Deeper insight into bag of tricks of bacteria

Cynthia Sharma studies how bacteria adapt to changing environments, focusing on RNA-binding proteins, about which very little is known so far. For this, she has now received an ERC Consolidator Grant endowed with two million euros.

Cynthia Sharma

Cynthia Sharma, head of the Chair of Molecular Infection Biology II and spokesperson of the Research Center for Infectious Diseases (ZINF) at the Julius-Maximilians-University Würzburg. (Image: Petra Thomas (IMIB))

When bacteria such as the foodborne pathogens Campylobacter jejuni or Salmonella infect humans, they usually encounter a hostile environment. However, thanks to various mechanisms, they can adjust to these conditions and have developed sophisticated survival and adaptation strategies.

Within the framework of a new research project, Cynthia Sharma focuses on a specific area of such cellular control that bacteria use to regulate their genes in response to environmental changes. Sharma and her team will explore a class of proteins that can bind RNA molecules and thereby exert major influence on gene expression and cellular processes in bacteria. So far, this class of proteins is largely unexplored.

Cynthia Sharma is head of the Chair of Molecular Infection Biology II and spokesperson of the Research Center for Infectious Diseases (ZINF) at the Julius-Maximilians-University Würzburg (JMU). She has now received a prestigious research award from the European Research Council (ERC): a Consolidator Grant endowed with two million euros. The ERC awards this type of grant to outstanding scientists with a promising career.

During the next five years, Sharma can use this grant to significantly advance her research. The funds for her project “Exploring the Expanding Universe of RNA-Binding Proteins in Bacteria”, or short bacRBP, will mainly be used for the expansion of her team, the purchase of consumables, and the development of new experimental technologies.

A vast and unexplored universe

The aim of her ERC Consolidator Grant is to identify and characterize RNA binding proteins in bacteria. “Our project is based on the hypothesis that there is a vast and largely unexplored universe of RNA binding proteins in bacteria that play crucial roles in cellular physiology”, says Sharma. “RNA-based gene regulation plays a central role in stress response and virulence control of bacterial pathogens,” she explains. In the past 20 years, research has mainly focused on small regulatory RNA molecules in the search for the players involved in RNA-based regulation. Research on RNA is also a major focus at the JMU, where important insights have been gained into the complex regulatory mechanisms involving RNA molecules.

Sharma and her team are now going one step further: they are interested in proteins that can bind to RNA molecules and regulate them. Only a few well-characterized examples are known in bacteria and have been identified long ago. They have a so-called RNA-binding domain with which they can interact with RNA. “This enables them to influence gene expression and, thus, physiological processes of bacteria”, explains the microbiologist.

Proteins with second jobs

Recent research results – also from Cynthia Sharma’s lab- have revealed that there are not only many more RNA-binding proteins out there, but there are also proteins that can interact with RNA despite the lack of canonical RNA binding domains. Among them are, e.g., metabolic enzymes or proteins important for cell division. The interaction of these proteins with RNA was surprising. “They seem to be moonlighting proteins with a second job”, says Sharma. However, it is still unclear if these proteins influence RNA or if rather the RNA influences the protein.

How many RNA-binding proteins exist in bacteria, what tasks do they perform and what are the regulatory mechanisms they are involved in? This is all still largely unknown. With the help of the ERC grant, Cynthia Sharma and her team aim to address and answer these questions over the next five years.

New method provides new insights

Why do we know so little about these proteins? One major reason is the challenge to identify such RNA-binding proteins in bacteria. Cynthia Sharma and her team have recently made significant progress in this area. “My lab has developed a fundamentally new method that can greatly facilitate the systematic identification of such proteins in bacteria”, she says.

With the help of this method, Sharma aims to search for RNA-binding proteins under different stress and infection-relevant conditions, with a particular focus on proteins lacking a canonical RNA-binding domain. This method will be combined with techniques from genomics, transcriptomics, and proteomics, in addition to approaches from molecular biology, microbial genetics, and high-resolution imaging techniques.

Three main goals

Sharma and her team aim to address three main goals in the bacRBP project:

  • the establishment of a widely applicable method for the systematic identification of RNA-binding proteins in diverse organisms
  • a greatly expanded set of RNA-binding proteins in the two model organisms Campylobacter and Salmonella
  • new insights into mechanisms of gene regulation and cell division in bacteria.

“With the bacRBP project, we hope to significantly advance our understanding of RNA-binding proteins and the way they regulate physiological processes in bacteria”, Sharma says. This could not only reveal fundamental biological principles, but also contribute to the development of novel biotechnological methodologies or antimicrobial strategies. This is an increasingly important aspect in view of the growing resistance of many bacteria to common antibiotics.

Cynthia Sharma’s CV

Cynthia Sharma studied biology with a focus on biophysics, bioinformatics, and computer science at the Heinrich-Heine-University in Düsseldorf. She obtained her PhD in bacterial RNA biology at the Max Planck Institute for Infection Biology in Berlin (MPIIB) in 2009.

After short postdoctoral work at the MPIIB and the National Institutes of Health (NIH) in Bethesda, she joined the Research Center for Infectious Diseases (ZINF) in Würzburg as a junior group leader in 2010. Since 2017, she is the Chair of Molecular Infection Biology II in Würzburg and spokesperson of the ZINF since 2018. Her lab studies gene regulation and CRISPR-Cas immune systems in bacterial pathogens.

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