Autotransporter proteins (ATs) are exceptionally elegant yet complex proteins ideally positioned on the bacterial cell surface (or released) for interactions with the host. ATs consist of three basic domains: a Nterminal signal sequence, a """"""""passenger domain"""""""" (PD) of variable size and finally a (3-domain of 250-300 amino acids at the C-terminus that facilitates translocation of the PD across the outer membrane. Although more than 1000 have been identified by in silico analyses a relatively few have been studied in detail as to their molecular and biological function. The Yaps (predicted ATs) of Y. pestis represent an excellent opportunity to do this as (a) they do not appear to be closely related to the already well studied ATs and thus are likely to encode novel functions, and (b) Y. pestis is amenable to molecular, genetic and biological studies. We have, preliminary data indicating that all ten of the yaps are expressed during infection. We also demonstrated that most of the Yaps are localized and exposed on the bacterial surface, while the others appear to be released into the culture supernatant. In addition, we have constructed deletion mutations in all of the ten yaps in a fully virulent Y. pestis strain and have begun testing the effect of these mutations on virulence. While these tests are ongoing, four of these mutants clearly have phenotypes in a bubonic plague model of infection. These results are consistent with our hypothesis that the yaps play a role in pathogenesis. The studies proposed here to examine the host response to Y. pestis and the role of Yaps in hat response (Aims 1 &2) are based on the observation that many yap mutations appear to affect early vents and/or dissemination of Y. pestis. These studies should inform us not only about key host responses during Y. pestis infection, but they should also give us important clues as to host targets of the Yaps. This ll complement the structural work described in Aim 3 aimed at defining important functional domains of the Yaps and also at providing a foundation for future screening for broad spectrum small molecule inhibitors of ATs.

Public Health Relevance

The autotransporters (ATs) of Y. pestis are not closely related to the best characterized ATs and thus may provide novel functions important for understanding the biology of this organism and for understanding the functions of ATs in general. Due to their potential role in virulence and location on the surface of the pathogen they are promising therapeutic/vaccine targets.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
5U54AI057157-10
Application #
8375890
Study Section
Special Emphasis Panel (ZAI1-DDS-M)
Project Start
2012-03-01
Project End
2014-02-28
Budget Start
2012-03-01
Budget End
2013-02-28
Support Year
10
Fiscal Year
2012
Total Cost
$203,859
Indirect Cost
$54,684
Name
University of North Carolina Chapel Hill
Department
Type
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
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