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Neutrophil antimicrobial proteins enhance Shigella flexneri adhesion and invasion.
Cell Microbiol. 2010 Aug; 12(8):1134-43
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10 Aug 2010
Interesting Hypothesis, New Finding
DOI: 10.3410/f.4547975.4410079
This paper surprisingly shows that sublethal concentrations of antimicrobial proteins (AMPs) released by neutrophils can actually promote Shigella flexneri adhesion to and invasion into epithelial cells. This finding suggests a novel way for how this bacterium usurps weapons produced by the host to...Continue reading
This paper surprisingly shows that sublethal concentrations of antimicrobial proteins (AMPs) released by neutrophils can actually promote Shigella flexneri adhesion to and invasion into epithelial cells. This finding suggests a novel way for how this bacterium usurps weapons produced by the host to promote its own survival.
Neutrophils are generally able to kill bacteria using mechanisms including neutrophil extracellular traps (NETs), phagocytosis, and degranulation. As anticipated, increasing concentrations of an extract of purified human neutrophils in the presence of S. flexneri resulted in decreased bacterial viability in this study. However, in the presence of sublethal concentrations of this extract, similar to those encountered during the early stages of infection, there was actually an increase in bacterial adherence to epithelial cells. By using purified components, it was revealed that bactericidal permeability increasing protein (BPI) was responsible for this increased adherence and subsequent invasion. Interestingly, another serum protein that has a similar sequence and secondary structure, LPS-binding protein (LBP), did not show this effect. One of the differences between BPI and LBP is the charge of these molecules, suggesting that an electrostatic interaction with the surface of the bacteria may in part be responsible for these observations. It is very interesting that LL-37, another cationic antimicrobial, showed no effects on adhesion or invasion alone but could act synergistically with BPI. The authors hypothesize that this could be due to the different binding sites of the two proteins on bacterial LPS; however, this remains to be investigated. Although neutrophils are required for bacterial clearance, the findings reported here suggest that low levels of charged AMPs that are present early in infection may aid S. flexneri in altering its surface charge and escaping into epithelial cells, where it can multiply and spread. Further investigation into the specific interactions that allow this change in electrostatic charge could provide valuable insight into the molecular aspects of early Shigella infection. By understanding these interactions, it may be possible to modulate the surface charge to enhance host-protective mechanisms. While AMPs are not exploited in this manner by all invasive enteric bacteria, the surface charge interactions between the pathogen and host are likely critical for all encounters.
Neutrophils are generally able to kill bacteria using mechanisms including neutrophil extracellular traps (NETs), phagocytosis, and degranulation. As anticipated, increasing concentrations of an extract of purified human neutrophils in the presence of S. flexneri resulted in decreased bacterial viability in this study. However, in the presence of sublethal concentrations of this extract, similar to those encountered during the early stages of infection, there was actually an increase in bacterial adherence to epithelial cells. By using purified components, it was revealed that bactericidal permeability increasing protein (BPI) was responsible for this increased adherence and subsequent invasion. Interestingly, another serum protein that has a similar sequence and secondary structure, LPS-binding protein (LBP), did not show this effect. One of the differences between BPI and LBP is the charge of these molecules, suggesting that an electrostatic interaction with the surface of the bacteria may in part be responsible for these observations. It is very interesting that LL-37, another cationic antimicrobial, showed no effects on adhesion or invasion alone but could act synergistically with BPI. The authors hypothesize that this could be due to the different binding sites of the two proteins on bacterial LPS; however, this remains to be investigated. Although neutrophils are required for bacterial clearance, the findings reported here suggest that low levels of charged AMPs that are present early in infection may aid S. flexneri in altering its surface charge and escaping into epithelial cells, where it can multiply and spread. Further investigation into the specific interactions that allow this change in electrostatic charge could provide valuable insight into the molecular aspects of early Shigella infection. By understanding these interactions, it may be possible to modulate the surface charge to enhance host-protective mechanisms. While AMPs are not exploited in this manner by all invasive enteric bacteria, the surface charge interactions between the pathogen and host are likely critical for all encounters.
Acknowledgments
I would like to thank Laura Porter for their assistance in the preparation of this evaluation.
Disclosures
None declared
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Goldberg J: F1000Prime Recommendation of [Eilers B et al., Cell Microbiol 2010, 12(8):1134-43]. In F1000Prime, 10 Aug 2010; DOI: 10.3410/f.4547975.4410079. F1000Prime.com/4547975#eval4410079
F1000Prime Recommendations, Dissents and Comments for [Eilers B et al., Cell Microbiol 2010, 12(8):1134-43]. In F1000Prime, 25 May 2013; F1000Prime.com/4547975
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Shigella flexneri is an enteric pathogen that causes massive inflammation and destruction of the human intestinal epithelium. Neutrophils are the first cells of the innate immune system recruited to the site of infection. These cells can attack microbes by phagocytosis, Neutrophil Extracellular Trap (NET) formation and degranulation. Here, we investigated how neutrophil degranulation affects virulence and show that exposure of Shigella to granular proteins enhances infection of epithelial cells. During this process, cationic granular proteins bind to the Shigella surface causing increased adhesion which ultimately leads to hyperinvasion. This effect is mediated by changes in the surface charge, since a lipopolysaccharide (LPS) mutant with a negative surface shows enhanced hyperinvasion compared with wild-type Shigella. We propose that Shigella evolved to use host defence molecules to enhance its virulence and subvert the innate immune system.
DOI: 10.1111/j.1462-5822.2010.01459.x
PMID: 20331641
