18 research outputs found
The role of released ATP in killing Candida albicans and other extracellular microbial pathogens by cationic peptides
A unifying theme common to the action of many cationic peptides that display lethal activities against microbial pathogens is their specific action at microbial membranes that results in selective loss of ions and small nucleotides chiefly ATP. One model cationic peptide that induces non-lytic release of ATP from the fungal pathogen Candida albicans is salivary histatin 5 (Hst 5). The major characteristic of Hst 5-induced ATP release is that it occurs rapidly while cells are still metabolically active and have polarized membranes, thus precluding cell lysis as the means of release of ATP. Other cationic peptides that induce selective release of ATP from target microbes are lactoferricin, human neutrophil defensins, bactenecin, and cathelicidin peptides. The role of released extracellular ATP induced by cationic peptides is not known, but localized increases in extracellular ATP concentration may serve to potentiate cell killing, facilitate further peptide uptake, or function as an additional signal to activate the host innate immune system at the site of infection
Cathelicidin and its role in defence against bacterial infections of epithelial cells
Cathelicidins are antimicrobial peptides (AMPs) that were first discovered to have
microbicidal properties but more recently to be multifunctional immunomodulators and thus
important in influencing host defence against infectious disease. Whilst roles in various
organs have been demonstrated, their expression patterns in health and disease in other
organs are less clear and their key immunomodulatory functions remain undefined,
particularly with regard to the balance of immunomodulatory properties and microbicidal
activity in their ability to promote defence against infection.
I therefore set out to describe LL-37 expression (human cathelicidin) in the female
reproductive tract (across the menstrual cycle) and in the lung (during specific lung diseases),
to define the effects on the function of airway epithelial cells during bacterial infection and to
evaluate the key in vivo roles of endogenous cathelicidin (using a knockout mouse model) as
well as the effect of therapeutic administration of LL-37 in a pulmonary Pseudomonas
aeruginosa infection model.
I demonstrated that cathelicidin protein and transcription shows a cyclical pattern of
expression in female reproductive tissues which is maintained at high levels in decidua. LL-
37 protein was also detected in hTERT endometrial epithelial cells but despite the suggestion
that cathelicidin may be regulated by steroid hormones there was no direct effect of
progesterone on transcription. LL-37 is barely detected in healthy airways however is well
known to increase during infection or inflammation. I observed that sputum from patients
with bronchiectasis showed a correlation between the level of LL-37, TNF, MPO and chronic
colonisation of Pseudomonas aeruginosa. Patients with lung cancer expressed much less LL-
37 than the bronchiectasis patients but there was a trend towards increased production postsurgery
compared to pre-surgery.
LL-37 was previously shown by our lab to selectively promote BAX and caspase-dependant
death of infected epithelial cells. I went on to show that this appears to be a partially caspase-
1 dependent mechanism and that human bronchial epithelial (HBE) cells and A549 cell lines
both express several of the components required to form inflammasomes, a caspase-1
dependant form of inflammatory cell death.
Finally, I showed using murine models that cathelicidin enhances bacterial clearance during
pulmonary infection in vivo, a response which is defective in mice lacking endogenous
cathelicidin and that administration of exogenous, synthetic LL-37 at the time of infection
can promote an early protective neutrophil influx in the absence of endogenous cathelicidin
production