The human pathogen Chlamydia trachomatis is a significant concern in the United States due to its prevalence and the combined health and socioeconomic impact of acute and chronic disease. Chlamydiae are obligate intracellular pathogens and possess the ability to modulate host-cell functions while sequestered within a membrane-bound vacuole. Expression of a virulence-associated type III secretion system (T3SS) represents one mechanism employed to modulate critical host cell pathways. During the past funding cycle, we identified multiple chlamydial T3S substrates capable of influencing these host cellular processes. The C. trachomatis locus containing the identified effector protein CT694 contains multiple substrates that are deployed by infectious particles during or subsequent to the invasion process. We propose to elucidate molecular mechanisms regarding the anti-host activities of these proteins and delineate the consequences of effector activity on the ability of Chlamydiae to establish and maintain a specialized intracellular niche. A combination of methods designed to identify interactions of chlamydial proteins with host targets will be employed to establish relevant functions. The consequences of these interactions will be investigated in both a tissue culture infection model and a murine model of acute chlamydial infection. We furthermore propose to evaluate whether differences in these effectors among chlamydial species account for any of the distinct, species-specific events related to early chlamydial development. The chlamydial type III secretion system represents an attractive, yet relatively unexplored, mechanism to achieve modulation of host cell activities. Given the comparative difficulty associated with study of obligate intracellular bacteria, investigation of host pathways specifically targeted by the type III secretion mechanism continues to represent a productive approach to elucidate novel pathogenic mechanisms. These studies will lead to an enhanced understanding of Chlamydia-mediated disease and have the potential to yield novel preventative and treatment therapies.

Public Health Relevance

Chlamydia trachomatis; an agent of sexually transmitted disease; relies on a specializedsecretion mechanism to deploy proteins exerting anti-host activities essential to pathogenesis.This proposal contains work designed to identify these anti-host proteins and determine theirspecific contributions to chlamydial disease.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Host Interactions with Bacterial Pathogens Study Section (HIBP)
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Hiltke, Thomas J
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University of Kentucky
Schools of Medicine
United States
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Mueller, K E; Plano, G V; Fields, K A (2014) New frontiers in type III secretion biology: the Chlamydia perspective. Infect Immun 82:2-9
McKuen, Mary J; Dahl, Gerhard; Fields, Kenneth A (2013) Assessing a potential role of host Pannexin 1 during Chlamydia trachomatis infection. PLoS One 8:e63732
Engstrom, Patrik; Nguyen, Bidong D; Normark, Johan et al. (2013) Mutations in hemG mediate resistance to salicylidene acylhydrazides, demonstrating a novel link between protoporphyrinogen oxidase (HemG) and Chlamydia trachomatis infectivity. J Bacteriol 195:4221-30
Fields, K A; McCormack, R; de Armas, L R et al. (2013) Perforin-2 restricts growth of Chlamydia trachomatis in macrophages. Infect Immun 81:3045-54
Chellas-Géry, B; Wolf, K; Tisoncik, J et al. (2011) Biochemical and localization analyses of putative type III secretion translocator proteins CopB and CopB2 of Chlamydia trachomatis reveal significant distinctions. Infect Immun 79:3036-45
Hower, S; Wolf, K; Fields, K A (2009) Evidence that CT694 is a novel Chlamydia trachomatis T3S substrate capable of functioning during invasion or early cycle development. Mol Microbiol 72:1423-37
Betts, Helen J; Wolf, Katerina; Fields, Kenneth A (2009) Effector protein modulation of host cells: examples in the Chlamydia spp. arsenal. Curr Opin Microbiol 12:81-7
Betts, H J; Twiggs, L E; Sal, M S et al. (2008) Bioinformatic and biochemical evidence for the identification of the type III secretion system needle protein of Chlamydia trachomatis. J Bacteriol 190:1680-90
Chellas-Gery, Blandine; Linton, Camille N; Fields, Kenneth A (2007) Human GCIP interacts with CT847, a novel Chlamydia trachomatis type III secretion substrate, and is degraded in a tissue-culture infection model. Cell Microbiol 9:2417-30
Wolf, K; Betts, H J; Chellas-Gery, B et al. (2006) Treatment of Chlamydia trachomatis with a small molecule inhibitor of the Yersinia type III secretion system disrupts progression of the chlamydial developmental cycle. Mol Microbiol 61:1543-55