Ajankohtaista

Open doctoral student positions at the Department of Biological and Environmental Science, University of Jyväskylä

2. Evolutionary obstacles and opportunities that govern the dynamics of mobile genetic elements in microbial communities

Resistance to antibiotics along with increased virulence has turned bacterium Klebsiella pneumoniae into one of the most notorious hospital pathogens. Genetically it is a complex puzzle: K. pneumoniae strains carry large conjugative and smaller non-conjugative plasmids; the number of integrated viruses and integrative and conjugative elements (ICEs) vary between bacteria, and some isolates have multiple CRISPR-loci defending the host against external genetic invaders whereas others have none. While the bacterial chromosome provides much of the genetic background for the mobile elements to operate in, it is usually the mobile elements that determine the resistance and virulence of individual strains. This interaction between chromosomal background (that drift away from each other due to neutral mutations) and mobile elements (that often change from one background to another) is understood only to some extent. Elements that are not adapted to the host induce fitness costs and thus are selected against. On the other hand, acquiring a novel element at the right moment can rescue the strain from otherwise lethal situation (for example during antibiotic therapy) or provide unique openings for reproduction (for example by providing genes that allow exploitation of host resources). Mobile elements can also force their uptake even in conditions where it is not favorable to the host.

In the proposed PhD project, the interaction of conjugative elements acquired from epidemic K. pneumoniae against novel genetic backgrounds (other hosts) are mapped in an attempt to understand evolutionary obstacles and opportunities that govern the dynamics of mobile genetic elements in microbial communities. This research provides insights to the emergence of novel hospital pathogens as well as helps determine fundamental eco-evolutionary rules behind inter-host genetic exchange. Methodologically, the project involves microbiology with bacteria, molecular biology, genetics and some bioinformatics. Also, if the applicant is interested, there are opportunities for developing computational models. The applicant would join a dynamic research group that studies antibiotic resistant bacteria originating from hospitals across the world. The project is done in collaboration with researchers from Karolinska Institute (Sweden), National Center for Biotechonology Information (NCBI, USA) and University of Cambridge (UK).

A successful applicant would have a background in cellular and molecular biology, evolutionary genetics, or a related field.

Further information: Academy Research Fellow Matti Jalasvuori, Email: matti.jalasvuori@jyu.fi.; mattijalasvuoriresearch.blogspot.fi.

3.Structural and functional characterization of M23 family metalloendopeptidases that lyse bacterial cell wall peptidoglycans

Staphylococcus aureus is a major human and veterinary pathogen. The evident increase in S. aureus resistance to antibiotics demands for the development of new, efficient and cost-effective chemotherapeutics. The use of autolysins (bacterial peptidoglycan hydrolases) for the prevention and treatment of S. aureus infections has been under vivid research and shown very promising results. Autolysins play an important role in the maintenance of the bacterial cell wall. The S. aureus cell wall is composed of two polymers, peptidoglycan and teichoic acid. The former provides the structural framework of the bacterium and protects against turgor pressure, whereas the latter controls the overall surface charge affecting e.g. the activity of peptidoglycan hydrolases and surface adherence ability of the bacterium. To date, two autolysins have been tested as potential staphylolytic agents, S. simulans lysostaphin and Pseudomonas aeruginosa LasA. These cleave pentaglycine bridges present in peptidoglycan. Lysostaphin and LasA belong to the M23 family of zinc-dependent peptidases. Other M23 family members that have been structurally and/or functionally characterized are ALE-1 from S. capitis, LytM and LytU from S. aureus, and NMB0315 from Neisseria meningitidis. The overall structures of the enzymes are strikingly similar, the catalytic efficiencies are, nevertheless, markedly different.

The aim of the project is to unravel underlying structural basis for different substrate specificities, catalytic efficiencies as well as the catalytic mechanism of these very similar enzymes by using various biophysical and biochemical approaches. These studies pave the way for development of new therapeutic agents to treat S. aureus infections. The PhD student will engage in structural and functional characterization of this enzyme family by collecting and analyzing data on protein structure and dynamics along with substrate interactions and kinetics. The Permi Lab is the main user of a recently installed, state-of-the-art Bruker Avance III HD NMR spectrometer operating at 800 MHz of ¹H frequency, and has access also to a recently upgraded Bruker Avance III 500 MHz NMR spectrometer. The group has also modern facilities for protein production and purification.

We are looking for a motivated PhD applicant having a Master’s degree in Biology/Chemistry or a related field, and some experience at least in one of the following topics: Structural biology/structural bioinformatics, protein biochemistry, biophysical characterization of proteins, NMR spectroscopy, X-ray crystallography. Additional experience on MD simulations, programming, statistics or bioinformatics is beneficial but not essential.

Further information: Professor Perttu Permi, Email: Perttu.Permi@jyu.fi, Tel. +358 (0)40 8054288

4. Virus-nucleus interactions

Understanding of virus-nucleus interactions is essential for discovering improvements and novel strategies in development of herpes simplex virus type 1 (HSV-1) anti-virals and HSV-1 mediated gene therapy. Moreover, viral infections manipulate the nucleus, and serve as excellent model systems for the characterization of nuclear processes. Our studies advance the current research of virus-nucleus interactions by an interdisciplinary approach involving cell biology and biophysics, combined with state-of-the-art techniques of microscopy imaging, advanced image analysis, and biophysical modeling.

This PhD project aims to unravel the structural changes of chromatin and viral egress dynamics during the lytic infection with HSV-1. In continuation of our prior studies on HSV-1 reorganization of chromatin architecture (1, 2), we will further analyze the mechanisms of viral impact on chromatin structure and detailed dynamics of viral nuclear exit. These studies are done in close collaboration with Prof. Carolyn Larabell (National Center for X-ray Tomography, Lawrence Berkeley National Laboratory, CA, USA; 1, 3) and other collaboration partners with expertise in advanced imaging, modeling, biophysics, virology and viral therapy.

The doctoral student will benefit from supportive research training environment and receive co-supervision by group leader and the senior members of the research team. He/she will use state-of-the-art imaging techniques in University of Jyväskylä, Tampere and Helsinki, attend advanced practical courses on imaging (e.g. EMBO) and national and international scientific meetings, and do site visits in international labs.

We are looking for a highly motivated PhD candidate with a Master’s degree and background in one or several of these areas or a related field: cell biology / microbiology / virology / advanced imaging including live cell imaging, confocal microscopy, EM etc. / biophysics, to conduct the experimental work.

Further information: Group leader, senior lecturer Maija Vihinen-Ranta, Email: maija.vihinen-ranta@jyu.fi