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RNA Biology of Clostridium difficile

Electron microscopic image showing Clostridium difficile (Manfred Rohde (2007), Helmholtz Centre for Infection Research, Braunschweig).

The Pathogen

Clostridium difficile is a gram-positive, obligate anaerobic, spore-forming bacterium that is a leading cause of antibiotic-associated diarrhea in industrialized countries. In healthy individuals, infection with C. difficile spores (CDI) results in asymptomatic colonization, but after antibiotic treatment, C. difficile causes a wide spectrum of pathologies ranging from diarrhea to fulminant colitis or sepsis. One of the major risk factors for C. difficile infection is antibiotic treatment which dramatically changes the intestinal milieu in favor of C. difficile spore germination. The vegetative cells of C. difficile will start producing and releasing toxins that eventually cause the clinical symptoms of the disease. This intestinal life cycle is accompanied by an ever-changing gut environment, from the antibiotic-induced disruption of the microbiota to the pathogen-induced inflammatory host response, which is reflected in the complex regulatory network connecting environmental signals (such as the availability of carbon sources) with the expression of central virulence factors such as the toxins.

Research focus

Post-transcriptional control of determinants of pathogenicity 

While the transcriptional regulators governing virulence expression have been studied for many years, we have only little knowledge of potential RNA-based mechanisms of virulence regulation in C. difficile. To advance our current knowledge about the RNA biology of C. difficile we want to:

  • generate a high-resolution map of the primary transcriptome of C. difficile to facilitate the discovery of small regulatory RNAs.
  •  functionally characterize newly identified sRNAs and their cognate RNA-binding proteins
  • identify their roles in C. difficile virulence using in vivo models of infection.
  • compare clinical isolates to understand how differences in the transcriptome of these closely related strains contribute to the different disease outcomes observed in the clinic.

Programmable Antibiotics against Clostridium

The primary strategy for treating bacterial infections is the use of antibiotics. However, in the case of C. difficile it is also the primary risk factor for contracting an infection with this pathogen. Hence, a targeted treatment strategy will be vital for successfully combating C. difficile infections in the future. Therefore, we want to explore synthetic oligonucleotides such as peptide nucleic acids (PNAs) as a potential drug to interfere with cellular pathways of C. difficile that are important for outgrowth and virulence factor expression during infection. To do so we will study several aspects such as mechanisms of drug delivery into the bacterial cell, modes of action and efficiency of different target pathways.

Inflammation-associated signatures of C. difficile central metabolism

To better understand C. difficile virulence we need to gain a deeper understanding of its metabolism during growth in the inflamed environment of the gut. These studies will further be vital to understanding the role of sRNAs in regulating virulence and to identifying targets for RNA-based intervention strategies. Therefore, we plan to:

  • identify metabolic pathways associated with inflammation
  • explore the impact of inflammation-associated signals on C. difficile central metabolism and the expression of virulence determinants