PerspectiveMicrobiology

Virulence or Competition?

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Science  08 Jun 2012:
Vol. 336, Issue 6086, pp. 1238-1239
DOI: 10.1126/science.1223303

The human gastrointestinal tract harbors trillions of bacterial cells belonging to more than 1000 species (1), and there are 10 times as many bacterial cells within the gastrointestinal tract as there are human cells within our bodies (2). The gastrointestinal microbiota plays essential roles in human nutrition, physiology, development, immunity, and behavior, such that disrupting the structure and balance of this community leads to dysbiosis and disease (35). This important balance between host and microbiota can be severely disrupted by environmental stimuli. One of the most common insults to the microbiota that induces dysbiosis is infectious diseases. On page 1325 of this issue, Kamada et al. (6) propose that competition between resident microbes and pathogens is influenced by the expression of virulence factors by pathogens and by the nutritional requirements of both populations. These dynamics can steer the survival, colonization, and clearance of pathogens in the gut.

Citrobacter rodentium is a pathogen of mice that models the enteric infection of the human pathogens enteropathogenic Escherichia coli and enterohemorrhagic E. coli. Infection by these microbes causes inflammation within the gut that diminishes the overall numbers of bacteria in the microbiota, giving an initial competitive advantage to the pathogen (7, 8). These pathogens use a molecular syringe-like mechanism, called a type III secretion system, to cause extensive actin rearrangements in the host's intestinal epithelial cells (enterocytes), promoting bacterial colonization at the interface of the intestinal epithelia (9). Type III secretion systems have been largely regarded as bacterial virulence factors, even though these secretion systems can be found in soil bacteria in the absence of host-pathogen associations.

To determine how C. rodentium establishes enteric infection, Kamada et al. compared its ability to colonize pathogen-free conventional mice and germ-free mice (which lack gastrointestinal microbiota). They show that in germ-free mice, the type III secretion system is not necessary for intestinal colonization, whereas it is essential in conventional mice. The authors also show that expression of the type III secretion system occurs in the earlier stages of infection and is reduced at later stages, and that in conventional mice, expression of the type III secretion system plays a key role in intestinal colonization. However, in germfree mice, even in the absence of the type III secretion system, C. rodentium is proficient in intestinal colonization, but is outcompeted by the microbiota in conventional mice. Infection with C. rodentium changes the structure of the microbial community, decreasing the number of anaerobes and increasing the numbers of γ-Proteobacteria (7). Kamada et al. make the seminal observation that C. rodentium can be outcompeted by other γ-Proteobacteria such as E. coli, but not by Bacteroides, and that this competition is governed by carbon source availability. Bacteroides is a glycophagic bacterial phylum that can use complex polysaccharides as carbon sources, whereas γ-Proteobacteria (E. coli and C. rodentium) are restricted to monosaccharides. By shifting the composition of the microbiota toward γ-Proteobacteria (7), C. rodentium actually undermines its ability to colonize the host by increasing competition for the same nutrient sources. Conversely, this shift in the microbiota composition during C. rodentium infection might be a “probiotic strategy” to control enteric infection.

Pathogen versus commensals.

The mammalian gut microbiota is present in the loose outer mucus layer of the intestine. During early infection, an invading pathogen expresses a repertoire of virulence factors to compete for a colonization niche. These factors allow pathogens to penetrate the inner mucus layer and colonize the epithelium, replicate, and trigger inflammation. Later in infection, expression of virulence factors decreases. There is also a change in the composition of the microbiota to compete with the pathogen for nutrients. Together, these changes aid in pathogen clearance.

CREDIT: C. BICKEL/SCIENCE

One the major challenges faced by bacteria within communities is acquiring carbon to synthesize primary metabolites. The mammalian gastrointestinal tract harbors trillions of indigenous bacteria whose coexistence relies on the ability of each member to use one or a few limiting resources. Invading pathogens must compete with the microbiota for these resources to establish colonization. These pathogens must be aggressive in their search for a colonization niche, which they achieve by precisely coordinating expression of virulence traits such as the type III secretion system. However, Kamada et al. urge us to rethink the concept of type III secretion systems as virulence traits, and to consider whether these molecular syringes may have evolved as tools for niche adaptation in bacterial communities. C. rodentium uses its type III secretion system to colonize enterocytes, which is a niche devoid of microbial flora (10), allowing it to flourish. However, the shift of microbial composition toward the nutrient-competing γ-Proteobacteria, combined with the reduced expression of type III secretion systems, sets up C. rodentium for eventual failure to colonize its host.

The link between carbon metabolism and virulence expression is a key step in the ability of pathogens to recognize suitable sites for colonization, and contributes to the dynamic and volatile interactions between the host, pathogens, and the microbiota. Further insights into these associations may have implications for therapeutic approaches that manipulate their dynamics in diseased or ill states.

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