– address important scientific questions;

The timely application of plague prevention measures depends on our abilities to rapidly recognize human cases and threatening situations, such as plague epizootics in animals. Our ability to effectively target limited plague prevention resources also depends on our understanding of the factors affecting the transmission and maintenance of the plague bacterium (Yersinia pestis) in nature. At present, the basic ecology and dynamics of epizootic plague (periods of rapid spread in highly susceptible hosts) are fairly well understood in certain plague foci, but debate continues on the mechanisms for maintaining plague during inter-epizootic periods. Some have proposed that partially resistant rodents become chronically infected carriers, while others have advocated that Yersinia pestis is maintained for extended periods in flea vectors or in soil. At present none of these hypotheses can be excluded and it is possible that more than one is important for the maintenance of Y. pestis in nature. Maintenance mechanisms also might vary between geographically isolated plague foci or depend on the virulence characteristics or other properties of the Y. pestis strains that predominate in a given focus. Another factor to consider is whether a particular focus is ancient or newly established. For example, many plague foci in Kazakhstan are believed to have existed for at least thousands of years while those in the United States were established during the last pandemic and have existed for less than a hundred years. It can be hypothesized that plague strains in ancient foci will show considerable adaptation to local rodent hosts, vectors, and environmental conditions. By contrast, plague strains in recently established foci would be expected to evolve relatively rapidly, but still exhibit less regional variation and adaptation to local conditions than those from older foci. Strains in recently established foci also might be more likely to have characteristics that favor rapid epizootic spread, such as occurred during the major pandemics and other widespread outbreaks. The degree of host or vector adaptation to Y. pestis infection also can be expected to vary with the age of a given focus and from region to region. Each of the above factors could have profound implications for the epidemiology and prevention of human plague.

Our project will examine potential mechanisms for maintaining plague in Kazakh and U.S. plague foci, and determine whether Yersinia pestis strain characteristics, host resistance patterns, and flea-Yersinia pestis interactions differ between foci. First, we will examine whether chronic infection of rodents is an important mechanism for the extended survival of plague bacteria in natural foci. During these studies, the immunological characteristics of selected resistant and susceptible rodent hosts from Kazakhstan and the U.S. will be examined, particularly with reference to the events leading to intracellular killing of plague bacteria by phagocytes. Second, we will compare the dominant flea vectors from each foci to determine whether differences exist in the vector competencies of these fleas and their abilities to maintain plague bacteria for extended periods of time in on-host or off-host environments. Third, we will analyze strains from Kazakh and U.S. foci to identify key differences in virulence factors, biochemical properties, molecular genetics, and the ability to survive in various environments, such as rodent hosts, flea vectors, and possibly soils. For these in-depth strain analyses, we plan to bring a large collection of Y. pestis strains from Kazakhstan to the CDC laboratory in Fort Collins. We also will examine various bacteriophage strains that have been collected in central Asia and are known to infect Y. pestis. As part of the project, Kazakh scientists will visit CDC-Fort Collins for periods of up to one year to participate in microbiological, molecular, immunological, and entomological studies. Additional analyses of Y. pestis and bacteriophage strains, as well as studies of rodent hosts and vectors, will be completed in Kazakh laboratories. These will include examinations of how certain Y. pestis strain characteristics are favored during infection of rodent hosts or flea vectors, or during residence in non-host environments such as soil.

The information gained from our collaborative research will be very useful for:

– designing improved prevention and control techniques;

Additionally, the collaborative work will serve as a basis for further cooperation and exchanges, resulting in significant public health benefits for both programs. A more complete description of the study is provided in the Scope of Study section of this proposal.