cytolytic peptides for intracellular infection

[Guest guest]

2 weeks ago I posted about PMID 11906603, in which short amphipathic

peptides were used, in vitro and in mice, to selectively destroy

macropahges infected with Brucella abortus. I wondered whether this

might be a generalizable method of attacking intracellular

infections refractory to abx treatment (as for example brucellosis

itself can be).

But, the answer is maybe not. First of all, according to the review

article PMID 15721833, it has been found that Brucella abortus

LPS " is not degraded by murine macrophages. It remains intact in the

cells before translocating to the membrane where it forms structures

referred to as macrodomains [which, fascinatingly, accumulate MHC II

and may interfere with MHC II antigen presentation]. "

This property, apparently(?) unique to Brucella LPS as far as is

known, may underlie the ability of certain peptides to destroy

Brucella-infected macrophages with high specificity. But perhaps

not - after all, the same peptides have extremely little activity

against B abortus itself, which certainly doesnt prove/disprove

anything, but is suggestive. Further, it is not clear that the

peptides have a special affinity for infected cells; it may be that

they also accumulate in the membranes of normal cells but are

removed by healthy processes before causing damage.

But, even if these peptides were/are able to lyse macrophages

infected with many types of pathogens, there remains the problem of

the release of noxious substances. Dumping of inflammatory cytokines

may be one hazard and dumping of the contents of microbicidal

granules may(?) be another. Yet in the experiments of Yokum et al

several peptides were able to reduce bacterial load greatly without

harming the subject mice. However, those mice may have escaped a

thrid pitfall due to a special charecteristic of Brucella abortus.

It turns out that " purified LPS from wild-type B abortus is 500-

1000x less potent that LPS from E coli in inducing the production of

inflammatory cytokines, " according to PMID 15721833. Thus, it may be

that with any non-Brucella gram-negative pathogen, the use of

cytolytic peptides to destroy infected cells would dump enough

bacteria into the humor to cause endotoxic shock, and severe damage

or death. Since this is potentially such a great difficulty for the

cytolytic approach, I am gazing more in other directions just now.