Our previous work under the RMRCE demonstrates that immunological protection against a Francisella tularensis infection can be elicited with an acellular vaccine, and in particular, a membrane preparation from this bacterium admixed with an adjuvant inducing a Th1 response is required to generate a protective adaptive immune response. Further, the level of protection elicited by a specific antigen preparation can be dramatically altered based on the adjuvant and route of delivery. Thus, tools are available to assess more precisely the innate and adaptive responses required for protection against F. tularensis. The humoral and cellular immune responses are both required to achieve optimal protection, with a B1b cell mediated IgM response being of greatest importance for early (3 days post-vaccination) protective immunity. These data along with the observation that the membrane protein fraction (MPF) admixed with the CLDC adjuvant stimulates inactivated macrophages to clear virulent F. tularensis leads us to hypothesize that surface structures of F. tularensis are critical targets for vaccine development and that stimulation of the proper innate response and T cell independent humoral immunity against surface structures can be exploited for a therapeutic vaccine to augment standard antibiotic treatment against F. tularensis and prevent relapse. To further these studies we will 1) identify F. tularensis surface proteins and non-protein structures that are targets for vaccine and therapeutic development;2) elucidate protective immune responses elicited by adjuvant complexed accellular preparations and LVS vaccination;and 3) assess therapeutic vaccination to augment conventional chemotherapeutic treatment of tularemia and prevent relapse. This research project fits within the RMRCE Integrated Research Focus on Immunomodulation, Adjuvants and Vaccines, and will interact directly with RP1.2 and utilize the resources of Cores E and F.

Public Health Relevance

The work proposed in the application will provide detailed information allowing the development of an acellular vaccine against tularemia. Further, these efforts will demonstrate whether therapeutic vaccination augments standard chemotherapy against an acute bacterial infection and can prevent relapse. Such an approach would have broad implications to the treatment of infections by highly virulent bacterial pathogens.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
5U54AI065357-09
Application #
8465795
Study Section
Special Emphasis Panel (ZAI1-DDS-M)
Project Start
Project End
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
9
Fiscal Year
2013
Total Cost
$199,855
Indirect Cost
$51,630
Name
Colorado State University-Fort Collins
Department
Type
DUNS #
785979618
City
Fort Collins
State
CO
Country
United States
Zip Code
80523
Gibson, Christopher C; Zhu, Weiquan; Davis, Chadwick T et al. (2015) Strategy for identifying repurposed drugs for the treatment of cerebral cavernous malformation. Circulation 131:289-99
Wang, Hong; Siddharthan, Venkatraman; Hall, Jeffery O et al. (2014) Autonomic deficit not the cause of death in West Nile virus neurological disease. Clin Auton Res 24:15-23
Scharton, Dionna; Bailey, Kevin W; Vest, Zachary et al. (2014) Favipiravir (T-705) protects against peracute Rift Valley fever virus infection and reduces delayed-onset neurologic disease observed with ribavirin treatment. Antiviral Res 104:84-92
Shives, Katherine D; Beatman, Erica L; Chamanian, Mastooreh et al. (2014) West nile virus-induced activation of mammalian target of rapamycin complex 1 supports viral growth and viral protein expression. J Virol 88:9458-71
Calvert, Amanda E; Dixon, Kandice L; Delorey, Mark J et al. (2014) Development of a small animal peripheral challenge model of Japanese encephalitis virus using interferon deficient AG129 mice and the SA14-14-2 vaccine virus strain. Vaccine 32:258-64
Richert, Laura E; Rynda-Apple, Agnieszka; Harmsen, Ann L et al. (2014) CD11cýýý cells primed with unrelated antigens facilitate an accelerated immune response to influenza virus in mice. Eur J Immunol 44:397-408
Soffler, Carl; Bosco-Lauth, Angela M; Aboellail, Tawfik A et al. (2014) Pathogenesis of percutaneous infection of goats with Burkholderia pseudomallei: clinical, pathologic, and immunological responses in chronic melioidosis. Int J Exp Pathol 95:101-19
Porta, Jason; Jose, Joyce; Roehrig, John T et al. (2014) Locking and blocking the viral landscape of an alphavirus with neutralizing antibodies. J Virol 88:9616-23
Jones-Carson, Jessica; Zweifel, Adrienne E; Tapscott, Timothy et al. (2014) Nitric oxide from IFN?-primed macrophages modulates the antimicrobial activity of ?-lactams against the intracellular pathogens Burkholderia pseudomallei and Nontyphoidal Salmonella. PLoS Negl Trop Dis 8:e3079
Phillips, Aaron T; Schountz, Tony; Toth, Ann M et al. (2014) Liposome-antigen-nucleic acid complexes protect mice from lethal challenge with western and eastern equine encephalitis viruses. J Virol 88:1771-80

Showing the most recent 10 out of 181 publications