Salmonella enterica as a model for intracellular parasitism
The bacterial species Salmonella enterica includes more than 2000 so-called serovars, many of which infect man and animals, possibly even plants. In man, S. enterica mainly causes two types of diseases; a rather common variant in the form of an inflammatory gastroenteritis, and a severe form termed typhoid or paratyphoid fever affecting annually no less than 20 million individuals. On top of this burden, S. enterica is increasingly becoming resistant to antibiotics.
S. enterica is a bacterium closely related to Escherichia coli and easily accessible in terms of biochemical and genetic probing. A very hallmark of salmonellosis is the tight interplay between the pathogen and host cells. Thus, S. enterica has served as a classical model organism not only for dissecting basic cellular biochemical and genetic principles, but also for dissecting aspects of bacterial intracellular parasitism. This prospect of combining basic biochemistry and bacterial genetics with microbial pathogenesis provides the basis of our very research interests.
We have previously demonstrated that S. enterica experience dramatic differential in environment as it transits form an external milieu into the intravacuolar compartment of mammalian cells. In part, this environmental shift is primed by innate host defence measures, such as the production of reactive oxygen (ROS) and nitrogen species. This had leaded us to probe for the involvement of various oxidoprotective mechanisms in the virulence of the bacteria. Our results indicate that S. enterica possesses several overlapping measures for protection in the form of enzymes degrading ROS and repairing ROS-mediated protein damage. In addition, some of the enzymes involved, such as the thioredoxin 1 and the ScsABCD oxidoreductases, are also engaged in regulating virulence.
Apart from damaging protein and lipids, ROS-species also affect nucleic acids. In E. coli and man RNA damaged by oxidation is degraded by an exoribonuclease termed polybucleotide phosphorylase (PNPase). In S. enterica the gene for PNPase (pnp) is tightly linked to a gene coding for a lipoprotein NlpI and an RNA helicase DeaD. Mutational inactivation of either PNPase or NlpI results in redox-associated phenotypes regarding bacterial virulence. Thus, a further ambition is to probe to what extent RNA degradation in S. enterica is affected by oxidative stress, and to what extent PNPase, NlpI and DeaD contribute to the regulation of virulence gene expression, notably under oxidative stress.
In all, we wish to detail the interplay between bacterial 'house-keeping' functions, such redox management, and the very ability of bacteria to cause disease and colonization. Furthermore, as the antibacterial activities of selected antibiotics are connected to induction of endogenous redox stress, our findings may also aid the development of future regimens for antibacterial treatment.