P. Scott Hefty
- MB Undergraduate Studies Director
Molecular Mechanisms of Chlamydia Pathogenesis
Chlamydia trachomatis and Chlamydia pneumoniae are among the most significant bacterial pathogens afflicting humans. According to the Centers for Disease Control, C. trachomatis has the highest incidence of infection among all reported infectious diseases in the United States. Globally, it is the most prevalent sexually-transmitted bacterial disease, as well as the most-common cause of non-heritable blindness. According to serological analyses, close to 80% of the adult population has been exposed to C. pneumoniae. C. pneumoniae infections are strongly correlated with development of atherosclerosis and heart disease, the leading cause of death in the U.S. Together, these observations highlight the extreme importance of Chlamydia infections to public health.
Despite this enormous impact on public health, surprisingly little is known about C. trachomatis and C. pneumoniae including aspects of basic biology, genetics, and pathogenesis. This is indicative of the challenges inherent to chlamydial research such as, lack of a system for directed genetic manipulation and inability to cultivate organisms axenically. However, new tools and technological advances in fields such as biochemistry, genetics/genomics, and structural biology have opened new avenues of research and facilitated our ability to understand the unique biology of this medically important bacterial pathogen.
Chlamydia are obligate intracellular bacteria maintained through a characteristic bi-phasic developmental cycle that is intimately linked with pathogenesis. This virulence defining developmental cycle is governed predominately at the transcriptional level; however, there remain critical gaps in our understanding of developmental regulatory mechanisms in Chlamydia. As such, one of the primary long-term goals of our research is to contribute to a delineation of the key molecular mechanisms that function to regulate chlamydial development and pathogenesis.
An additional challenge to understanding the biology and pathogenesis of Chlamydia is the relatively high percentage (~25-35%) of encoded proteins with unknown function. Given the absence of a system for directed genetic manipulation in Chlamydia, we have addressed this challenge by initiating a collaborative structural genomics project that enlists both computational and experimental approaches.
Antibiotic therapy is effective in treating Chlamydia infections. However, a large portion (estimates as high as 75%) of C. trachomatis infected individuals are asymptomatic and continue to be contagious. In the absence of a safe and effective vaccine, developing vaginal delivered microbicides effective against C. trachomatis infections is a high priority. Through collaborative efforts, we have initiated multiple, complimentary and cohesive projects to identify and develop vaginal delivered microbicide components that are safe and effective against C. trachomatis infections.
Selected Publications —
Kemege, K.E., Hickey, J.M., Barta, M.L., Wickstrum, J., Balwalli, N., Lovell, S., Battaile, K.P., and P.S. Hefty (2015). Chlamydia trachomatis protein CT009 is a structural and functional homolog to the key morphogenesis component RodZ and interacts with division septal plane localized MreB. Molecular Microbiology. Feb.; 95(3):365-82
Barta, M.L., Thomas, K., Yuan, H., Lovell, S., Battaile, K.P., Schramm, V.L., and P.S. Hefty (2014). Structural and biochemical characterization of Chlamydia trachomatis hypothetical protein CT263 supports that menaquinone synthesis occurs through the futalosine pathway. J. Biol. Chem. Nov. 14;289(46):32214-29
Osaka, I. and P.S. Hefty (2014). Lipopolysaccharide-binding alkylpolyamine DS-96 inhibits Chlamydia trachomatis infection by blocking attachment and entry. Antimicrob Agents Chemother. Jun;58(6):3245-54
Barta, M.L., Hickey, J.M., Anbanandam, A., Dyer, K., Hammel, M., and P.S. Hefty (2014). Atypical response regulator ChxR from Chlamydia trachomatis is structurally poised for DNA binding. PLoS One. Mar 19;9(3)
Barta, M.L., Lovell, S., Sinclair, A.N., Battaile, K.P., and P.S. Hefty (2014). Chlamydia trachomatis CT771 (NudH) is an asymmetric Ap4A hydrolyase. Biochemistry Jan. 14;53(1):214-24
Barta, M.L., Hickey, J., Kemege, K.E., Lovell, S., Battaile, K.P., and P.S. Hefty (2013). Structure of CT584 from Chlamydia trachomatis refined to 3.05A resolution. Acta Crystallogr Sect F Struct Biol Cryst Commun. Nov.; 69:1196-201
