Archive for the ‘Posts’ Category
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.
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 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
Bacterial 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
This isn’t a research blog as such, just an attempt to get everyone to read a new perspective article entitled “Animals in a bacterial world”. Here at microbelog we’ve been banging on about how important symbioses between bacteria and eukaryotes are for a quite a while now. So imagine our excitement to read this article in the latest issue of the Proceedings of the National Academy of Sciences USA. Although slightly evangelical (or as one of my evolutionary biologist colleagues put it “messianic”), this is well worth a read. It’s also good to see Carl Woese and Lynn Margulis, both of whom sadly passed away recently, getting the credit they deserve. Facts like one third of human DNA is bacterial in origin is the kind of thing that gets us very excited! This is a call to arms and it’s certainly never been a more exciting time to be a microbiologist!
Image credit: Picture of a captive leaf-cutter ant colony taken by Andrew Smith, John Innes Centre, Norwich 2012.
A recent study led by Professor Tracy Palmer at the University of Dundee discovered a new way by which bacteria can insert proteins into membranes, using two different transport machines. Here she gives us the lowdown on what it’s all about…
All cells are surrounded by lipid membranes; they keep the insides in, and the outsides out, but sometimes bacteria need to bring a molecule from the environment into the cell, or vice versa. The membrane itself is pretty much impermeable, so the cell uses specialised proteins to make channels in the membrane so they can control what moves from one side to the other.
Who decides which research should be funded? What are the flaws in the process? In this editorial, Matt Hutchings wonders if there might be a better way.
We scientists like to joke (or rather, complain) that applying for government funding is a bit like playing the lottery: winning is mostly luck. Often there is no rhyme nor reason that one grant application is funded while another isn’t, it ultimately depends on who reviews it, whether they like it and whether it fits with the strategic priorities dictated by the government. This is taxpayers’ money after all and the government don’t like to take risks with it for something as apparently unimportant as science. As Professor Brian Cox pointed out recently, our government spent more on bailing out the banks than they have spent on research funding “since Jesus”.
According to UK research council criteria, in order to be funded, the research should address issues that are relevant to the public, or perhaps more cynically, research that fits in with the current government’s election promises. In biology (our field) these relevant issues include: healthy ageing, food security and bioenergy, which can mean that important research areas are overlooked (for example, the research councils don’t fund research aimed at discovering new antibiotics).
More of a problem is that all proposed research projects must have a guaranteed “impact” (the new buzz word), which usually means publishing highly-cited articles in top tier journals, exploiting research to make money and communicating that science to inspire the general public (outreach).
This all seems reasonable given the amount of taxpayers’ money at stake, but as any scientist will tell you, funding research that guarantees results is unlikely to lead to any major discoveries. This is usually because the applicant has: (a) done the research already and knows the results (but isn’t telling the research council); or (b) is pretty much certain of what they’ll discover. What we need, and what has made the UK the most successful research nation on Earth over the last 450 years, is additional funding for blue skies research. This is the research that is perhaps slightly off the wall, but occasionally leads to a very important discovery.
A post I wrote about the phylogeny of Archaea has become one of the most popular articles on the Wellcome Trust blog in 2011. I’m as surprised as you are. That said, the science in it is super interesting – I interviewed Dr Steve Kelly, from the University of Oxford, who has published some work showing from where all eukaryotic cells may have evolved.
You can read the it here.
A very happy New Year from Matt and I, thanks for taking the time to read our posts and we’ll be back in 2012 with lots of new stories!
This video shows a live experiment carried out at the University of Southampton demonstrating that copper very effectively kills MRSA. This raises the possiblity that copper surfaces could be introduced into hospitals and used to cover areas that are frequently touched by patients, visitors and healthcare professionals. We think this is pretty cool!
The video was originally posted here: http://www.southampton.ac.uk/promotion/copper_02.shtml
How do we judge whether a research paper is any good? One straightforward way is to measure how often the article is downloaded online – but that doesn’t tell us if the readers actually thought the article was significant once they’d read it. Instead we can monitor how often an article is cited in the writings of other scientists. We can even do this for all the articles published by a particular journal (for example, in the last two or five years) and divide the total cites by the number of articles published to get an impact factor: Bingo, journal impact instantly measured!
Impact factors are a flawed and derided metric but – whisper it – by and large they also reflect many microbiologists’ perceptions and prejudices about the status of the journals in which we publish. When drafting a manuscript, it’s likely that each of us approaches choosing which journal we want to submit our work to in much the same way: we assess the scope and significance of the piece of work to be written up and then have a gut instinct as to which journal will accept it.
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Eusocial insects are remarkable creatures, they divide their labour, care for their young and some of these insects developed agriculture long before modern humans evolved. Now it seems they could offer us a way out of the current energy crisis and our crippling reliance on fossil fuels.
Releasing the sugars trapped in lignocellulose is the rate limiting step in bioethanol production and currently relies on chemical and mechanical treatment. Termites feed on plant detritus and their guts can efficiently convert lignocellulose (also known as wood) into sugars. So how do they do it?
The Escherichia coli (E. coli) bacterium is commonly found in the guts of humans and other mammals. Most E. coli strains are harmless, but some – including enterohaemorrhagic E. coli (EHEC) – cause severe disease. EHEC is transmitted to humans primarily through consumption of contaminated foods, such as undercooked meat and unpasteurised milk1.
The recent EHEC outbreak in Germany is unusual because it was probably spread by salad leaves and has infected 2400 people, killed 24 and left many more with serious complications as a result of infection. Although the outbreak appears to have peaked, it raises a terrifying new spectre of drug-resistant, infectious bacteria being spread by something as seemingly innocuous as salad. It’s also pretty embarrassing for health ministers in Germany who wrongly pointed at Spanish cucumbers as the source of this new “superbug” and have been warned by the EU health minister not to issue any more premature – and false – health warnings 2.
In fact, reports that this is a completely new strain are incorrect3 and outbreaks of Salmonella- and E. coli-induced food poisoning caused by contaminated salads are also nothing new. The problem is that the bacteria can actually infect salad leaves, spinach, cucumbers and tomatoes so that washing them does not make them safe to eat. It seems this outbreak is not the start of something new: it’s happened before, and it’s pretty certain that it will happen again. Unless we start cooking our salads…