How does a Salmonella pathogen outcompete beneficial intestinal microorganisms? It triggers an immune response that generates a compound from intestinal gas that it can utilize as an energy source. See Article p. 426
Infection often leads to inflammatory immune responses; no surprises there. It has long been speculated, however, that the ability to induce intestinal inflammatory responses favours pathogen growth1. Most hypotheses on how this might occur have centred on nutrient release through tissue damage or on the intestinal epithelial cells secreting macromolecules, such as extracellular matrix proteins, that can be used as nutrient sources. But the underlying molecular mechanisms of inflammation-induced nutrient availability for pathogens have remained largely elusive. In a remarkable paper on page 426 of this issue, Winter et al.2 connect the production by the mammalian host of reactive oxygen species — as part of the inflammatory response to the pathogenic bacterium Salmonella enterica serotype Typhimurium — to a unique, metabolic pathway in the pathogen that allows it to compete with the resident gut microbiota.
Winter et al. capitalized on an observation made in 1923 that, during fermentation, bacteria of the genus Salmonella could use the sulphur-containing compound tetrathionate as an electron acceptor to generate more energy and so to grow to a higher density. That observation led to the application of a growth medium containing tetrathionate to enrich salmonellae in stool specimens of human patients with acute infectious diarrhoea — gastroenteritis3. It is not clear where in nature tetrathionate exists, but it has been detected in humid soils, most probably generated by sulphate-reducing microbial communities in the soil4.
Winter and colleagues tested an extraordinary hypothesis that proposed that tetrathionate could be generated in the intestinal tract of vertebrates. They reasoned that sulphur-containing thiosulphates are abundant in the intestinal lumen, as mammalian cells convert toxic hydrogen sulphide gas (produced by the microbiota and by the consumption of sulphur-containing food) to these compounds5. The thiosulphates could then be oxidized to tetrathionate through the action of reactive oxygen species, because the phagocytic immune-system cells that are recruited to sites of Salmonella invasion to kill the invaders generate reactive oxygen species as an antibacterial mechanism.
In elegant experiments in mice, the authors show that, indeed, the ability to metabolize tetrathionate promotes S. Typhimurium colonization of the host. They also show that this compound is formed in vivo by an inflammatory response that generates oxygen radicals. These observations link inflammation and invasion of host tissues to a molecular mechanism for replication and dissemination of a pathogen within the intestinal tract.
The only other known pathogen with an intact tetrathionate pathway is Yersinia enterocolitica. Yersinia pestis — the bacterium responsible for plague, which is transmitted through flea bites — has evolved from Y. enterocolitica and is no longer an intestinal pathogen. In the light of Winter and colleagues' results, this correlation suggests that the inflammatory responses that Y. enterocolitica induces also promote its tetrathionate-respiration-dependent growth in the intestinal tract, and that this property was lost in Y. pestis as its mode of transmission changed from occurring via the mammalian intestinal tract to flea bites.
The ability of salmonellae to replicate in host cells is essential for their colonization of the intestine and their persistence there. These bacteria invade the intestinal epithelium using an interspecies protein-transport system known as the type III secretion system (T3SS), which promotes cytoskeletal rearrangements in mammalian cells and leads to bacterial uptake by the normally non-phagocytic epithelial cells6. Winter et al. find that salmonellae require the T3SS to exploit the tetrathionate pathway for colonization and replication in the gut. Intriguingly, the T3SS itself is known to lead to activation of a pro-inflammatory pathway7.
Genes encoding components of both the T3SS and the tetrathionate-respiration pathway in Salmonella have a different nucleotide content from each other and from the core, evolutionarily conserved, genome content: roughly 50% of the core conserved genome consists of adenine and thymine bases, whereas the T3SS genes are rich in adenine/thymine and the tetrathionate genes are guanine/cytosine rich (my own unpublished observations). The T3SS and tetrathionate respiration therefore were likely to have been acquired through horizontal gene transfer, after Salmonella differentiated from other intestinal bacteria such as the commensal Escherichia coli.
Salmonellae must have acquired the tetrathionate pathway at the same time as or after the acquisition of the T3SS, because Winter et al. find that the T3SS is required for tetrathionate-dependent replication. It could be that the recognition of the T3SS by the innate immune system led to the selection for acquisition of tetrathionate respiration by S. Typhimurium as an essential growth and colonization strategy. So this paper2 further suggests that the evolutionary driving force for the inflammatory periods, which we call disease and which result from host–pathogen interactions, may be microorganism dissemination and transmission. By inference, intestinal pathogens may resemble their highly co-evolved counterparts elsewhere, such as infectious agents on the skin (herpes simplex virus) and airways (Mycobacterium tuberculosis), that are responsible for chronic and episodic diseases for which the inflammatory periods are essential for transmission to new hosts.
Winter and co-workers' findings raise important issues about the unknown interactions between the microbiota, intestinal pathogens and their human hosts that could have a great impact on health. The challenge will be to develop technologies for monitoring the overall metabolism of each of these interacting components. By combining metagenomic analysis and modelling of the microbiota with functional studies of these microorganisms, researchers might be able to tap the rich source of information available within the human intestinal tract to better understand health and disease.
Stecher, B. & Hardt, W. D. Trends Microbiol. 16, 107–114 (2008).
Winter, S. E. et al. Nature 467, 426–429 (2010).
Bohls, S. W. & Mattman, L. H. J. Lab. Clin. Med. 35, 654–657 (1950).
Starkey, R. L. Soil Sci. 70, 55–66 (1950).
Levitt, M. D., Furne, J., Springfield, J., Suarez, F. & DeMaster, E. J. Clin. Invest. 104, 1107–1114 (1999).
Haraga, A., Ohlson, M. B. & Miller, S. I. Nature Rev. Microbiol. 6, 53–66 (2008).
Miao, E. A. et al. Proc. Natl Acad. Sci. USA 107, 3076–3080 (2010).
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