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Archive for April 2013

Clues to the evolution of disease?

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What are a group of genes that help Mycobacterium tuberculosis infect mammalian cells doing in a harmless soil bacterium? Dr Paul Hoskisson explains his recent research, which is helping us understand the evolutionary roots of disease.

mce Scientists invest a lot of time and resources in trying to understand how bacteria cause disease. Generally, this involves studying a particular gene, or group of genes, in a pathogenic (disease-causing) bacterium to see what function it has during the infection process. In my laboratory, we have been trying to understand the evolutionary processes that cause these genes to develop.

Bacteria need some specialist skills if they’re going to cause disease: they must avoid being destroyed by the immune system, enter and multiply within host cells, and produce toxins. Bacteria have been around on Earth a lot longer than humans, which suggests that the genes needed to cause disease in humans have either evolved recently and rapidly (in evolutionary terms) or been co-opted from existing genes in harmless bacteria.

We noticed that the soil bacterium Streptomyces coelicolor has a cluster of genes that are very similar to pathogenicity genes present in Mycobacterium tuberculosis, the causative agent of tuberculosis. Other work has shown that these genes, known as mce (mammalian cell entry) genes, are used by M. tuberculosis to colonise and survive inside human immune cells called macrophages. We disrupted these genes in S. coelicolor to see what happened.

As the mce genes are used by M. tuberculosis to infect and survive in macrophages, we wanted to see what happened to the mce-deficient S. coelicolor mutants under similar conditions. However, because S. coelicolor lives in the soil, it rarely encounters any immune cells, so we had to get creative.

Rather than use immune cells, we used amoebae. This might not seem like an obvious choice, but these single-celled organisms are eukaryotic, just like immune cells, and engulf bacteria in a similar way. We got a strange result when we fed the S. coelicolor mce mutants to the amoebae: the amoebae all died (see image above). This effect has been seen in M. tuberculosis as well – mce mutants are hyper-virulent and much better at killing immune cells than regular M. tuberculosis. This is counterintuitive, but while the mutant M. tuberculosis strain may be excellent at killing macrophages, it is unable to cause disease in a whole animal – presumably because of the presence of the complete immune system, which is much more complex.

We did a little detective work and discovered that the mce genes encode a transporter that bacteria use to take up sterol (a type of fat), which they can use as a source of food, from the environment. It is thought that M. tuberculosis uses this transporter to take up sterols because other nutrients are hard to find inside macrophages.

One location where Streptomyces encounters sterols in the environment is around the roots of plants, an environment known as the rhizosphere. We showed that the S. coelicolor mce mutant is poorer at colonising plant roots than the wild-type S. coelicolor, which suggests that sterols are an important carbon source for these bacteria.

We suggest that as these bacterial species adapted to their particular environment – soil in the case of the Streptomyces and human immune cells for M. tuberculosis – their respective mce genes evolved to operate under the different conditions. Understanding how the selection process has led to the changes in function are essential to our appreciation of the evolution of virulence in bacteria and could significantly aid our understanding of the emergence of pathogenic bacterial strains.

Paul Hoskisson

Paul A Hoskisson is a lecturer in microbiology at the University of Strathclyde. His research focuses on antibiotic-producing actinomycetes and emerging actinomycete pathogens.

Image adapted from the original article published in Scientific Reports article under the Open Access license.

Clark LC et al. Mammalian cell entry genes in Streptomyces may provide clues to the evolution of bacterial virulence. Sci Rep 2013;3:1109. doi:10.1038/srep01109

Written by microbelog

29/04/2013 at 9:49 am

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No barrier to cell division

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L-form_bacteria-Mark_Leaver_Newcastle_UniversityBacterial cells are surrounded by a highly cross-linked cell wall that has to be constantly broken down and remade as the cells get bigger. Since most bacteria reproduce by dividing the cell into two they also have to build a new bit of cell wall in the middle of the cell to make two daughter cells. In bacteria the FtsZ protein forms a Z ring to mark this site of cell division and all the other cell division proteins assemble on this Z ring and remodel the cell wall.

Despite this, it has been known for a long time that some bacteria can exist as L forms which have lost their cell wall. Even more amazing, these L-form bacteria don’t need FtsZ to divide and instead they just bud off membrane vesicles, some of which contain DNA and enough proteins to form a new cell.

Jeff Errington’s group in Newcastle recently made stable L forms of a bacterium called Bacillus subtilis, effectively reversing 3 billion years of evolution . These bacteria can live without a wall or FtsZ but they still need a cell membrane to contain the cell contents and in another groundbreaking paper Jeff’s group have shown that simply increasing the amount of membrane the cell makes is enough to make these L-forms divide.

The beauty of these L forms is that they help us to understand how the first living cells, reproduced themselves around 4 billion years ago. In the absence of a cell wall and a complicated cell division machinery they simply increased their surface area to volume ratio in order to propagate. And that, frankly, is amazing.

Mercier R, Kawai Y and Errington J (2013). Excess membrane synthesis drives a primitive mode of cell proliferation. Cell 152 997-1007.

Image credit: The Red Lexicon on Wikimedia Commons

Posted by Matt Hutchings

Written by microbelog

25/04/2013 at 2:54 pm

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