Yersinia pestis, the highly virulent agent of plague, is a biological weapon. Strategies to prevent plague have been sought for centuries, however neither an FDA approved vaccine nor the molecular basis of plague immunity are established. Immunization of animals or humans with live-attenuated (non-pigmented) Y. pestis strains raises protective immunity, however associated side effects prohibit the use of whole cell vaccines in humans. Previous efforts to develop subunit vaccines combined two protein antigens, F1 and LcrV, to prevent bubonic and pneumonic plague. This GLRCE funded research program addresses the need for plague vaccines and also seeks to understand the molecular basis of plague immunity. Our work demonstrated that Y. pestis F1 pili are dispensable for the pathogenesis of bubonic or pneumonic plague. During infection, breakthrough mutants emerge that henceforth escape plague immunity derived from either F1 subunit vaccines or live-attenuated strains. Breakthrough mutants carry IS1541 insertions in cafIA (which specifies the usher for pilus assembly), indicating that F1 pili are not a suitable vaccine component. LcrV subunit vaccines were shown to protect mice and non-human primates against bubonic and pneumonic plague. LcrV displays immune modulatory effects. A variant, V10, lacks these properties, but retains the ability to raise protective immunity. LcrV is positioned at the tip of type III needles and antibodies against LcrV protect immune cells from Yersinia type III injection of effector Yops, a virulence mechanism that blocks bacterial phagocytosis and NF-KB activation by host immune cells. Plague bacteria preferentially inject phagocytes and this target selection requires CD14 and TLR6 on the surface of immune cells. LcrVmediated engagement of CD14/TLR2/TLR6 triggers signal transduction cascades, IL-10 release as well as suppression of proinflammatory cytokines. Goals of this renewal application are to develop subunit vaccines for plague protection and to appreciate plague immunity at a molecular level by determining the nature of protective antibodies and Y. pestis escape variants. Other work will determine the contributions of TLR2, TLR6 and CD14 towards Y. pestis selection of targets for type III injection and unravel the mechanisms whereby the pathogen evades the development of immunity during plague infections.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
5U54AI057153-10
Application #
8448672
Study Section
Special Emphasis Panel (ZAI1-DDS-M)
Project Start
2013-03-01
Project End
2014-02-28
Budget Start
2013-03-01
Budget End
2014-02-28
Support Year
10
Fiscal Year
2013
Total Cost
$334,744
Indirect Cost
$92,300
Name
University of Chicago
Department
Type
DUNS #
005421136
City
Chicago
State
IL
Country
United States
Zip Code
60637
Schuld, Nathan J; Vervacke, Jeffrey S; Lorimer, Ellen L et al. (2014) The chaperone protein SmgGDS interacts with small GTPases entering the prenylation pathway by recognizing the last amino acid in the CAAX motif. J Biol Chem 289:6862-76
Sharma, Preeti; Wang, Ningyan; Kranz, David M (2014) Soluble T cell receptor V? domains engineered for high-affinity binding to staphylococcal or streptococcal superantigens. Toxins (Basel) 6:556-74
Pensinger, Daniel A; Aliota, Matthew T; Schaenzer, Adam J et al. (2014) Selective pharmacologic inhibition of a PASTA kinase increases Listeria monocytogenes susceptibility to ?-lactam antibiotics. Antimicrob Agents Chemother 58:4486-94
Becker, Russell E N; Berube, Bryan J; Sampedro, Georgia R et al. (2014) Tissue-specific patterning of host innate immune responses by Staphylococcus aureus ?-toxin. J Innate Immun 6:619-31
Schiano, Chelsea A; Koo, Jovanka T; Schipma, Matthew J et al. (2014) Genome-wide analysis of small RNAs expressed by Yersinia pestis identifies a regulator of the Yop-Ysc type III secretion system. J Bacteriol 196:1659-70
Stach, Christopher S; Herrera, Alfa; Schlievert, Patrick M (2014) Staphylococcal superantigens interact with multiple host receptors to cause serious diseases. Immunol Res 59:177-81
Lifshitz, Ziv; Burstein, David; Schwartz, Kierstyn et al. (2014) Identification of novel Coxiella burnetii Icm/Dot effectors and genetic analysis of their involvement in modulating a mitogen-activated protein kinase pathway. Infect Immun 82:3740-52
Merriman, Joseph A; Nemeth, Kimberly A; Schlievert, Patrick M (2014) Novel antimicrobial peptides that inhibit gram positive bacterial exotoxin synthesis. PLoS One 9:e95661
Schneewind, Olaf; Missiakas, Dominique (2014) Genetic manipulation of Staphylococcus aureus. Curr Protoc Microbiol 32:Unit 9C.3.
Wang, Ya-Ting; Missiakas, Dominique; Schneewind, Olaf (2014) GneZ, a UDP-GlcNAc 2-epimerase, is required for S-layer assembly and vegetative growth of Bacillus anthracis. J Bacteriol 196:2969-78

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