Our overall objective is to develop approaches for effective vaccination against pulmonary tularemia. Our strategy will involve an innovative combination of vaccine approaches that will exploit TLR/NLR agonists identified in Subproject 2 and anti-oxidant F tularensis (Ft) mutants developed in Subproject 3. During the previous funding period, we made considerable progress (see Program Overview), including the demonstration that significant protection in C57BL/6 mice against the highly virulent type A strain of Ft, SchuS4, can be induced by i.n. inoculation of FcR-targeted inactivated LVS ( Ft). This is the first case to our knowledge in which an inactivated vaccine has provided protection against Ft SchuS4. In addition, anti-oxidant mutants (AAO) of Ft were found to induce partial protection against SchuS4 in the highly sensitive C57BI/6 mouse strain. 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 SchuS4. Specifically, we will: 1) Determine the ability of i.n. vaccination with FcR-targeted immunogens in combination with use of anti-oxidant mutants (AAO) of Ft generated in Subproject 3, and /or TLR/NLR agonists identified in Subproject 2, to maximally enhance the immune response to, and levels of protection against, mucosal (i.n.) challenge with Ft SchuS4 at challenge doses up to 20,000 CPU;2) Establish the impact of Ft LVS, AAO Ft LVS and AAO Ft SchuS4, both in live and inactivated forms, on processing and presentation by M0 and DC of non-targeted and FcRtargeted Ft antigen in the presence or absence TLR/NLR agonists;and 3) Define the effector mechanisms responsible for enhanced protection after i.n. vaccination with protective immunogens identified in Aim 1 including testing the postulate that synergy between humoral and cellular immune mechanisms is required for induction of effective protection. The roles of TLR/NLRs and ROS/RNS in both inductive and effector phases will also 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 platforms 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.
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.
|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) FcÎ³R 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 FcÎ³RIIB. 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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