Webinars du réseau "Phages.fr"

Devon Conti, PhD student in "Bacteriophage Bacterium Host", Pasteur Institute, Paris

Florian Tesson, PhD student in "Molecular Diversity of Microbes" (MDM), Intitut Pasteur, Paris

Julián Bulssico, Postdoctoral scientist - Laboratoire de Chimie Bactérienne, Marseille, France

Antibiotic resistance is a major threat to public health, pushing the scientific community to develop alternative strategies. One of these is therapy combining bacteriophages and antibiotics, which is already administered in compassionate care. The combination of these two types of antibacterial, indeed, often displays a synergistic effect. This can be observed as enhanced phage propagation within a bacterial population in the presence of antibiotics. Despite the importance of such interactions, the molecular basis of synergy is far from being fully deciphered.

In our work, we characterised phage propagation in the presence of antibiotics. To achieve this, we developed powerful microscopy and image analysis techniques to visualize phage infection on E. coli with single-cell resolution. Our results suggest that synergy is remarkably conditioned by the structuration of the media in which phage and bacteria interact:

In well-mixed, liquid environments we assessed the impact of filamentation-inducing antibiotics on phage predation. We observed that impaired E. coli division enhances phage killing by phages HK620, T4, T5 and T7. Additionally, our novel tracking techniques allowed us to quantify the heterogeneity in phage infection. We observed that, due to their enlarged sizes, filaments are infected and lysed more often than regular-sized cells, which in turn limits SOS-mediated bacterial mutagenesis.

In semisolid media, we measured the impact of several synergistic antibiotics (ciprofloxacin, ceftazidime and mecillinam) on both phage T5 and T7, propagating in E. coli MG1655, expecting to find common effects that could explain enhanced phage propagation. We concluded that antibiotic-induced changes in bacterial morphology are crucial for the occurrence of synergy, and that two different altered shapes (spheroids and filaments) can lead to this effect.

Overall, we present new insights on the intricate interplay between phage, antibiotics, and bacteria, contributing to the characterization of epidemic propagation in bacterial populations suffering different types of stress, and highlighting the role of the spatial structuration of the system.

Watch the video here

Pathogens have fueled the diversification of intracellular defense strategies that collectively define cell-autonomous innate immunity. In bacteria, innate immunity is manifested by a broad arsenal of defense systems that provide protection against phages. The complexity of the bacterial immune repertoire has only been realized recently and is now suggesting that innate immunity has commonalities across the tree of life: many components of eukaryotic innate immunity are found in bacteria where they protect against phages. Here, I summarize recent findings on the conservation of innate immune pathways between prokaryotes and eukaryotes. I show that bacterial defense mechanisms can in turn catalyze the discovery of novel molecular players of eukaryotic innate immunity. We recently described ATP nucleosidases, immune effectors which cleave ATP molecules into adenine and ribose-5'-triphosphate during phage infection, thereby depriving phages of energy. Using phylogenetic analyses, we found that the immune ATP nucleosidase domain is found in a variety of eukaryotic organisms ranging from fungi to corals and insects, where it is embedded in a diverse set of proteins with a typical immune architecture. Taken together, our findings suggest that ATP degradation represents a novel mechanism of innate immunity that is conserved across the tree of life, highlighting the potential of bacterial defenses to expand our knowledge of eukaryotic immunity.