You can't beat a beta-defensin

Jimi Wills headshot

Meet Dr Jimi Wills. With over 20 year of experience as an academic scientist, working with diverse partners in wet and dry labs across sectors, Jimi is now a Senior Software Engineer at Firefinch Software. Firefinch are a group of experienced software engineers and problem solvers, with a combined 50+ years in biotechnology, engineering and manufacturing.

Jimi was part of a multidisciplinary collaboration that published a paper in Nature last month, evaluating the role of Human Beta Defensin 2 in the treatment of atopic dermatitis. Learn about the findings in his blog!

Biological molecules are insanely cool. One of my favourite classes of molecules is peptides, which are short chains of amino-acids. There are nominally 20 amino acids typically used in protein synthesis, but many can be chemically modified, and short peptides frequently have other amino-acids too. Ultimately, there's a whole alphabet of amino-acids that your cells can turn into tiny words... words that do things.

For me, Human Beta Defensin 2 (HBD2) epitomises these little biochemical verbs, and here's why...

It's been known for a while that HBD2 is protective against the bacterium Staphylococcus aureus (S. aureus; colloq.: Staph), though despite being a potent antimicrobial, HBD2 does not attack S. aureus directly. Instead, it is protective against a particular Staph enzyme called V8. V8 is a protease that attacks proteins in the skin. These proteins normally form a scaffold around the cells called the Extra-Cellular Matrix (ECM), and chopping them up enables S. aureus to get a foothold by weakening the skin barrier. This can exacerbate atopic dermatitis, aka eczema... So, on the off chance you've not heard of it: welcome to Earth, we have eczema!

In fact, if you are human, and you do have skin, there's an unbearably large probability that S. aureus is already living on your skin. "So if it’s everywhere, how do we keep it out and help eczema patients?" asks Dr Jennifer Shelley PhD, lead author of a recent study into the role of HBD2 in defending against atopic dermatitis, published in Nature Scientific Reports.

The first, and really a very obvious question was: is HBD2 directly inhibiting the action of the nasty V8 enzyme? Surprisingly, the answer is no. "When we looked at how the HBD2 and enzyme interacted with each other, without the cells or anything else, we didn’t see any direct contact or obvious dynamic between the two. Also, when we looked directly at where HBD2 goes in the cell layer (fluorescent labelling and electron microscopy), it didn’t form a [hypothesised] protective blanket or block the ECM proteins in any obvious way" observes Shelley. Despite not directly stopping the enzyme, when added to cells in culture, HBD2 clearly protects the cells themselves from V8 damage.

So, if HBD2 doesn't stop the enzyme doing its thing, what the heck is going on?

Another hypothesis was that maybe it promotes wound repair. This part involves a scratch-wound healing assay with special HaCaT cells, a type of skin cell used in lab cultures. The assay measures the movement of cells in response to mechanically scraping some of the cells (and their ECM) off a part of the dish they are growing in. This is a well-established model for studying skin healing behaviour in these cells. The idea is that if HBD2 encourages cells to heal, they should be moving around more to find and fill-in gaps. But the presence of HBD2 didn't seem to have any effect on the cells, so wound repair mechanisms are not the answer.

Back to the drawing board.

To generate some new leads, we analysed the general impact of HBD2 on these cells by looking at their proteome. In the same way the genome is just all the genes, the proteome is all the proteins. But while the genome of a cell (typically) doesn't change, the proteome is dynamic and responsive to cellular stimuli. In fact, most cellular responses are actually carried out by proteins, and many of those involve changes in the type or number of proteins in the cells. In this case, our stimulus is the addition (or not) of HBD2 during V8 assault. So, are there any clues here?

Actually, not many, which is kinda nice, because it's less work to follow up. But also, known proteases inhibitors were conspicuously absent from the list of suspects, so we think HBD2's modus operandi is probably not to increase the amount of these protective molecules... which also fits with the observation that the protease is clearly still active. But one lead was LAMB1, a special type of protein called a Laminin, that is part of the ECM. We also noted that a couple proteins involved in cell-adhesion and collagen production were involved. Finally, there were some enzymes involved in metabolism, which suggests the cells were just trying harder when HBD2 was added! So it looks like HBD2 is stimulating the cells to work harder and repair the damaged ECM more quickly.

Must try harder!

And that's all folks... for this investigation anyway. It was an awful lot of work to get here, but what's shown is that HBD2, and peptides like it, could be effective drugs against Staph exacerbation of eczema. These wonderful little molecules probably work by encouraging skin cells to generate more ECM proteins, quickly replacing those chopped up by the Staph's V8 protease enzyme, but that story is to be continued...

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