Osaka, I. and P.S. Hefty (2013). Simple resazurin-based microplate assay for measuring Chlamydia infections. Antimicrob Agents Chemother. June; 57(6):2838-40
Osaka, I., Hills, J.M., Kieweg, S.L., Shinogle, H.E., Moore, D.S., and P.S. Hefty (2012). An automated image based method for rapid analysis of Chlamydia infection as a tool for screening anti-chlamydial agents. Antimicrob Agents Chemother. Aug; 56(8):4184-8
Kemege K.E., Hickey J.M., Lovell S., Battaile K.P., Zhang Y., and P.S. Hefty (2011). Ab initio structural modeling of and experimental validation for Chlamydia trachomatis protein CT296 reveal structural similarity to Fe(II) 2-oxoglutarate-dependent enzymes. J. Bact. Dec;193(23):6517-28
Hickey J.M., Lovell S., Battaile K.P., Hu L, Middaugh C.R., and P.S. Hefty (2011). The atypical response regulator protein ChxR has structural characteristics and dimer interface interactions that are unique within the OmpR/PhoB subfamily. J. Biol. Chem. Sep 16; 286 (37):32606-16
Hickey JM, Weldon L, and P.S. Hefty. (2011). The atypical OmpR/PhoB response regulator ChxR from Chlamydia trachomatisforms homodimers in vivo and binds a direct repeat of nucleotide sequences. J. Bact. Jan;193(2):389-98
Markham AP, Jaafar ZA, Kemege KE, Middaugh CR, and P.S. Hefty. (2009). Biophysical characterization of Chlamydia trachomatis CT584 supports its potential role as a type III secretion needle tip protein. Biochemistry. Nov. 3;48(43):10353-61
Hickey JM, Hefty P.S., and Lamb AL. (2009). Expression, purification, crystallization and preliminary X-ray analysis of the DNA-binding domain of a Chlamydia trachomatis OmpR/PhoB-subfamily response regulator homolog, ChxR. Acta Crystallogr Sect F Struct Biol Cryst Comm. Aug 1;65(pt 8):791-4
Abromiatis, S., Hefty, P.S., and R.S. Stephens (2009). Chlamydia pneumoniae encodes a functional aromatic amino acid hydroxylase. Fems Immunol Med Microbiol. 55 (2):196-205
Hefty, P. S. and R. S. Stephens (2007). Chlamydial type III secretion system is encoded on ten operons preceded by sigma 70-like promoter elements. J Bacteriol 189(1): 198–206.
Koo, I. C., D. Walthers, P. S. Hefty, L. J. Kenney and R. S. Stephens (2006). ChxR is a transcriptional activator in Chlamydia. Proc Natl Acad Sci U S A.
Hua, L., P. S. Hefty, Y. J. Lee, Y. M. Lee, R. S. Stephens and C. W. Price (2006). Core of the partner switching signaling mechanism is conserved in the obligate intracellular pathogen, Chlamydia trachomatis. Mol Microbiol 59 (2): 623–36.
Hefty, P. S. and R. S. Stephens (2006). Sigma 28 regulates expression of a tail-specific protease in Chlamydia. Proc. Int'l. Symp. on Hum. Chlamydial Inf. 11: 25–28
Alitalo, A., T. Meri, T. Chen, H. Lankinen, Z. Z. Cheng, T. S. Jokiranta, I. J. Seppala, P. Lahdenne, P. S. Hefty, D. R. Akins and S. Meri (2004). Lysine-dependent multipoint binding of the Borrelia burgdorferi virulence factor outer surface protein E to the C terminus of factor H. J Immunol 172(10): 6195–201.
Brooks, C. S., P. S. Hefty, S. E. Jolliff and D. R. Akins (2003). Global analysis of Borrelia burgdorferi genes regulated by mammalian host-specific signals. Infect Immun 71(6): 3371–83.
Alitalo, A., T. Meri, H. Lankinen, I. Seppala, P. Lahdenne, P. S. Hefty, D. Akins and S. Meri (2002). Complement inhibitor factor H binding to Lyme disease spirochetes is mediated by inducible expression of multiple plasmid-encoded outer surface protein E paralogs. J Immunol 169(7): 3847–53.
Hefty, P. S., C. S. Brooks, A. M. Jett, G. L. White, S. K. Wikel, R. C. Kennedy and D. R. Akins (2002). OspE-related, OspF-related, and Elp lipoproteins are immunogenic in baboons experimentally infected with Borrelia burgdorferi and in human Lyme disease patients. J Clin Microbiol 40 (11): 4256–65.
Hefty, P. S., S. E. Jolliff, M. J. Caimano, S. K. Wikel and D. R. Akins (2002). Changes in temporal and spatial patterns of outer surface lipoprotein expression generate population heterogeneity and antigenic diversity in the Lyme disease spirochete,Borrelia burgdorferi. Infect Immun 70 (7): 3468–78.
Hefty, P. S., S. E. Jolliff, M. J. Caimano, S. K. Wikel, J. D. Radolf and D. R. Akins (2001). Regulation of OspE-related, OspF-related, and Elp lipoproteins of Borrelia burgdorferi strain 297 by mammalian host-specific signals. Infect Immun 69 (6): 3618–27.
Hefty, P. S. and R. C. Kennedy (1999). Immunoglobulin variable regions as idiotype vaccines. Infect Dis Clin North Am 13 (1): 27–37, vi.
Watts, A. M., J. R. Stanley, M. H. Shearer, P. S. Hefty and R. C. Kennedy (1999). Fetal immunization of baboons induces a fetal-specific antibody response. Nat Med 5(4): 427–30.
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