Escherichia coli bacteria associated with Crohn’s disease persist within phagolysosomes
Section snippets
Crohn’s disease: from dysbiosis to phagocytes’ colonization
Crohn's disease (CD) results from a chronic inflammatory response localized in the gastrointestinal tract accompanied by an increase of the epithelial-barrier permeability 1, 2 and an imbalance in the intestinal microbiota 3, 4 (Figure 1). Within inflamed tissues, immune cells secrete pro-inflammatory cytokines such as IL-6, IL-12, IL-23, IL-34, TNF-α, and IFN-y [5], a hallmark of CD. The microbial dysbiosis seems to contribute to CD etiology by promoting chronic relapses of the inflammation 6,
Intracellular adherent invasive Escherichia coli life
Within intestinal epithelial cells, LF82 is located in vacuoles or free in the host-cell cytoplasm [12]. LF82 does not seem to induce lysis or apoptotic death of epithelial cells. However, it causes mitochondria fragmentation and dysfunction [23]. Functional autophagy limits intracellular LF82’s replication [24]. In response, LF82 manipulates autophagy by impairing sumoylation [25]. The physiological status of intracellular LF82 during epithelial cell infection remains unknown.
Within
Intracellular LF82 persisters
A short time after phagocytosis, most LF82 switch from a replicative to a nonreplicative state [30••] (Figure 3). Bacteria lacking DksA fail to stop cytokinesis and die more frequently, suggesting that stringent response plays an important role in this transition. We postulated that the nutrient scarcity in the phagocytic vacuole triggers the switch [30••]. Macrophage lysis revealed that a significant portion of the nonreplicative LF82 (≈1%) also became antibiotic-tolerant persisters, a huge
Biofilm combined with persisters gives the maximum protection
Early during infection, the ability for LF82 to curb growth is important to promote survival, however, the ability to generate persisters from this nongrowing population modestly influences initial colonization. In this regard, persistence can be envisioned as a bonus status acquired by some of the nonreplicative bacteria. Differently from Salmonella, the proportion of LF82 persisters in the population increased when the antibiotic-tolerance assay was repeated 24 hours post infection (≈10% of
Therapeutic strategies for Crohn’s disease, should we care about persisters?
Current treatments for inflammatory bowel disease (IBD) target the immune system by suppressing overactive inflammation. High doses of steroids are prescribed to palliate the symptoms, and then a background treatment consisting of immune modulators is used. However, new therapies attempt to suppress steroids by replacing them with monoclonal antibodies targeting TNFα, IL-12, IL-23, or integrin α4β7 43, 44. Macrophages derived from blood monocytes of CD patients are defective in controlling
Conclusion
AIEC is the youngest family of the large group of E. coli pathogens. Recent sampling efforts revealed their very frequent carriage in CD but also their large phylogenetic heterogeneity. Compared with known intestinal pathogenic E. coli, they do not cluster in a specific pathogroup and do not present prominent genetic determinants. Current hypotheses propose that combinations of single-nucleotide polymorphisms transform commensal E. coli in bacteria with adherent and invasive phenotypes [19].
Conflict of interest statement
None.
Acknowledgements
We thank Maude Guillier and members of the lab for careful reading and suggestions on the paper. Research from the laboratory was funded by ANR, France, with the reference ANR-18-CE35-0007-PERSIST3R and ANR-10-LABX-54 MEMOLIFE and by the Saint Michel Foundation, France, of the Collège de France.
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