Cellular and molecular biology of the interaction between the human pathogen Chlamydia trachomatis and the mucosal epithelium
Research SummaryMy laboratory conducts research on the interaction of the human pathogen Chlamydia trachomatis with the epithelium. Two major research questions we are addressing is the mechanism by which Chlamydia subverts host cell signaling to hijack the host cytoskeleton and vesicular transport to facilitate infection and nutrient acquisition. Using quantitative fluorescence imaging in conjunction with cutting-edge genetic manipulation, e.g. CRISPR/Cas9, we are able to evaluate infection-dependent changes in the dynamics and behavior of host proteins of interest. We also use three-dimensional mixed-cell cultures and ex vivo organ cultures to identify non-cell autonomous effects of Chlamydia infection on neighboring uninfected cells. These changes to cell-cell interactions are likely to contribute to the development of histopathological hallmarks of chlamydia, the disease.
The other major research interest is the mechanism of chlamydial adaptation to immunological and nutritional stresses, specifically at the level of gene expression. In projects related to this theme, we use a systems biology approach to determine genome-wide alterations to changes in transcription (single-cell and batch RNA sequencing), ribosomal profiling, and chromatin immunoprecipitation and sequencing (ChIP-seq) to gain in-depth mechanistic insights into gene regulatory changes during development and response to stress.
Research PublicationsBrinkworth AB, Wildung MR, Carabeo RA. (2018) Genomewide transcriptional responses of iron-starved Chlamydia trachomatis reveal prioritization of metabolic precursor synthesis over protein translation. mSystems. doi: 10.1128/mSystems.00184-17
Nogueira AT, Braun KM, and Carabeo RA. (2017) Characterization of the growth of Chlamydia trachomatis in in vitro-generated stratified epithelium. Front Cell Infect Microbiol. doi: 10.3389/fcimb.2017.00438.
Pokorzynski ND, Thompson CC, and Carabeo RA. (2017) Ironing out the unconventional mechanisms of iron acquisition and gene regulation in Chlamydia. Front Cell Infect Microbiol. doi: 10.3389/fcimb.2017.00394.
Nogueira AT, Pedrosa AT, Carabeo RA. (2016) Manipulation of the Host Cell Cytoskeleton by Chlamydia. Curr Top Microbiol Immunol. PMID: 27197645
Thwaites TR, Pedrosa AT, Peacock TP, Carabeo RA (2015) Vinculin Interacts with the Chlamydia Effector TarP Via a Tripartite Vinculin Binding Domain to Mediate Actin Recruitment and Assembly at the Plasma Membrane Front Cell Infect Microbiol 5, 88
Thwaites T.R., Nogueira A.T., Campeotto I., Silva A.P., Grieshaber S.S., and Carabeo R.A (2014) The Chlamydia effector TarP mimics the mammalian LD motif of paxillin to subvert the focal adhesion kinase during invasion J. Biol. Chem. 289, 30426-42
Thompson C.C., Nicod S., Malcolm D., Grieshaber S.S., and Carabeo R.A. (2012) An iron-dependent transcriptional regulator is generated from cleavage of the YtgC permease in Chlamydia trachomatis Proc. Nat. Acad. Sci. U.S.A. 109, 10546-51
Brinkworth, A.J., Malcolm, D.S., Pedrosa, A.T., Roguska, K., Shahbazian, S., Graham, J.E., Hayward, R.D., and Carabeo, R.A. (2011) Chlamydia trachomatis Slc1 is a type III secretion chaperone that enhances the translocation of its invasion effector substrate TARP Mol Microbiol. 82, 131-44
Carabeo RA (2011) Bacterial subversion of host actin dynamics at the plasma membrane Cell Microbiol.
Fields, K.A., Heinzen, R.A., and Carabeo, R. (2011) The obligate intracellular lifestyle Front Microbiol. 2, 99
Thompson, C.C., and Carabeo, R.A. (2010) An optimal method of iron starvation of the obligate intracellular pathogen, Chlamydia trachomatis Front. Microbio. 2, 20
Ouellette, S., Dorsey, F., Moshiach, S., Cleveland, J., and Carabeo, R.A. (2011) Chlamydia Species-Dependent Differences in the Growth Requirement for Lysosomes PLoS ONE
Ouellette, S., and Carabeo, R.A. (2010) A Functional Slow Recycling Pathway of Transferrin is Essential for Chlamydial Intracellular Growth Front. Microbiol.
Tietzel, I., El-Haibi, C., and Carabeo, R.A. (2009) The Human Guanylate Binding Proteins Potentiate the Anti-Chlamydial Effects of Interferon-g PLoS ONE 4(8)
Lane, B.J., Mutchler, C, and Carabeo, R.A. (2008) Chlamydial Invasion Involves TARP binding of Two distinct Rac-specific Guanine Nucleotide Exchange Factors PLOS Pathogens 4
Molmeret, M., Santic, M., Asare, R., Carabeo, R.A., Kwaik, Y.A. (2007) Rapid Escape of the dot/icm Mutants of Legionella pneumophila Into the Cytosol of Mammalian and Protozoan Cells Infect. Immun. 75, 3290-3304
Carabeo, R.A., Dooley, C.A., Grieshaber, S.S., and Hackstadt, T (2007) Rac Interacts with Abi-1 and WAVE2 to Promote an Arp2/3-dependent Actin Recruitment During Chlamydial Invasion Cell. Microbiol. 9, 2278-2288
Clifton, D.R., Dooley, C.A., Grieshaber, S.S., Fields, K.A., Carabeo, R.A., Hackstadt, T (2005) Tyrosine Phosphorylation of the Chlamydia Effector Protein Tarp is Species-Specific and Not Required for Recruitment of Actin. Infect. Immun. 73, 3860-3868
Clifton, D.R., Fields, K.A., Grieshaber, S.S., Dooley, C.A., Fischer, E.R., Mead, D.J., Carabeo, R.A., Hackstadt, T (2004) A Chlamydial Type III Translocated Protein is Tyrosine Phosphorylated at the Site of Entry and Associated with Recruitment of Actin Proc. Nat. Acad. Sci. U.S.A. 101, 10166-10177
Carabeo, R.A., Grieshaber, S.S., Dooley, C.A., Hasenkrug, A., and Hackstadt, T (2004) Requirement for the Rac GTPase in Chlamydia trachomatis Invasion of Non-phagocytic Cells Traffic 5, 418-425
Carabeo, R.A., Mead, D.J., Hackstadt, T (2003) Golgi-dependent transport of cholesterol to the Chlamydia trachomatis inclusion Proc. Natl. Acad. Sci. USA. 100, 6771-6
Carabeo, R.A., Grieshaber, S.S., Fischer, E., Hackstadt, T (2002) Chlamydia trachomatis induces remodeling of the actin cytoskeleton during attachment and entry into HeLa cells. Infect. Immun. 70:3793-803. Infect. Immun. 70, 3793-803
Carabeo, R.A., Hackstadt, T (2001) Isolation and characterization of a mutant Chinese hamster ovary cell line that is resistant to Chlamydia trachomatis infection at a novel step in the attachment process Infect. Immun. 69, 5899-904