Meyer D.F., Noroy C., Moumène A., Raffaele S., Albina E., Vachiéry N., 2013. Searching algorithm for type IV secretion system effectors 1.0: a tool for predicting type IV effectors and exploring their genomic context. Nucleic Acids Research, 41: 9218-9229. Doi: 10.1093/nar/gkt718
Emerging and Exotic Animal Disease Control (UMR CMAEE)
During an infection, bacteria prove stronger than their host, overcoming its defences and causing symptoms. To this end, they secrete proteins within the host's cells that enable them to exploit its cellular machinery to their own ends and overcome its immune responses. To study the mechanisms involved in these early stages of infection, a team from CIRAD and INRA recently developed software that serves to identify these proteins and analyse their genomic context. This is an important step on the way to understanding pathogenic bacteria functioning and developing new treatments against animal and zoonotic bacterial pathogens.
To succeed in infecting a host, bacterial pathogens have to penetrate its cells without triggering any defence mechanisms and overcome its cellular machinery so as to multiply. However, this "success" relies on a subtle balance between the two partners. Understanding the molecular mechanisms that underlie this balance is a major step towards the development of new treatments against bacterial pathogens.
One of the methods used by bacteria to cause diseases consists in releasing proteins that disrupt cell functioning in their host. To identify those proteins, a team from CIRAD recently developed a novel generic software.
Many aspects of the life of bacteria require them to release proteins into their extracellular environment. To this end, they have several more or less complex macromolecular secretion systems, graded from I to VI.
Type IV secretion systems (SST4), which act as veritable molecular syringes, serve to inject type IV effector proteins (ET4) into the cells of their host.
Such effectors have been identified in many bacterial pathogens (Agrobacterium tumefaciens, Bartonella henselae, Brucella abortus, Anaplasma spp., Ehrlichia chaffeensis, Coxiella burnetii, Legionella pneumophila ). They play a vital role in infection and in disease development and, as such, are prime targets for understanding bacterial virulence.
To predict this type of effectors and analyse their genomic context, a team from CIRAD and INRA developed software called S4TE (pronounced "satay"). Its algorithm takes account of the known characteristics of effectors, such as the eukaryotic domains involved in protein-protein interactions, localization signals and their properties (positive charge, basicity or hydrophobicity). It can easily be parameterized by users, who conduct their research by specifying the variables that correspond to those characteristics.
Its originality lies in its modularity, its flexibility, the quality of its predictions and the fact that it is the only type IV effector prediction tool available on line. It is also the only one that can be applied to any bacterial genome.
The software can also be used to look at the genomic context of type IV effectors. It includes tools for analysing the proportion of certain bases (G and C) in the bacterial genome and the spatial distribution of effectors in line with that proportion. Moreover, it also serves to explore genome architecture and study effector distribution as a function of local gene density.
With its scoring function, which combines the different outputs and compares the score obtained with a predefined threshold, the software also proposes prediction quality indicators, calculated based on the almost exhaustive list of type IV effectors of L. pneumophila. This function is of great use in choosing the targets to be validated experimentally.
Using the software, the CIRAD team was able to identify 22 effectors potentially released by the type IV secretion system in the model bacterium Ehrlichia ruminantium, which transmits a fatal tropical disease of ruminants.
The presence of some of these effectors was predictable given their homology with effectors that had already been characterized. Other effectors, on the other hand, appear to be unique within the bacterial kingdom and specific to this bacterium. They make up new effector families, which could play a decisive role in the disease.
Research into type IV effectors is vital in order to understand the molecular mechanisms at play during bacterial infection and, eventually, to be able to inhibit them using new vaccines or new antibacterial molecules.
S4TE provides scientists with an easy-to-use tool for rapidly identifying type IV effectors whose function in infection processes they can subsequently study.