20 February 2012
Detailed investigations of how a bacterium that causes dysentery in humans infects its host has yielded insights that may represent new vaccine targets and could ultimately help confront the challenges raised by other species of increasingly antibiotic-resistant bacteria that cause different diseases in humans, animals and plants.
The Shigella bacterium is a water-born organism that can be transmitted through contaminated food or water, or through human contact. Each year Shigellosis disease leads to around 20 million cases and 600,000 deaths, mainly in children under five in resource-poor countries. When populations in such countries become malnourished or displaced through political conflicts or war, the disease can spread rapidly.
To date, no effective vaccine has been developed to bolster immunity against Shigella. Among the difficulties is the fact that there are 16 different variants of the bacterium - exposure to one does not provide immunity to all. The over-use of antibiotics also means that the bacterium has grown increasingly resistant - when a new infection occurs, it is harder to treat.
Once in the body, Shigella invades the colon by secreting protein toxins that manipulate and destroy the cells lining the large intestine, leading to acute dysentery. The process through which this occurs is known as ‘protein translocation’. Toxic proteins are produced by the bacterium when it enters its host. Upon contact with a cell lining the colon, the bacterium secretes these toxins into this cell, using a specialised ‘injection device’. The toxins manipulate the cell in order to force it to take up the pathogen. Once the pathogen is inside the first cell, it releases further toxins which replicate and spread to neighbouring cells. The cellular structures that ought to maintain the integrity of the colon are destabilised, opening up channels through which the bacterium is able to invade the entire intestinal system.
It is the complexities of the toxin injection apparatus, as the critical factor in disease development, which is being investigated by Dr Ariel Blocker, from Bristol University’s School of Cellular and Molecular Medicine, in collaboration with Professor Keiichi Namba from the University of Osaka and Professor Susan Lea from Oxford University.
Dr Blocker explains: “The proteins that are present at the very exterior of the ‘needle’ the bacterium’s injection apparatus would form an ideal target for a vaccine, given that they could be more easily targeted than any component within the bacterium itself. Components of the needle tip represent potential protective antigens; proteins which could mobilise the immune system into creating antibodies released in the gut that would neutralise to the bacterium before it has a chance to initiate disease.”
Dr Blocker is also involved with collaborations with chemists and a start-up pharmaceutical company linked to the Umea Centre for Microbial Research in a bid to develop drugs that, unlike current therapeutics, would weaken the bacterium without killing it directly, as antibiotics do. This would allow the immune system to clear it more easily once infection had occurred whilst avoiding the strong pressure towards resistance emergence that antibiotics impose.
Through links with international groups such as the International Vaccine Institute in Korea, Dr Blocker hopes these investigations will assist with the development of a diagnostic kit that would allow for the bacteria to be identified early in vulnerable populations, representing an important first step in the fight against disease.
Dr Blocker adds: “Shigella are far from the only pathogenic bacterial species that possesses such injection devices; very similar devices are widespread in bacterial species that have put interaction with plant and animal hosts at the centre of their life cycles. By taking a fundamental and integrated approach, what we learn through studies on Shigella could be used to design broad-spectrum chemical inhibitors of these systems. These could represent powerful new anti-bacterial agents at a time when antibiotic resistance is increasing.”
Please contact Aliya Mughal for further information.
Image by S Schuller, Wellcome images
By taking a fundamental and integrated approach, what we learn through studies on Shigella could be used to design broad-spectrum chemical inhibitors of these systems. These could represent powerful new anti-bacterial agents at a time when antibiotic resistance is increasing.