A University of Leicester researcher has discovered how a protein in the blood linked to defence against meningitis plays a more vital role than previously understood in the body’s immune defence system. The published research has helped to advance medical understanding of how the body defends against disease and heals itself. The study also reveals that the same protein, properdin – discovered half a century ago - can also harm internal organs under certain circumstances. Lack of the protein in the human body has previously been linked to susceptibility to meningitis. But the new findings by Cordula Stover of the Department of Infection, Immunity and Inflammation at the University of Leicester assign hitherto unappreciated importance to this protein of the immune defence. Dr Stover, a Lecturer in Immunology, said:
I have a broad interest in immune mechanisms of health and disease, though recently, I have focused on a particular component of the first line immune defence, a protein called properdin. Properdin deficiency in families, though rare, predisposes people to develop meningococcal meningitis, usually with poor outcome of the infection. I hypothesised that the importance of properdin extends beyond this particular infectious disease, and that indeed it is an important player in health generally, and that its importance becomes apparent in conditions involving both acute and chronic states of inflammation.
Now Dr Stover’s paper published in the Journal of Immunology demonstrates that properdin plays a significant role in the survival of conditions relating to surgical perforation of the gut and activation of the immune system by wall components of bacteria. In conditions relating to multi-organ dysfunction, a complication which can occur in response to severe sepsis, properdin however aggravates organ damage.
So far, the system properdin is a part of - the so-called complement system - is classified as a first line, innate, acutely effective immune activation mechanism. This work shows that the activity of properdin extends beyond the acute phase and, importantly, that properdin is stepping onto the stage as an important player in different inflammatory conditions. As the worldwide burden of chronic inflammatory disease increases, it is of practical relevance to understand the contribution of this immune protein.
Leicester students certainly appear to be happy bunnies: it came joint top for teaching quality and overall satisfaction in the National Student Survey two years in a row and the drop-out rate is notably low. The appeal might lie in the friendly and compact campus - a 10-minute walk from one end to the other, providing you don’t get sidetracked by any of the on-campus facilities. Victoria Park next door is a convenient and popular place to relax when the weather is good. As well as that, Leicester puts up a consistently strong academic performance across all its subject areas. It’s understandably proud of its most famous research achievement: the development of DNA genetic fingerprinting. Add on Leicester, a lively, multicultural city with great facilities and transport links, and it’s no wonder everyone is so pleased to be there.
My University of Leicester colleague Dr Primrose Freestone is interested in how stress can influence susceptibility to bacterial infection. As far back as the beginning of the first millennium physicians such as Galen had recognised that stress could affect health. Galen noted that melancholy women were more likely to develop ill humours and deadly swellings (tumours) on their breasts. But it was not until about two thousand years later that scientific investigations began which looked at how being stressed might make you ill. Most of those investigations have occurred in the area of psychoneuroimmunology, and have systematically looked at the connection between the stresses perceived by the central nervous system and how it changes the physiology of the body. It is now known that stress causes the production and release into the mammalian body’s circulation of hormones such as adrenaline and noradrenaline. These stress hormones give you the energy to run away from a danger. In addition to this response, work done over the past several decades at experimental and epidemiological levels has also shown that stress can have marked effects on health, and is a risk factor for a variety of health conditions ranging from acne to cancer. Stress hormones can directly affect the function of that key defence of our bodies, the immune system, which can have considerable health implications.
While the human body’s response to external stress was once a positive influence on the likelihood its chance of survival (such as our ancient ancestors avoidance of becoming a meal for a hungry wolf), in our largely predator-free modern world, our hormonal response to stressful events (the production of adrenaline and noradrenaline) is little different to those ancient life-threatening scenarios. Thus emotional stress can cause hormonal chances (and effects on the immune system) similar to life threatening situations. In particular, common lifestyle chronic stresses such as poverty, divorce and bereavement, have all been associated with reductions in immune function. People under these stresses are more susceptible to a range of health conditions in which the immune system plays a direct role, such as infection and the initiation and outcome of certain types of cancer. You can particularly see this among students taking exams, especially medical and dentistry students. They develop more colds, coughs and similar infections. And it is well known among dentists that emotional stress is a significant risk factor in the development of gum disease. There is evidence of a greater instance of latent tuberculosis reactivating in highly stressed individuals, even when you exclude factors such as economics and social status. How strongly do you feel about your existence and controlling your destiny? People who don’t feel in control tend to get more infections.
