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.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Specialized Center--Cooperative Agreements (U54)
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University of North Carolina Chapel Hill
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Guo, Haitao; Gao, Jianmei; Taxman, Debra J et al. (2014) HIV-1 infection induces interleukin-1? production via TLR8 protein-dependent and NLRP3 inflammasome mechanisms in human monocytes. J Biol Chem 289:21716-26
Emery, Felicia D; Stabenow, Jennifer M; Miller, Mark A (2014) Efficient inactivation of Burkholderia pseudomallei or Francisella tularensis in infected cells for safe removal from biosafety level 3 containment laboratories. Pathog Dis 71:276-81
Pop, Laurentiu M; Barman, Stephen; Shao, Chunli et al. (2014) A reevaluation of CD22 expression in human lung cancer. Cancer Res 74:263-71
Rice, Amanda D; Adams, Mathew M; Lindsey, Scott F et al. (2014) Protective properties of vaccinia virus-based vaccines: skin scarification promotes a nonspecific immune response that protects against orthopoxvirus disease. J Virol 88:7753-63
Zellweger, Raphaƫl M; Eddy, William E; Tang, William W et al. (2014) CD8+ T cells prevent antigen-induced antibody-dependent enhancement of dengue disease in mice. J Immunol 193:4117-24
Agnihothram, Sudhakar; Yount Jr, Boyd L; Donaldson, Eric F et al. (2014) A mouse model for Betacoronavirus subgroup 2c using a bat coronavirus strain HKU5 variant. MBio 5:e00047-14
Krumm, Stefanie A; Yan, Dan; Hovingh, Elise S et al. (2014) An orally available, small-molecule polymerase inhibitor shows efficacy against a lethal morbillivirus infection in a large animal model. Sci Transl Med 6:232ra52
Zhao, Jincun; Li, Kun; Wohlford-Lenane, Christine et al. (2014) Rapid generation of a mouse model for Middle East respiratory syndrome. Proc Natl Acad Sci U S A 111:4970-5
de Alwis, Ruklanthi; de Silva, Aravinda M (2014) Measuring antibody neutralization of dengue virus (DENV) using a flow cytometry-based technique. Methods Mol Biol 1138:27-39
Blake, Lauren E; Garcia-Blanco, Mariano A (2014) Human genetic variation and yellow fever mortality during 19th century U.S. epidemics. MBio 5:e01253-14

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