972
Name
Albany Medical College
Department
Type
DUNS #
190592162
City
Albany
State
NY
Country
United States
Zip Code
12208
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

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