UNIVERSITY OF MASSACHUSETTS
The Role of LPS and Toll-like Receptors in Plague, Award Number R01AI057588 from the NIH - Institute of Allergy and Infectious Diseases, is proposing to use Y. pestis strains that generate modified LPS to study evasion and activation of innate immunity by the plague bacillus. Our model system appears well suited to describe efficient innate immune mechanisms against Y. pestis, and our long-term goal is to define such mechanisms and bacterial countermeasures. 1.) Y pestis expresses LpxP, a lipid A biosynthesis gene that likely is necessary for the production of a hexa-acyl TLR$-activating LPS at lower temperatures. We propose to study regulation of LpxP expression at 37C, as regulation appears necessary for virulence. 2.) We also wish to study the role of evasion of LPS-TLR4 signaling in the evolution of Y. pestis to a highly virulent pathogen from its closest ancestor, Y. pseudotuberculosis (Y. ptb), which only may cause a mild gastroenteritis. Interestingly, Y. ptb harbors an LpxL gene. Our proposal suggests studies of Y. ptb LpxL function, this will include expression of Y. ptb LpxL in Ypestis, and study LPS activity and structures. 3.) Preliminary results indicate that interleukin-1 (IL-1) release and signaling is effective in clearing infection with Y. pestis-LpxL, more so than TNF and type I IFN. We will analyze mechanisms by which Y. pestis induces and is controlled by IL-1, in vitro and in vivo.