CE12 - Génétique, génomique et ARN

Staphylococcus aureus sRNA-mediated adaptation to metal-based host defense strategies – MetalAureus

Submission summary

Staphylococcus aureus is an opportunistic human pathogen responsible for a wide range of superficial and severe systemic infections. Even more alarming is the emergence and worldwide spread of hypervirulent multidrug-resistant isolates such as methicillin-resistant S. aureus (MRSA), which is included in the World Health Organization priority pathogens list for the research and development of new antibiotics. Hence, there is an urgent need to explore new therapeutic avenues to tackle this global health concern.
A promising strategy is to emulate and strengthen existing host defense mechanisms such as those modulating metal bioavailability. Indeed, host immune cells, especially neutrophils and macrophages, either restrict access to essential metals or poison S. aureus with toxic metals overload. Despite experiencing both metal-related feast (metal toxicity) and famine (nutritional immunity), S. aureus possesses efficient adaptative mechanisms to survive. Notably, our preliminary data point out the crucial role of small regulatory RNAs (sRNAs). Since their discovery in the early 1980’s, accumulated results have depicted sRNAs as key actors in virtually all aspect of bacterial physiology (e.g. primary metabolism, cell division or virulence). Usually described as 50 to 500 nt-long RNA fragments, sRNAs are mostly involved in the post-transcriptional regulation of a subset of messenger RNAs forming their interactome. Interestingly, our recent data support the existence of a functional analog of the well-characterized sRNA RyhB, the real orchestra conductor during iron (Fe) starvation in Escherichia coli, which quickly re-establishes Fe homeostasis. Moreover, we identified the first manganese (Mn)-responsive sRNA, RsaC. The major function of RsaC is to spare intracellular Mn2+ via the repression of non-essential Mn-containing proteins like the superoxide dismutase A (SodA). In parallel, RsaC plays a critical role in the oxidative stress response by promoting the alternative Fe-SodM-dependent pathway to detoxify reactive oxygen species (ROS), notably produced by immune cells to eradicate S. aureus. Remarkably, RsaC has a broader role in iron and zinc stress responses, but also in the synthesis of virulence factors, strengthening the crucial role of sRNAs in connecting metal-related countermeasures and pathogenicity.
Through the MetalAureus project, we intend to reveal the pivotal role of sRNAs in S. aureus survival and adaptation to both metal starvation and toxicity, typically encountered during infection. As S. aureus needs to strictly balance the cellular level of various essential metals, our working hypothesis is that additional metal-responsive sRNAs remain to be identified. For this purpose, we plan the unprecedented identification of all sRNAs involved in the homeostasis of 6 metals (i.e. Fe, Mn, Zn, Cu, Co and Ni) regarded as crucial for S. aureus physiology and virulence. Then, we will decipher their functions by revealing their whole interactome using innovative and complementary high-throughput RNA sequencing technologies (DBRI and MAPS). This will first be performed in controlled growth conditions (e.g. specific metal-depleted media or metal overload) to untangle intricate and intertwined regulatory networks and to facilitate data interpretation in more complex physiological conditions. Indeed, the ultimate goal is to scrutinize both host metal-based defense strategies and S. aureus countermeasures during host-pathogen interaction using the powerful Dual RNA-seq method.
The MetalAureus project represents an exceptional opportunity to understand the mechanisms employed by S. aureus to evade metal-based immune defenses and to cope with promising metal-related therapeutic strategies (e.g. metal chelators or metal-based antimicrobials). This is notably of paramount importance to tailor and exploit these alternatives to the classical antimicrobial compounds.

Project coordination

David Lalaouna (Architecture et Réactivité de l'ARN (UPR 9002))

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.

Partner

The Hebrew University of Jerusalem
CIRI CENTRE INTERNATIONAL DE RECHERCHE EN INFECTIOLOGIE
ARN Architecture et Réactivité de l'ARN (UPR 9002)

Help of the ANR 246,162 euros
Beginning and duration of the scientific project: December 2020 - 36 Months

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