Mini Review
Sugar metabolism, an additional virulence factor in enterobacteria

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Abstract

Enterobacteria display a high level of flexibility in their fermentative metabolism. Biotyping assays have thus been developed to discriminate between clinical isolates. Each biotype uses one or more sugars more efficiently than the others. Recent studies show links between sugar metabolism and virulence in enterobacteria. In particular, mechanisms of carbohydrate utilization differ substantially between pathogenic and commensal E. coli strains. We are now starting to gain insight into the importance of this variability in metabolic function. Studies using various animal models of intestinal colonization showed that the presence of the fos and deoK loci involved in the metabolism of short-chain fructoligosaccharides and deoxyribose, respectively, help avian and human pathogenic E. coli to outcompete with the normal flora and colonize the intestine. Both PTS and non-PTS sugar transporters have been found to modulate virulence of extraintestinal pathogenic E. coli strains. The vpe, GimA, and aec35-37 loci contribute to bacterial virulence in vivo during experimental septicemia and urinary tract infection, meningitis, and colibacillosis, respectively. However, in most cases, the sugars metabolized, and the precise role of their utilization in the expression of bacterial virulence is still unknown. The massive development of powerful analytical methods over recent years will allow establishing the knowledge of the metabolic basis of bacterial pathogenesis that appears to be the next challenge in the field of infectious diseases.

Introduction

The bacterial family Enterobacteriaceae includes many well-studied bacteria that are normal inhabitants of the intestine of healthy individuals. Other members of this family are found in soil, plants, and water. However, under certain circumstances, some enterobacteria, within genera such as Escherichia, Salmonella, and Yersinia, can also be dangerous pathogens in humans and animals. Studies over the last 30 years have identified and described numerous virulence factors (VFs) – including adhesins/invasins, toxins, iron acquisition systems, and mechanisms to evade the immune response – and the genes encoding them. There is now a substantial body of knowledge about the development of intestinal and extraintestinal syndromes caused by these bacteria. However, the characterization of these VFs is not sufficient to understand infectious disease mechanisms. Indeed, we also need to understand how pathogenic bacteria adapt their metabolism to derive carbon and energy from the environment, allowing them to grow, to survive, and to colonize their hosts at intestinal and extraintestinal sites. Studies of the links between metabolism and virulence could provide not only new insights into host–pathogen interactions, but also new perspectives in understanding the metabolic basis of bacterial pathogenesis.

A number of physiological studies have shown that the regulation of expression of many VFs is controlled by nutrient availability (Somerville and Proctor, 2009). However, the regulatory mechanisms linking a particular metabolic system to the production of a specific VF are still poorly understood. A recent symposium brought researchers in these different fields together for the first time (Metabolism Meets Virulence, International Symposium, Hohenkammer, Germany, April 2009). Pathogenic enterobacteria have developed two strategies to compete with normal flora and colonize infectious sites. They can modify their metabolism in response to environmental changes by regulating catabolic pathways, the components of which are encoded by the core genome. Many transcriptomic, proteomic, and metabolomic studies have been carried out to decipher the essential pathways in bacteria during infection. Indeed, comparative genomic and growth analyses of the pathogenic E. coli O157:H7 (strain EDL933) and the non-pathogenic E. coli K-12 (strain MG1655) have shown that there are no major differences in the gene systems that encode and regulate the pathways for carbon source utilization and no differences in nutritional usage in vitro between these two strains. However, these strains use different carbon sources for the colonization of the streptomycin-treated mouse intestine (Fabich et al., 2008). Pathogenic bacteria can also adapt to changing nutrient supplies by expressing specific genes that are not present in the genomes of commensal isolates. For example, uropathogenic bacteria need to take advantage of available nutrients present in urine, comprising a dilute mixture of amino acids and small peptides. One potential nutrient in urine is d-serine, which is toxic for commensal strains but is degraded by a d-serine deaminase (DsdA) in uropathogenic strains. Approximately 85% of pyelonephritis- and urosepsis-associated E. coli isolates carry at least one dsdXA operon for d-serine utilization. Recently, a dsdA gene was identified in uropathogenic Staphylococcus saprophyticus isolates, but not in other staphylococcal species. One study showed a uropathogenic E. coli CFT073 dsdA mutant displaying a hyper-colonization phenotype in a murine model of urinary tract infection (UTI) (Anfora et al., 2007); however, another study showed a S. saprophyticus dsdA mutant to be less virulent than the parental strain in experimental infections (Sakellaris et al., 1999). Thus, catabolism of d-serine may act as either a fitness trait or a signal for virulence gene expression, depending on the strain and environmental conditions.

Section snippets

Carbohydrate metabolism is important for virulence mechanisms in enterobacteria

The metabolic flexibility of enterobacteria is related to genetic diversity and dynamic organization of the genome, which seem to be general characteristics of these bacteria. The sequencing of more than 50 genomes of E. coli strains has been completed or is in progress (http://www.genomesonline.org/gold.cgi). This has revealed differences encompassing up to 1 Mb of sequence in genomes ranging from 4.5 to 5.5 Mb in size. Although comparative and functional analyses of the genome have improved our

Carbohydrate transporters in enterobacteria

Dozens of families of primary and secondary transporters allowing the uptake of essential nutrients have been described (Saier, 2000). Two families have been found to appear ubiquitously in all classifications of living organisms. There are the ATP-binding cassette (ABC) superfamily and the major facilitator superfamily (MSF). Functionally and structurally different sugar transporters have been identified in enterobacteria. Primary, active ABC transporters, coupling transport against a

Carbohydrate metabolism and colonization of the intestine by commensal and pathogenic enterobacteria

The intestine is the primary niche of most enterobacteria among which E. coli is predominant (Harmsen et al., 2002). Colonization of the intestine is the first step of host infectivity for pathogenic enterobacteria, including all categories of pathogenic E. coli. Intestinal pathogenic E. coli strains are rarely found in the fecal flora of healthy hosts. Extraintestinal pathogenic E. coli, however, stably colonize the intestine without inducing clinical symptoms. These bacteria constitute the

Carbohydrate metabolism and virulence of enterobacteria

Both in vitro and in vivo studies have shown a role for carbohydrate metabolism in the virulence of pathogenic enterobacteria colonizing humans, animals, and plants. The following examples illustrate the variety of metabolic pathways that may be involved in enterobacterial pathogenesis (Table 1).

The best-characterized pathways mediating sugar catabolism in bacteria are glycolysis, the pentose phosphate pathway, and the Entner–Doudoroff pathway. Glycolysis is required for the in vitro

Conclusions

As reviewed here, increasing numbers of studies are demonstrating a link between the transport and metabolism of various carbohydrates and virulence in enterobacteria. However, in most cases, the carbohydrates metabolized and the precise role of their utilization in the expression and regulation of bacterial virulence have yet to be determined. A fundamental role of such metabolic processes may be to facilitate the adaptation of the bacteria to its host environment by allowing the bacteria to

Acknowledgements

C. Le Bouguénec is supported by the Institut Pasteur, and C. Schouler is supported by Nationale Institute for Agricultural Research (INRA). The authors are partners in the ERA-NET pathogenomics project, Deciphering the Intersection of Commensal and Extraintestinal Pathogenic E. coli, which is supported by the ANR.

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