Stress hormones may not only affect the competence of the immune system. We have found that they also act directly on bacteria to increase both their growth and virulence (ability to cause an infection). In fact, we and others have now shown that for dozens of infectious bacteria the presence of human stress hormones is a signal for the bacteria that they are inside a potential host, and that this host is stressed, its immune defences weakened, and the time is opportune to begin their attack. The stress hormones adrenaline and noradrenaline can turn blood that is normally very hostile to bacteria into a kind of bacterial tomato soup. Addition of these stress hormones to blood or serum will enable 10 bacteria to grow to 100 million cells in less than a day. To add to the health issues relating to stress, our work has also shown that drugs which are chemically similar to the catecholamine stress hormones adrenaline and noradrenaline can also have unexpected side effects which may increase the susceptibility to infection of the patient taking them. This includes infections which stem from intravenous lines, and more recently, the discovery that catecholamine stress hormones and structurally similar drugs extensively used in intensive care units to improve function of the heart and kidneys of critically ill patients can in less than a day bring back to active life Staphylococcus aureus bacteria so damaged by antibiotics that they appear to be dead. However, the news is not all bad, as intriguingly, we have also found that the same drugs that counter stress hormone effects in humans (for instance to lower blood pressure) can be used to stop bacteria responding to stress hormones.
Tuberculosis has had many names, including consumption, scrofula and the great white plague, but whatever you call it, this disease still claims one life every 10 seconds and global mortality rates are increasing despite the use of chemotherapy (Drugs versus bugs: in pursuit of the persistent predator Mycobacterium tuberculosis. 2008 Nature Reviews Microbiology 6: 41-52). Why have we not progressed further towards the eradication of this disease? There are many answers, including politics and poverty, and some less shameful excuses such as HIV and drug resistance. Whatever the reason, without new weapons in the armory against TB, the disease will continue to make ground.
Two factors, persistence and resistance, make the treatment of Mycobacterium tuberculosis infections particularly difficult. The term persistence describes the survival of the causative organism despite the use of antibiotics. The local concentration of antibiotics in lesions such as granulomas might not be adequate to kill the cells, or some bacteria might adopt a physiological state that renders them less susceptible to antibiotics. For these reasons, drug treatments must be extended. Currently, even the most effective regimes require a combination of at least 3 drugs and last for six months. Because patients feel better within 1 2 weeks, they have little motivation to continue with therapy, so the current World Health Organization guidelines call for treatment to be directly observed (DOTS). This can be difficult to provide in much of the world, including the areas where tuberculosis rates are highest.
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There is an excellent chance that patients who have tuberculosis can be cured using currently available drugs if they complete the required course of therapy. But what characteristics should new drugs have to improve on current treatments?
Oral bioavailability: to avoid the need for injections.
Good tolerance: to avoid unwanted side-effects might cause treatment to be abandoned.
Widespread usability: including AIDS patients, young children and pregnant women.
Compatibility with anti-retroviral drugs: because co-infection with HIV and TB is common.
Infrequent dosing: once a day drugs improve treatment compliance.
Activity against drug-resistant TB strains: possibly the most important factor with the rise of MDR and XDR-TB.
Rapid clearance of chronic infection: so that treatment times can be shortened.
Affordability: so they can be used in the areas of the world where TB is most prevalent.
Mycobacterium tuberculosis has no significant animal or environmental reservoirs and shows limited genetic diversity. In spite of this, TB continues to be a widespread and devastating disease. The need for new faster-acting drugs is clear. Recent work by my colleague Dr Mark Carr from the School of Biological Sciences at the University of Leicester might help in future drug development. The M. tuberculosis ESAT-6/CFP-10 complex consists of two proteins which, together, allow the bacteria to survive inside white blood cells. Removal of the genes for these proteins from the TB genome renders the bacteria unable to cause disease. Similarly, studies of the structure of the protein complex have shown that removal of a “long arm” from the molecule prevents the complex s ability to bind to the outer surface of human white blood cells. In the structure of the ESAT-6/CFP-10 complex above, the “long arm” is in red on the right side of CFP-10. When this is intact, it allows the complex to attach to the outside of host white blood cells. When the long arm is cleaved off, the complex shows greatly reduced attachment. This data provides an insight into the important components of this complex. Mark Carr says: “Current work is attempting to identify the exact components of the human white blood cells that this complex is targeting. Once found, this should give us a greater knowledge of the action of these molecular weapons of TB and give us the edge in the war against an ancient, reawakened foe.”
The results of the 2007 UK National Student Survey are out, and once again they show that the University of Leicester is the most satisfying place to study for a degree in Biology. It’s hard to beat a 100% satisfaction score:
The post holder will be required to develop and conduct research on the molecular biology of Burkholderia pseudomallei virulence in collaboration with other scientists both within and outside the Department of Infection, Immunity and Inflammation.
The postholder will advise University of Leicester staff on regulatory requirements and best practice for work with hazardous chemicals, biological agents and genetically modified organisms. Additional duties will include monitoring safety performance and providing training programmes. Candidates should be science graduates with relevant postgraduate experience and excellent interpersonal skills. Knowledge of genetic modification principles and procedures is essential.
Post Doctoral Research Associate