Plague has killed millions of humans, providing objective concern that Yersinia pestis could be used to threaten public health. Y. pestis evolved from Y. pseudotuberculosis. Both are lymphotropic and cause strikingly bi-phasic illnesses: initial bacterial replication without inflammation gives way to profound inflammation, tissue destruction, and clinical disease. Replication without effective host responses in early infection is also characteristic of Burkholderia and Francisella. Only early intervention can save infected patients and a better understanding of the initial stages of infection, and how innate responses are delayed, will improve approaches to diagnosis and treatment. Bacterial attributes and host responses during early lymph node infection remain largely unstudied. Yersinia surface and secreted proteins, which are likely to be critical for early infection and are also candidates for subunit vaccines or diagnostic markers, will be identified using proteomics, bioinformatics and expression array studies. Investigation will focus on bacterial strains with defined mutations in genes known to regulate surface changes and comparing bacteria responding to environmental stimuli that effectively mimic the host environment. Bacterial mutants lacking these proteins will be assessed for growth in host lymph nodes using an experimental system that is not complicated by the myriad effects of the plasmid-encoded secretion system. Host contributions to limiting bacterial growth in the lymph node, and the lymphoid proliferation triggered by Yersinia infections, will be investigated to understand which lymphocytes are proliferating and whether or not they are activated and contributing cytokines to help limit infection. Precise modulation of inflammation is required for bacterial replication to occur in vivo, and therefore the contributions of both cellular activation and the production of cytokines will be evaluated in the context of host responses to: i) bacterial strains that colonize lymph nodes, and ii) defective hyper-inflammatory strains that fail to colonize. This project will provide a greater understanding of innate immune responses to infection and provide relevant data for designing optimal diagnostic and treatment strategies that favor quality outcomes for the infected host.

Public Health Relevance

Bacterial replication that avoids host innate immune responses during initial infection is a common feature of Gram negative pathogens being studied in the NWRCE. Bacterial attributes that allow Yersinia and Francisella to grow in lymph nodes during infection are largely unknown. The role of host responses in lymph nodes during infection are also largely unknown, and success in treating and diagnosing these diseases will be improved by a better understanding of the host and pathogen contributions to early stages of infection.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
5U54AI057141-10
Application #
8447090
Study Section
Special Emphasis Panel (ZAI1-DDS-M)
Project Start
Project End
2015-02-28
Budget Start
2013-03-01
Budget End
2014-02-28
Support Year
10
Fiscal Year
2013
Total Cost
$234,575
Indirect Cost
$73,904
Name
University of Washington
Department
Type
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
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