Our proposed research underscores several major concepts such as the issue of rickettsial virulence, rickettsial fitness in diverse vertebrate and invertebrate hosts, and molecular dynamics of pathogen-host (flea/rat) interactions. In this competing renewal application, we build upon recent accomplishments, and now focus on dissecting the molecular correlates that define the murine typhus zoonosis. Thus, we will use an integrated approach including the combination of rickettsial genome data mining, pathogen phylogenomic analysis and empirical studies to investigate the patterns of rickettsial and host transcriptome profiles and to define whether host-association directs the degree of rickettsial virulence.
The aims of this competitive renewal is to (1) determine if flea immune response proteins limit the growth of R.
typhi (Aim I) and (2) functionally characterize a set of rickettsial genes that were identified as having a potential role in virulence (Aim II).
The specific aims of the proposal are designed to highlight the strategies employed by both the host and the Rickettsia typhi to ensure their own survival. Under the aim I, we will test the hypothesis that flea immune responsive proteins limit R. typhi growth. To implicate an interaction between R. typhi and each immune responsive protein in vivo, immunological, biochemical and molecular approaches will be used to demonstrate colocalization and anti-rickettsial properties of each immune responsive protein. Additionally, RNAi will be used to determine if suppression of immune gene expression affects rickettsial growth in vivo. Under the second aim we will test the hypothesis that secretory proteins play a cardinal role in rickettsial virulence. In order to assess this hypothesis, we will utilize an integrated approach that includes a genome-wide identification and molecular analysis of R. typhi secretory proteins and functional analysis of selected potential virulence genes by anti-sense RNA technology. PROJECT NARRATIVE: Murine typhus is a good example of a disease whose importance is not adequately appreciated except by the patient, and, even today, in most parts of the world, he will never know what ails him because the diagnosis will not be made. An intimate association between the causative agent of murine (endemic) typhus, Rickettsia typhi, rats and their fleas underlie the expansion of this disease into rural communities as the urbanization of rural settings is on the increase. Thus, R. typhi not only re-emerge in many coastal regions of the world as a result of relaxed hygiene but also become an emerging pathogen in rural animal populations. Our proposed research underscores several major concepts in rickettsial virulence and pathogenesis by using murine typhus animal model. Our research advances the understanding the biology of R. typhi by providing information on pathogen gene products that could be used in developing better rickettsial vaccines and/or therapeutics.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI017828-29
Application #
8299129
Study Section
Bacterial Pathogenesis Study Section (BACP)
Program Officer
Mukhopadhyay, Suman
Project Start
1982-09-01
Project End
2013-05-31
Budget Start
2012-06-01
Budget End
2013-05-31
Support Year
29
Fiscal Year
2012
Total Cost
$563,696
Indirect Cost
$184,044
Name
University of Maryland Baltimore
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
188435911
City
Baltimore
State
MD
Country
United States
Zip Code
21201
Gillespie, Joseph J; Kaur, Simran J; Rahman, M Sayeedur et al. (2015) Secretome of obligate intracellular Rickettsia. FEMS Microbiol Rev 39:47-80
Pelc, R S; McClure, J C; Sears, K T et al. (2014) Defending the fort: a role for defensin-2 in limiting Rickettsia montanensis infection of Dermacentor variabilis. Insect Mol Biol 23:457-65
Kang, Yan-Jun; Diao, Xiu-Nian; Zhao, Gao-Yu et al. (2014) Extensive diversity of Rickettsiales bacteria in two species of ticks from China and the evolution of the Rickettsiales. BMC Evol Biol 14:167
Rahman, M Sayeedur; Gillespie, Joseph J; Kaur, Simran Jeet et al. (2013) Rickettsia typhi possesses phospholipase A2 enzymes that are involved in infection of host cells. PLoS Pathog 9:e1003399
Driscoll, Timothy; Gillespie, Joseph J; Nordberg, Eric K et al. (2013) Bacterial DNA sifted from the Trichoplax adhaerens (Animalia: Placozoa) genome project reveals a putative rickettsial endosymbiont. Genome Biol Evol 5:621-45
Gillespie, Joseph J; Joardar, Vinita; Williams, Kelly P et al. (2012) A Rickettsia genome overrun by mobile genetic elements provides insight into the acquisition of genes characteristic of an obligate intracellular lifestyle. J Bacteriol 194:376-94
Ceraul, Shane M; Chung, Ashley; Sears, Khandra T et al. (2011) A Kunitz protease inhibitor from Dermacentor variabilis, a vector for spotted fever group rickettsiae, limits Rickettsia montanensis invasion. Infect Immun 79:321-9
Sutten, Eric L; Norimine, Junzo; Beare, Paul A et al. (2010) Anaplasma marginale type IV secretion system proteins VirB2, VirB7, VirB11, and VirD4 are immunogenic components of a protective bacterial membrane vaccine. Infect Immun 78:1314-25
Rahman, M Sayeedur; Ammerman, Nicole C; Sears, Khandra T et al. (2010) Functional characterization of a phospholipase A(2) homolog from Rickettsia typhi. J Bacteriol 192:3294-303
Gillespie, Joseph J; Brayton, Kelly A; Williams, Kelly P et al. (2010) Phylogenomics reveals a diverse Rickettsiales type IV secretion system. Infect Immun 78:1809-23

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