B. Joseph Hinnebusch, Ph.D.

Chief, Plague Section
Senior Investigator

Plague Section

Description of Research Program

Xenopsylla cheopis flea infected with Yersinia pestis. The foregut of this flea is blocked by a Y. pestis biofilm, which is prerequisite for efficient transmission.

Yersinia pestis, the agent of bubonic and pneumonic plague, is one of the most virulent of human bacterial pathogens and is well known historically for its ability to cause devastating pandemics. Plague remains an international public health concern and periodically re-emerges in the form of sudden large outbreaks, most recently in India and Africa. The isolation of antibiotic-resistant strains of Y. pestis and the potential use of Y. pestis by bioterrorists increase the urgency for better medical countermeasures against plague.

We study the genetic and molecular processes underlying plague transmission, infection, and immunity; applying modern molecular biology, genomics, and immunology tools to the flea and small rodent infection models that we have established. One goal is to identify and determine the function of Y. pestis genes that mediate transmission by fleas. Detailed understanding of the interaction with the insect vector may lead to novel strategies to interrupt the transmission cycle. For example, determining the antigens expressed on the Y. pestis surface as the bacteria exit the flea and enter the mammal may help in the design of new vaccines and diagnostics.

Plague is a highly fulminant disease that rapidly leads to life-threatening sepsis. Our in vivo gene expression and immunologic analyses indicate that this depends in large part on a number of Y. pestis virulence factors that dampen, retard, or otherwise thwart the mammalian innate immune response. We are interested in understanding the detailed function of these factors and determining their specific targets and mechanisms of action. Use of the natural flea-borne transmission route and systems to examine the intradermal flea-bacteria-host transmission interface are important elements of this work, enabling us to take into account the effects of vector saliva and other factors specific to the microenvironment of the flea-bite site. We are also using our animal model systems to identify and evaluate new Y. pestis antigens for use in plague vaccines and diagnostics and to characterize the host response to naturally acquired infection.

Major Areas of Research 

• Interactions of Yersinia pestis with its rat-flea vector Xenopsylla cheopis that lead to transmission
• Mechanisms of Yersinia pestis pathogenicity and immune evasion
• Aspects of the flea-bacteria-host transmission interface that influence nascent infection and immunity
• Characterization of a protective immune response to plague; new plague vaccines and diagnostics

Research Group Members

Back row, left to right: B. Joseph Hinnebusch, Ph.D.; Christopher F. Bosio, Ph.D.; Julie A. Callison, M.S. Front row, left to right: Viveka Vadyvaloo, Ph.D., postdoctoral fellow; Jason E. Comer, Ph.D., postdoctoral fellow; Clayton Jarrett, M.S. Not pictured: Yicheng Sun, Ph.D., postdoctoral fellow

Selected Publications

To view a complete listing, visit PubMed.

Sebbane F, Lemaître N, Sturdevant DE, Rebeil R, Virtaneva K, Porcella SF, Hinnebusch BJ. Adaptive response of Yersinia pestis to extracellular effectors of innate immunity during bubonic plague. Proc Natl Acad Sci U S A. 2006 Aug 1;103(31):11766-71.

Sebbane F, Jarrett CO, Gardner D, Long D, Hinnebusch BJ. Role of the Yersinia pestis plasminogen activator in the incidence of distinct septicemic and bubonic forms of flea-borne plague. Proc Natl Acad Sci U S A. 2006 Apr 4;103(14):5526-30.

Sebbane F, Gardner D, Long D, Gowen BB, Hinnebusch BJ. Kinetics of disease progression and host response in a rat model of bubonic plague. Am J Pathol. 2005 May;166(5):1427-39.

Lorange EA, Race BL, Sebbane F, Joseph Hinnebusch B. Poor vector competence of fleas and the evolution of hypervirulence in Yersinia pestis. J Infect Dis. 2005 Jun 1;191(11):1907-12.

Jarrett CO, Deak E, Isherwood KE, Oyston PC, Fischer ER, Whitney AR, Kobayashi SD, DeLeo FR, Hinnebusch BJ. Transmission of Yersinia pestis from an infectious biofilm in the flea vector. J Infect Dis. 2004 Aug 15;190(4):783-92.

Hinnebusch BJ, Rudolph AE, Cherepanov P, Dixon JE, Schwan TG, Forsberg A. Role of Yersinia murine toxin in survival of Yersinia pestis in the midgut of the flea vector. Science. 2002 Apr 26;296(5568):733-5.

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