Pneumococcal pathogenesis, regulation of bacterial virulence determinants.
Key words: Streptococcus pneumoniae, bacterial pathogenesis, two-component signaling systems, transformation, quorum sensing.
Description of Research
My laboratory studies the coordinated genetic responses through which the bacterium Streptococcus pneumoniae becomes adapted for survival in the respiratory tract. This pathogen is a leading cause of diseases including pneumonia, sepsis and meningitis, but all of these infections are generally preceded by colonization of the nasopharynx, which constitutes the critical first interaction with the host and represents the principal ecological niche for the bacterium.
A principal focus of our research is on the regulation of genetic competence in this organism. The competence response, which controls genetic exchange by transformation as well as other traits, is a prominent characteristic of the physiology of the organism and is important for its virulence as a pathogen. Competence has previously been considered to be an example of quorum-sensing in S. pneumoniae as it is regulated by the density of bacteria in a culture through the accumulation of a secreted peptide pheromone. We have characterized a serine protease (HtrA) found on the surface of the bacterium that represses the development of competence and thereby confers additional interesting regulatory properties on the signaling pathway. Members of the conserved family of HtrA proteases also serve to digest misfolded or denatured proteins, suggesting dual competing functions for pneumococcal HtrA, both inhibiting competence and degrading generic misfolded proteins.
These observations have led to the hypothesis that pneumococcal competence is modulated by the rate at which errors during protein synthesis result in production of proteins that have intrinsic folding defects. Recently, we have shown that competence is stimulated by an increasing frequency of errors during translation and conversely is repressed by increasing translational accuracy. In this context, HtrA functions as a biological error sensor that selectively represses signaling when biosynthetic errors are rare. We are particularly interested in the potential for this regulatory system to activate competence in response to the accumulation of random coding mutations in the genome that, as with translational errors, result in misfolded proteins. The laboratory is testing the model that in this way S. pneumoniae monitors the mutational load of the organism and initiates genetic exchange in response to an increasing burden of deleterious mutations.
A related area of research in the laboratory employs experimental evolution studies to characterize basic processes of mutation and selection in S. pneumoniae. Conducting a classical mutation accumulation experiment with this organism, we have found an unprecedented level of adaptation, suggesting a particularly high frequency of beneficial mutations. We are interested in the effects of regulated genetic transformation both in recombining these beneficial mutations and in correcting deleterious changes.
Please contact Dr. Sebert directly to discuss current rotation projects.
Marco Cassone?postdoctoral fellow
Alyssa Gagne?research technician
- Assistant Professor of Pediatrics at University of Pennsylvania School of Medicine (2005 – 2013)
- MD, Medicine, Stanford University (1995)
- BS, Zoology, Duke University (1990)
- Stevens, K.E., Chang, D., Zwack, E.E., Sebert, M.E.. Competence in Streptococcus pneumoniae is regulated by the rate of ribosomal decoding errors. mBio. Vol 2(5) . 2011:e00071-11.
- Stevens, K.E., Sebert, M.E.. Frequent beneficial mutations during single-colony serial transfer of Streptococcus pneumoniae. PLoS Genetics. Vol 7(8) . 2011:e1002232.
- Dawid, S., Sebert, M.E., Weiser, J.N.. Bacteriocin activity of Streptococcus pneumoniae is controlled by the serine protease HtrA via posttranscriptional regulation. Journal of Bacteriology. Vol 191. 2009:1509-1518.
- Kowalko, J.E., Sebert, M.E.. The Streptococcus pneumoniae competence regulatory system influences respiratory tract colonization. Infection and Immunity. Vol 76. 2008:3131-3140.
- Sebert, M.E., Patel, K.P., Plotnick, M., Weiser, J.N.. Pneumococcal HtrA protease mediates inhibition of competence by the CiaRH two-component signaling system. Journal of Bacteriology. Vol 187. 2005:3969-3979.
- Tabbutt S, Leonard M, Godinez RI, Sebert M, Cullen J, Spray TL, Friedman D.. Severe influenza B myocarditis and myositis.. Pediatric Critical Care Medicine. Vol 5. 2004:403-406.
- Sebert, M.E., Palmer, L.M., Rosenberg, M., Weiser, J.N.. Microarray-based identification of htrA, a Streptococcus pneumoniae gene that is regulated by the CiaRH two-component system and contributes to nasopharyngeal colonization. Infection and Immunity. Vol 70. 2002:4059-4067.
- Sebert ME, Manning ML, McGowan KL, Alpern ER, Bell LM.. An Outbreak of Serratia marcescens Bacteremia After General Anesthesia.. Infection Control and Hospital Epidemiology. Vol 23. 2002:733-739.