Yersinia pestis is best known as the causative agent of bubonic plague, a disease transmitted by the bite of infected fleas. However, if inhaled, this pathogen also produces a severe primary pneumonia known as pneumonic plague, which is both contagious and highly lethal. Although an experimental vaccine that consists of Y. pestis F1 and LcrV proteins has given encouraging results in murine models, an efficient vaccine against pneumonic plague in primates remains elusive. Moreover, F1-deficient strains of Y. pestis retain the ability to cause pneumonic plague, allowing for the potential breakdown of protection due to spontaneous or engineered loss of F1 expression in F1/LcrV vaccinated individuals. Experimental data from several groups, including our own, indicates that the pH 6 antigen (Psa fimbriae) is expressed on extracellular bacteria in vivo. We recently observed that vaccination with Psa affords significant protection against an attenuated Y. pestis strain in pulmonary infection experiments in mice.
The first aim of this study is to further verify the protective properties of Psa by challenging mice with the fully virulent strains KIM1001 and CO92. The value of an iron-treated mouse model for use with the attenuated pgm strain KIM5 will be investigated in parallel experiments. In vitro correlates of antibody- and T cell-mediated protection will be established. As we have shown that the Psa protein antigen induces a strong humoral response, passive protection by antibody transfer from vaccinated to naive mice will be evaluated. The involvement of T cell-mediated protection will be evaluated in B-cell deficient mice by immunization and T cell transfer experiments.
Our second aim i s to characterize the role of Psa in plague pathogenicity. We have shown that the Psa fimbriae are multimeric adhesins that mediate Y. pestis binding to human respiratory tract epithelial cells by interacting with high avidity to choline moieties of phosphatidylcholine, and with lower avidity to 21-linked galactosyl residues of glycolipids. As we (and others) have demonstrated that Psa accelerates Y. pestis dissemination in infected hosts, we shall evaluate whether Psa-mediated adhesion contributes to this response. Site-directed Psa fimbriated mutants unable to bind to choline or/and 21-linked galactosyl will be engineered and their disseminating properties will be investigated in mice. The results obtained will guide the design of polymeric inhibitors capable of blocking Psa-mediated bacterial adhesion. Identifying inhibitors that delay bacterial dissemination in vivo will support future development of adhesion inhibitors as anti-virulence therapeutics. The goal of our first aim is to determine if Psa would be a valuable immunogen to add to the current experimental F1-LcrV vaccine to offer a broader protection against plague and particularly the pneumonic form. The goal of our second aim is to determine if Psa-mediated adhesion contributes to virulence and if development of therapeutics designed to block Psa-mediated adhesion could delay disease progression, thereby improving the success of antibiotic treatments.

Public Health Relevance

This proposal's first goal is to determine the use of a Yersinia pestis surface structure, the Psa fimbriae, as a protective immunogen against plague. A second goal is to characterize the use of inhibitors of Psa, Psa acting as a virulence factor by supporting bacterial colonization of the host and disease progression. The result of these studies will provide a useful basis for future development of vaccines and drugs that support traditional antibiotic therapy.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Exploratory/Developmental Grants (R21)
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Special Emphasis Panel (ZRG1-IDM-A (90))
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Mukhopadhyay, Suman
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University of Pennsylvania
Schools of Veterinary Medicine
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Nair, Manoj K M; De Masi, Leon; Yue, Min et al. (2015) Adhesive properties of YapV and paralogous autotransporter proteins of Yersinia pestis. Infect Immun 83:1809-19
Bao, Rui; Nair, Manoj K M; Tang, Wai-kwan et al. (2013) Structural basis for the specific recognition of dual receptors by the homopolymeric pH 6 antigen (Psa) fimbriae of Yersinia pestis. Proc Natl Acad Sci U S A 110:1065-70
Bartra, Sara Schesser; Gong, Xin; Lorica, Cherish D et al. (2012) The outer membrane protein A (OmpA) of Yersinia pestis promotes intracellular survival and virulence in mice. Microb Pathog 52:41-6
Bao, Rui; Esser, Lothar; Sadhukhan, Annapurna et al. (2012) Crystallization and preliminary X-ray diffraction analysis of PsaA, the adhesive pilin subunit that forms the pH 6 antigen on the surface of Yersinia pestis. Acta Crystallogr Sect F Struct Biol Cryst Commun 68:1243-6
Guo, Jitao; Nair, Manoj K M; Galvan, Estela M et al. (2011) Tn5AraOut mutagenesis for the identification of Yersinia pestis genes involved in resistance towards cationic antimicrobial peptides. Microb Pathog 51:121-32
Galvan, Estela M; Nair, Manoj Kumar Mohan; Chen, Huaiqing et al. (2010) Biosafety level 2 model of pneumonic plague and protection studies with F1 and Psa. Infect Immun 78:3443-53