Popular Science Presentation
Our research focuses on two major areas:
A) Mycobacterial cell morphology and physiology and B) RNA biology.
A) Mycobacterial cell morphology and physiology
Bacteria of the genus Mycobacterium are acid fast, robust and they can inhabit various environmental reservoirs, e.g. ground and tap water, soil, animals and humans. This genus includes non-pathogenic environmental bacteria, opportunistic and highly successful pathogens, e.g., M. tuberculosis that causes tuberculosis (TB; ≈9 million new cases per year). M. tuberculosis is human-specific while the closely related M. bovis can infect humans and animals and cause TB in both.
Mycobacteria's adaptability to different conditions of stress from nutritional and oxidative deprivation is well established. It has also been reported that they display widely diverse morphological variants at different stages of their life cycles. Recent discovery in our and other laboratories of mycobacteria's capacity for sporulation has opened up unexpected avenues of enquiry into the molecular basis of pleiomorphism in response to stress and variation in growth conditions. If these morphological changes influence pathogenicity and persistence, then studies of the causes for pleiomorphic variation and the mechanisms of transition between different forms might provide new insights into the mechanisms of transfer, spread, dormancy and treatment of mycobacterial infections.
The aim of our studies is to understand the underlying molecular mechanisms behind morphological changes that mycobacteria undergo in response to different environmental stimuli and whether these changes play a role at and during infection. In our studies we focus on the fish pathogen Mycobacterium marinum, considered to be a model for M. tuberculosis. However, within the frame of our studies we also have taken a global approach where we study selected mycobacteria in order to map the physiological state in response to various growth conditions these mycobacteria are exposed to. These studies encompass sequencing the genomes of several mycobacterial species.
B) RNA biology
The tRNA genes are transcribed as precursors that need to be trimmed to generate matured and functional tRNAs. Almost all tRNAs carry a phosphate at their 5' ends due to the action of the endoribonuclease P, RNase P, which is responsible for the maturation of the 5'-termini of almost all known tRNAs in prokaryotes as well as in eukaryotes and as such it has a central role in precursor tRNA processing. RNase P is a ribonucleoprotein composed of one RNA subunit and dependent on origin, varying numbers of protein subunits (one in Bacteria, ≥ 4 in Archaea and 9-10 in Eukarya). However, irrespective of origin, the catalytic activity is associated with the RNA and RNase P RNA (RPR) catalyzes the trimming of the tRNA 5' end even without protein. Catalytic RNA are referred to as ribozymes. Moreover, RNase P activity based solely on proteins, PRORP, has recently been demonstrated in plants and human mitochondria. This adds further intrigue to the variation in the composition of the enzymatic activity responsible for generating tRNAs with matured 5' ends.
Over the years we have focused our studies to understand the mechanism of RNA mediated cleavage of RNA using E. coli RPR as a model system. We study the interaction between the RPR and its substrate as well as interactions between RNA and small ligands, e.g., metal ions and antibiotics. Our findings have increased our knowledge of: RNA mediated cleavage in general and how in particular the naturally occurring ribozyme RNase P RNA interacts and mediate cleavage of its RNA substrate; factors that are important for RNA metal ion and antibiotic interactions. More recently we have included PRORP in our studies with the aim to understand differences and similarities in processing of various precursors.