The switch from commensal to pathogenic is considered to be an important switch that has direct consequences on human health these can involve the acquisition of virulence genes or the accumulation of pathoadaptive mutations.
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Commensal to Pathogen Transition Mediated by Transposable Elements
Streptococcus pneumonia is a commensal bacterium that lives in the nasopharynx and forms part of the natural bacterial flora. However, it can invade the rest of the body in very old and very young people, resulting in pneumonia, sepsis, and meningitis. In attempts to understand the switch from harmless commensal to a deadly pathogen, a team from the University of Liverpool investigated the factors affecting the ability of pneumococcus to colonize the nasopharynx. the team found that T regulatory cells were activated by the pneumococcus and damping down the damaging proinflammatory response of the host immune system.
An induced T regulatory cells response in the upper airways reduces the risk of inflammatory damage that could result in the bacterial invasion on disease development. They achieve this by invading mannose receptor C type 1 (MRC-1) -proficient airway-dwelling immune cells, including DCs and alveolar macrophages.
The MRC-1 acts as a receptor for pneumococcal cytolysin pneumolysin (PLY), a virulence determinant, allowing them to gain access. This results in the dampening of the cytokine responses to establish intracellular residency of pneumococci, allowing them to survive in the airways.
E. coli is another example of a commensal bacteria that, is subject to commensal to pathogen transition, and also obtains this transition using transposable element insertion. This transition is similarly complex and involves changes in both the core and pan-genome.
In a study published in 2017, a research group investigated evolutionary paths when evolving pathogenicity, taken by commensal E. coli by experimental evolution under selective pressures to mimic those in vivo. They reported a commensal strain acquired a transposable insertion which resulted in improved intracellular survival, similar to Streptococcus and the acquisition of pathoadaptive traits is accompanied by changes in the transcript to of the macrophage is upon infection.
The increased intracellular survival was mediated through a delay of phagosome maturation and an increased ability to escape macrophages. This is analogous to the Streptococcus mode of action. As with Streptococcus, commensal E. coli rapidly acquires pathoadaptive mutations when subjected to constant pressure from macrophage phagocytosis, and these changes are seen are most pronounced in the transcriptome.
Alongside E. coli and Streptococcus, several intracellular pathogens have also evolved strategies to subvert the phagocytotic process. These include Mycobacterium tuberculosis (Mtb) and Legionella pneumophila, which impair phagosome maturation; S.flexneri which translocates to the cytoplasm to avoid degradation in phagolysosomes; and adherent-invasive E. coli have evolved to replicate in the phagolysosome.
Bacterial Pathoadaptivityin Response to Selective Pressure of the Immune System
Another way in which commensal bacteria may acquire pathogenicity is as a result of a response to encounters with cells of the mammalian immune system. This has been marked in the bacteria E. coli. In a study conducted in 2013, researchers studying benign E. coli bacteria thought to determine how evolved bacteria can escape that commensal role, and components of the host innate immune system (namely, phagocytosis), and killing mediated by macrophages).
When the E. coli were maintained in vitro under the selective pressure of host macrophages, commensal E. coli were seen to evolve in less than 500 generations. This resulted in the emergence of virulent clones that were able to escape phagocytosis and macrophage-mediated killing in vitro. Simultaneously, their pathogenicity in vivo was increased.
The mechanism driving this pathoadaptive process was attributed to the insertion of a single transposon into the promoter region of the E. coli yrfF gene. In addition to this transposition, the additional transposon event of the IS186 element into the promoter of an ATP-dependent serine protease gene, the Lon gene, was to enhance the rate of this pathoadaptive process. The intraspecies competition between those harboring beneficial mutations dominates the pathoadaptive process in which E. coli evolves towards virulence.
The Role of Other Selective Pressures in The Transition from Commensal to Harmful Bacteria
The transition toward pathogenicity can also be influenced by factors other than the immune system pressure. These include changes within the host environment and in comparison onset of illness, compromised immunity, changes in diet, subjection to antibiotic treatment, or stress whilst an example of a transition to pathogenicity is active C. difficile.
This is bacterium causes colitis. C. difficile is present at a low volume in the gastrointestinal tract. In a healthy gut microbiome, resistance against C. difficile expansion is provided. However, after antibiotic treatment which reduces the concentrations and the resultant protective effect of the microbiota, C. difficile can proliferate extensively and dominate the gut.
In this context, C. difficile then assumes a pathogenic role in the gut. These transitions to pathogenicity are thought to be mediated by metabolic changes in components of the microbiota. Work in the Drosophila gut microbiome shows that the catabolism of lumenal uridine by pathobionts produces uracil and ribose. These metabolites trigger inflammatory host immune responses and the upregulation of virulence genes. It also causes quorum sensing which also mediates the commensal to pathogen transition.
Cross-feeding among different populations of microbes can also mediate pathogenicity the commensal bacterium Streptococcus Gordonii produces L-lactate that is needed by Aggregatibacter actinomycetemcomitans to produce polymicrobial periodontal infection; the layer also increases respiratory and metabolism in the presence of S. Gordonii as it provides electron acceptors to increase ATP production, which subsequently increases virulence. With more energy, the pathobionts can produce toxins, adhesions, immunomodulatory proteins as well as other virulence factors.
These metabolic changes supplement the gene expression changes underpin transitions to pathogenicity.
Overall, the studies indicate that host-associated selective pressures coupled with genomic and phenotypic changes underpin strategies that facilitate commensal to pathogen transition.
References:
- Miskinyte M, Sousa A, Ramiro RS, de Sousa JAM, Kotlinowski J, Caramalho I, Magalhães S, Soares MP and Gordo I. The Genetic Basis of Escherichia coli Pathoadaptation to Macrophages. PLoS Pathog, 9(12): e1003802 DOI: 10.1371/journal.ppat.1003802
- Subramanian K, Neill DR, Malak HA, Spelmink L, Khandaker S, Dalla Libera Marchiori G, Dearing E, Kirby A, Yang M, Achour A, Nilvebrant J, Nygren PÅ, Plant L, Kadioglu A, Henriques-Normark B. Pneumolysin binds to the mannose receptor C type 1 (MRC-1) leading to anti-inflammatory responses and enhanced pneumococcal survival. Nat Microbiol. 2019 Jan;4(1):62-70. doi: 10.1038/s41564-018-0280-x. Epub 2018 Nov 12. PMID: 30420782; PMCID: PMC6298590.
- Proença JT, Barral, DC & Gordo I. (2017) Commensal-to-pathogen transition: One-single transposon insertion results in two pathoadaptive traits in Escherichia coli -macrophage interaction. Sci Rep. doi:10.1038/s41598-017-04081-1.
- Stevens EJ, Bates KA, King KC. (2021) Host microbiota can facilitate pathogen infection. PLoS Pathog. doi: 10.1371/journal.ppat.1009514.
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