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Molecular mechanisms governing Gram-positive bacterial pathogenesis
PI: Emmanuelle Charpentier, Professor
Molecular Infection Medicine Sweden (MIMS)
Umeå Centre for Microbial Research (UCMR)
Department of Molecular Biology
Department of Regulation in Infection Biology (REGI)
Helmholtz Centre for Infection Research (HZI)
Hannover Medical School (MHH)
A greater understanding of the fundamental mechanisms of regulation in pathogens is critical to generate new findings for possible translation into novel biotechnological and biomedical applications (e.g. genome editing tools, anti-infective strategies). A successful example of potential application of our research in biotechnology and medicine is our recent discovery of an RNA programmable genome editing tool (dual-RNA guided DNA cleavage enzyme Cas9) that stems from our analysis of the adaptive immune CRISPR-Cas system in bacterial pathogens.
Our laboratory investigates fundamental mechanisms of regulation in processes of infection and immunity with a focus on Gram-positive bacterial pathogens. We are interested in understanding how RNAs and proteins coordinate to modulate gene expression at the transcriptional, post-transcriptional and post-translational level. We study regulatory RNAs and proteins in various biological pathways such as horizontal gene transfer, adaptation to stress, physiology, persistence, virulence, infection and immunity. We particularly research on interference systems in the defense against genetic elements (CRISPR-Cas), small regulatory RNAs that interfere with pathogenic processes, protein quality control that regulate bacterial adaptation, physiology and virulence, and the mechanisms of bacterial recognition by immune cells.
We employ a combination of -omics, genetic, molecular, biochemical, physiological and cell infection approaches to identify new molecules and decipher their genesis, functions and modes of action at the molecular and cellular level. A favorite pathogen in the laboratory is Streptococcus pyogenes also called Group A streptococcus that can cause highly aggressive invasive infections such as toxic shock and necrotising diseases. In past years, we have also been investigating the genetics and biology of Listeria monocytogenes, Staphylococcus aureus and Streptococcus pneumoniae.
CRISPR/Cas: RNA-mediated interference in immunity
To protect themselves from the attack by invading alien genomes (phages, plasmids), bacteria and archaea have evolved an RNA-guided adaptive immunity system, called CRISPR-Cas (clustered, regularly interspaced short palindromic repeats–CRISPR-associated proteins). The system uses ribonucleoprotein complexes composed of short CRISPR RNAs (crRNAs) and Cas protein(s) to silence invading nucleic acid sequences in a sequence-specific manner. We are interested in deciphering the molecular mechanisms involved in the adaptation, expression and interference phases of the immune system and pursuing the detailed analysis of the recently discovered Cas9-tracrRNA:crRNA genome editing device.
Regulatory small RNAs
In addition to the CRISPR-associated RNAs, bacteria encode multiple other small RNAs (sRNAs) that play critical regulatory functions in major biological pathways. We have identified a number of cis-acting and putative trans-acting sRNAs in S. pyogenes. We are addressing the question how sRNAs integrate in the general regulatory network controlling pathogenesis and related mechanisms in this pathogen. We want to understand the regulation of sRNAs expression, and decipher their functions, interacting partners and modes of action at the molecular and cellular level.
Regulatory protein quality control
During infection, bacterial pathogens face a wide variety of adverse and fluctuating conditions within the host and have evolved multiple strategies to mount appropriate responses. In bacteria, Clp (Caseinolytic proteins)/HSP100 (heat-shock proteins) proteins are important components of the bacterial stress response, influencing adaptation, survival or virulence. We have identified substrates of Clps in Gram-positive pathogens and are now investigating the mechanisms of substrate targeting and degradation at the molecular and cellular level. We are also interested in the regulation of the clp response by arginine phosphoswitch.
Regulation by RNAs and proteins in innate immunity
Initial recognition of pathogens by the innate immune system constitutes the key step in defense against infectious microorganisms. An inappropriate recognition may result in insufficient immune responses, yet an over-activation of the immune system may be equally deleterious. Innate immune cells respond to S. pyogenes infection by producing pro-inflammatory cytokines in a manner dependent of the adaptor molecule MyD88. We are interested in investigating RNA- and protein-mediated mechanisms involved in the response of immune cells to this bacterial infection.
We acknowledge Umeå University (UmU), the Laboratory for Molecular Infection Medicine Sweden (MIMS), the Umeå Centre for Microbial Research (UCMR), the Swedish Research Council (VR), the Swedish Foundation for International Cooperation in Research and Higher Education (STINT), and the Kempe and Carl Tryggers Foundations for financial support. We wish to thank the Helmholtz Association for support of our future research in Germany. We are also grateful to the Austrian Science Fund (FWF), the Austrian Research Promotion Agency (FFG), the Vienna Science and Technology Fund (WWTF) and the European Community among other organizations that have financed our research over the past years.
The laboratory of Emmanuelle Charpentier at the MIMS is affiliated to the Department of Regulation in Infection Biology (REGI) at the Helmholtz Centre for Infection Research (HZI) and Hannover Medical School (MHH) in Germany.
We are always looking for motivated and enthusiastic PhD and Post-doc candidates who would like to join our group in the far North of Sweden or our affiliated new Department at the Helmholtz Centre for Infection Research and Hannover Medical School in Germany.