How fungi steal zinc from your body

I?ve been getting quite into the human microbiome lately, covering both vaginal bacteria and digestive tract bacteria. One thing I thought it might be interesting to highlight is that we talk about the human ?microbiome? rather than the human ?bacteriome? because it contains a range of microbial species including bacteria, fungi and even possibly blastocysts. There?s more life in your body than you might think.

So with this in mind I?m going to venture forth into the world of fungi.

One of the most famous human fungi, Candida Albicans, growing on a petri-dish. Content Providers(s): CDC/Dr. William Kaplan Creation Date: 1969

Candida albicans lives naturally on the human body in the mouth, intestines and around the urinary and reproductive areas. In normal circumstances they live there quite happily, however if they start to overgrow for any reason (such as if you?re taking antibiotics and remove the?competing?bacteria) they can cause an infection. Infections are usually cleared with a simple course of antifungals, either as a cream or as a tablet. Like all internal micro-organisms C. albicans faces challenges living within a human body, most?noticeably?the need for trace metal elements. While these are fairly easy to find in a soil environment, they are harder to get hold of inside a body.

In a recent PLoS Pathogens paper (reference 1 below) C. albicans cells were starved of zinc, and then grown either with or without the close proximity of human endothelial cells (the cells that line the inside of the human gasterointestinal tract). They used hyphal growth as a measure of overal fungal growth, the hyphae are the branching filamentous structures as shown in the picture below:

The hyphae of penicillium, showing the branching structure. You can also see the upright fruiting bodies with spores on the end (they look like little trees!) Creative Commons licence, credit link below.

What the researchers found was that fungi next to human cells were growing faster and longer hyphae than those growing alone. Furthermore, this growth effect could be replicated by adding a zinc supplement to the lonely cells. From this primary observation they explored further, injecting the human cells with a dye that specifically colours zinc (zinquin ? which actually adds a?fluorescent?label to the zinc). When tested, some of the dye was found inside the newly grown hyphae. The fungi seemed to be picking the zinc up from the human cells.

I?ve written before about bacteria that steal iron from human blood cells, and it looks like the fungi are using a similar sort of trick. One of the most common techniques for iron-stealing is the use of a siderophore; essentially a small molecule that binds very strongly to iron and can be sent out as a scavenger molecule to collect iron from surrounding human cells. The researchers put forward that C. albicans might use a similar system for picking up zinc, and started searching through the genome looking for a gene that coded for a protein with high zinc-binding ability. They found one, the gene pra1 which had multiple zinc binding sites.

Isolating the protein Pra1 and washing through to remove any attached metals showed that it was?capable?of?loosely?binding a large amount of attached zinc. Going back to the whole fungal cell they then made a mutant without the Pra1 gene to see if the hyphae still grew in the presence of human cells. What they found was interesting. Pra1-less cells still grew the same number of hyphae, but they were a lot smaller. Adding supplementary zinc restored hyphal length. The mutants lacking Pra1 clearly had no problem processing zinc, or growing hyphae, they just couldn?t get any zinc out of the human cells.

The DNA sequence of Pra1, with the zinc-binding sequences highlighted in red. Three different views of the 3D model of the protein are below. Image from reference 1

Having established fairly firmly that Pra1 is responsible for stealing the zinc from human cells (and the paper is well worth a read, there are some lovely graphs!) the researchers then looked at what effect this zinc-stealing had on the human cells, whether it was part of what made the C. albicans pathogenic. Was the zinc-stealing a discreet, unnoticed affair or did it have a negative effect on the human cells? Comparing the normal wild-type fungi to the Pra1-less mutant found that while in wild type the human cells were damaged both in the presence and absence of surrounding zinc, in the mutant there was far less human cell damage when no surrounding zinc was present. This may be due to the effect of Pra1, or it may just be that when times are hard and zinc is scarce the fungi is less?capable?of damaging surrounding human cells.

It?s a fascinating example of human-fungi interaction. Despite the fact that they are very different from the bacteria they live amongst, it seems that both fungi and bacteria can utilise similar strategies when it comes to foraging for nutrients within their human home.

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Credit link for Penicillium image.

Citiulo F, Jacobsen ID, Miram?n P, Schild L, Brunke S, Zipfel P, Brock M, Hube B, & Wilson D (2012). Candida albicans Scavenges Host Zinc via Pra1 during Endothelial Invasion. PLoS pathogens, 8 (6) PMID: 22761575

Source: http://rss.sciam.com/click.phdo?i=7b5ec713a9c8834e83d5ff99905cf87c

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