During infection, bacterial pathogens manipulate a vast range of host cellular functions to ensure their survival and replication. Among others, bacteria are known to induce reorganization of the host cell cytoskeleton and to modulate signal transduction pathways, membrane trafficking and pro-inflammatory responses. The deregulation of these key intracellular pathways is often achieved by delivering bacterial effector proteins into host cells using complex protein secretion systems.
However, the study of the impact of bacterial infections on the RNA metabolism of host cells and its consequences to the bacterial life cycle remain largely unexplored. A proper RNA metabolism is essential to a number host cell functions and therefore it is not surprising that pathogens have evolved sophisticated mechanisms to subvert these pathways to their own benefit. Viruses, for example, have been shown to modulate the levels of host microRNAs and to encode suppressor proteins that antagonize the small RNA-directed host immunity.
Our research is focused on determining if bacterial pathogens are able to interfere with the RNA metabolism of host mammalian cells, whether this is achieved through delivery of bacterial proteins or non-coding RNAs (ncRNAs) and, ultimately, to characterize how this may benefit or antagonize the bacterial life cycle.
Interplay between host cell microRNAs and bacterial infection
Despite previous studies, by us and others, showing that bacterial pathogens (e.g. Salmonella enterica, Helicobacter pylori) induce significant changes in the mammalian host microRNA expression profile, the generation of a comprehensive atlas of microRNAs regulated as a consequence of bacterial infection is clearly missing. Therefore, a major focus of our research is the identification of host microRNAs regulated upon infection with representative bacterial pathogens, as well as the characterization of the mechanisms by which bacteria modulate host cell microRNAs. Our goal is to determine whether different bacteria regulate a common set of host microRNAs or if a microRNA signature exists for infection with different bacteria, and to establish whether microRNAs are regulated in a cell-type specific manner. We are also working on the identification of host cell microRNAs that regulate bacterial infection. The identification of these microRNAs will be instrumental to the development of novel therapeutic approaches against pathogenic bacteria, either through the modulation of selected microRNAs, or of their targets.
Impact of bacterial pathogens on host cell RNA metabolism
The relationship between bacterial infections and RNA granules, in particular P-bodies (also known as mRNA processing bodies) and stress-granules, is another aspect of the bacterial-host interaction for which very little information is available. Considering that the formation and stability of RNA granules is strictly dependent on the cellular RNA metabolism, any perturbation induced by bacterial pathogens on RNA granules is most likely a consequence of their effect on host RNA metabolism.We aim to determine whether and how bacterial infections interfere with P-bodies, stress-granules, and/or their protein components. Moreover, we are working on the characterization of the impact of bacteria on host cellular mRNA processing, stability and surveillance pathways. The reciprocal effect of host RNA metabolism on bacterial infection will also be evaluated.
Effect of bacterial non-coding RNAs on key host intracellular pathways
One of the most intriguing questions that we aim to address is whether bacteria have developed a system(s) to actively introduce RNAs inside host cells to modulate key cellular functions. This hypothesis is particularly pertinent taking into consideration that bacteria have evolved very efficient secretion systems for proteins and that a number of non-coding RNAs with, so far, unknown function have been identified in bacteria.