Deciphering the genetics of food poisoning

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Scientists in Portugal and France managed to follow the patterns of gene expression in food-poisoning bacteria Listeria monocytogenes (L. monocytogenes) live during infection for the first time. The work about to be published in PLoS Pathogens shows how the bacterial genome shifts to better adapt to infection by activating genes involved in virulence and subversion of the host defences, as well as adaptation to the host conditions. This is the first time that the molecular interactions between L. monocytogenes and its host, as they occur during the different steps of infection, are followed in real time paving the way, not only to the development of new therapies against this potentially lethal bacterium, but also for the study of other pathogen/host interactions.

Scientist Live spoke with Didier Cabanes, one of the lead authors, about the study and its implications.

What prompted you to study real-time gene expression of Listeria during infection?

The gram-positive bacterium Listeria monocytogenes is the causative agent of listeriosis, a severe food-borne infection characterized by abortion, septicaemia, or meningoencephalitis. L. monocytogenes is an intracellular pathogen that has one of the highest hospitalisation and mortality rates among food-borne infections and has become one of the best-characterized bacterial systems for the molecular analysis of invasion and intracellular parasitism. However, our knowledge of its infectious process in vivo is still fragmentary.Virulence is a trait that only manifests in a susceptible host, involving a highly coordinated interaction between bacterial factors and host components. Also we thought that the best means to better understand the Listeria-host interaction, would be the development of a global approach to be used in a context where both elements of the host-pathogen interplay are accessible.

How did you design the experiment and why did you employ DNA arrays? What advantages did it offer?

Macroarray technology is a global approach that allows the determination of the transcriptional status of the bacteria at the level of the whole genome,  and that can in turn allow the identification of new bacterial genes critical for the infectious process, and lead to a better understanding of the molecular events responsible for Listeria infection. In order to determine the detailed expression kinetics of the complete L. monocytogenes genome in the course of the infection, and identified new Listeria virulence factors whose expression is highly up regulated in vivo, we compared expression profiles of L. monocytogenes grown in standard culture medium in exponential phase vs. bacteria recovered from mouse spleens 24, 48 and 72 hours after intravenous infection.

What did you learn about how Listeria infection occurs?

Our results indicate that in the spleen of infected mice, ? 20% of the Listeria genome is differentially expressed, essentially through gene activation, as compared to growth in rich broth medium. During infection, Listeria is in an active multiplication phase, as revealed by the high expression of genes involved in replication, cell division and multiplication. In vivo bacterial growth requires differential expression of genes involved in adaptation of the bacterial metabolism and stress responses, in particular to oxidative stress. Listeria interaction with its host induces cell wall metabolism and surface expression of virulence factors. During infection, L. monocytogenes also activates subversion mechanisms of host defenses, including resistance to cationic peptides, peptidoglycan modifications and release of muramyl peptides. We showed that the in vivo differential expression of the Listeria genome is coordinated by a complex regulatory network, with a central role for the PrfA-SigB interplay. In particular, L. monocytogenes up regulates in vivo the two major virulence regulators, PrfA and VirR, and their downstream effectors.

You discovered a new virulence factors. Can you describe them?

Mutagenesis of in vivo induced genes allowed the identification of novel L. monocytogenes virulence factors, including an LPXTG surface protein, and suggesting a role for S-layer glycoproteins and for cadmium efflux system in Listeria virulence. However, characterization of the exact role of these new virulence factors reserves further investigations.

What is the next step for your laboratory?

We currently try to characterize the function of the new virulence genes identified in our study, but we also try to identified other virulence factors by mutagenesis of target genes differentially expressed during mouse spleen infection. Our work provides a powerful tool for the detection of novel virulence determinants and a better understanding of the complex strategies used by pathogens to promote infections.

We are also planning to perform the same in vivo genome profile analysis on different infected organs (intestine, liver, brain) and using different animal models in order to identify organ- or host-specific virulence factors.





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