Stefano Marzi

Biography

Stefano Marzi, research director of the French National Centre for Scientific Research (CNRS), works in the unit RNA Structure and Reactivity (ARN) of the Institute for Molecular and Cellular Biology (IBMC). He is a member of P. Romby’s team “RNA Regulation in Pathogenic Bacteria” and leads a thematic group on the mechanisms of translation regulation in bacteria and deciphering their importance in host-pathogen interactions.

His multidisciplinary expertise spans structural, biophysical, biochemical, and genome-wide methodologies to investigate translation regulation in diverse organisms. This underscores his enduring fascination for the intricate mechanisms of ribosomes in protein synthesis. Presently, his research encompasses various facets of RNA biology in bacteria, aimed at unraveling the molecular intricacies of bacterial RNA regulatory elements, RNA modifications, and RNA-binding proteins governing mRNA translation and decay during adaptive processes (video; Bahena-Ceron et al., RNA 2024).

Stefano Marzi studied molecular biology at the University of Camerino, Italy. In 2001, during his doctoral studies on the mechanism of protein synthesis under the direction of C. Gualerzi, he moved to the US to join W. Hill and S. Lodmell’s team at the University of Montana, and then to the University of Pennsylvania (Philadelphia) to B. Cooperman’s team. His doctoral work earned him the RNA Society/Scaringe Young Scientist Award in 2003 for his major contributions to RNA biology. For his postdoctoral research on translation regulation, he joined C. and B. Ehresmann’s team at IBMC in Strasbourg in 2004. In collaboration with M. Yusupov and B. Klaholz (IGBMC), he used innovative structural approaches and discovered how structural and sequence features within messenger RNAs regulate gene expression (Marzi et al., Cell 2007). He entered the CNRS in 2007 as a researcher, where he obtained the habilitation to conduct research (HDR) in 2014. The French Society of Biochemistry and Molecular Biology (SFBBM) awarded him the Maurice Nicloux Prize in 2015, in recognition of his achievements. Dr. Marzi’s current research is supported by international and national grants and he is member of the IMCBio+ Interdisciplinary Thematic Institute.

Fellowship 2024

Dates - 01/10/2024-30/09/2026

Project summary

DEVELOPMENT OF DUAL RIBOSOME PROFILING TO UNCOVER TRANSLATION REGULATION IN HOST-PATHOGENIC BACTERIA INTERACTIONS AND PERSISTENCE

Gene expression, the process of converting genetic information into observable traits, is tightly regulated to connect cell physiology to internal and external environmental cues. This control operates at three levels: DNA transcription into mRNA, mRNA translation into proteins by ribosomes, and mRNA degradation. Pathogenic bacteria, and those inhabiting the human microbiota, utilize translation regulation to swiftly adapt to host environments and evade immune responses. Recent studies emphasize the pivotal roles of epitranscriptomic modifications in these processes, which alter RNA chemistry. Some pathogens can evade detection by invading host cells and persisting within them for prolonged periods, but their elusive nature and small numbers complicate their study. Staphylococcus aureus, a versatile pathogen causing diverse diseases, poses a significant global health threat. Its intracellular reservoirs fuel chronic infections, antibiotic resistance, and tissue dissemination. The mechanisms enabling S. aureus to survive antibiotics and form persister cells still remain poorly understood. Investigating these mechanisms in experimental infection models is vital for understanding staphylococcal pathogenesis, and for development of new therapeutic approaches.

In this project, our objective is to evaluate the alterations of S. aureus epitranscriptome and translation regulation in the development of persistency during its intracellular lifestyle. We will also examine how host cells adjust their own translation regulation in response to S. aureus infection. This type of analysis has never been attempted before and necessitates innovative methods including ribosome profiling to measure translation regulation at a detailed level and mapping of the RNA modification states using new generation sequencing methods. Additionally, we plan to use various human cell cultures, such as macrophages, neutrophils, and epithelial cells, alongside organoid 3D skin infection models, to mimic different stages of infection.

The outcomes of the project will be multiple: (i) at the methodological level, with the development of methods to study pathogenic bacteria translational control during infection and its correlation with the RNA modification state, (ii) at the basic research level, with a comprehensive understanding of translation regulation in S. aureus during infection and persistence development, (iii) at the medical level, with the identification of targets for elaboration of new strategies to interfere with virulence and/or bacterial persistence into host cells and to combat emerging bacterial resistance to clinically-relevant drugs. Our study might suggest a change in the treatment paradigm, which should consider not only the antibiotic susceptibility profile but also the diverse intracellular lifestyles of S. aureus when deciding on which therapy to apply to effectively eliminate the pathogen.