Tuesday, 29 November 2011

Aspergillus and Bacteria Team Up

Bacteria and fungi have often been traditionally suspected as being foes competing for the same food resources in their natural environment. Many antibiotics (e.g. Penicillin) for example are antibacterial substances synthesised by fungi, thought by many to be one way that fungi can beat their bacterial competitors to a meal.

It has now been suggested that that impression is too simplistic. Ingham et .al. has shown that Aspergillus fumigatus, a fungus important for the degradation of dead plant material (e.g. compost heaps) and which has an important impact on human health (e.g. aspergillosis), seems to work closely with a highly motile bacterium Paenibacillus vortex.

Paenibacillus is very able at moving over solid surfaces and forms characteristic swarms

Paenibacillus is very adept at moving but cannot travel across gaps, whereas Aspergillus is more than capable of bridging gaps. Aspergillus tends to use up all available nutrients in one place and then stop and sporulate. It then requires 'help' to transport its spores to another substrate and the best known of these is via air currents but that may not be available and is a wasteful process with many spores landing in areas where growth is not possible.

Aspergillus growing across gaps
Paenibacillus is demonstrated in this paper to be able to transport Aspergillus fumigatus spores from locations where there are few nutrients available to new areas where nutrients are plentiful, and where there are antibiotics present which will inhibit the growth of competing bacteria. The speed of movement is around 8cm per hour. 
  • Paenibacillus will not do this for other particles similar in size to Aspergillus spores.
  • Other swarming bacteria where tested and were found not to transport A. fumigatus spores.
  • Paenibacillus will not transport the spores of other fungi similar to A. fumigatus as efficiently as they do for A. fumigatus.
P. vortex flagella 'gripping' A. fumigatus spores during transport
It seems that we are left with a conclusion that P. vortex and A. fumigatus have developed a cooperative symbiotic relationship whereby the efficient spread of each is reliant on the other and each expends energy on behalf of the other when there is no apparent direct advantage for itself.

Friday, 25 November 2011

Newsbite: A Rare Aspergillosis Mimic

Myceliophthora thermophila is a thermophilic mould widely found in the environment
but rarely responsible for human infections. We describe a case of invasive Myceliophthora
thermophila infection mimicking invasive aspergillosis in a neutropenic patient
with haematological malignancy. Cross-reactivity with Aspergillus galactomannan assay
(GM) was demonstrated by repeated positive results and confirmed by cross-reaction
between the fungal isolate and the GM assay. The patient was successfully treated with
voriconazole. Potential GM cross-reactivity must be considered in future studies including
patients categorized as having probable invasive aspergillosis using the GM as the
only mycological criterion. more...

Thursday, 24 November 2011

New Machine gives Asthmatics Relief as they Sleep

National and international media are reporting a new alternative for relief from symptoms of asthma has been granted scientific approval by a recent paper in the journal Thorax.

Asthmatics often suffer from coughs and wheezes at night and current medication involves 2 expensive drugs that must be used frequently.  It has been previously noted that night-time exposure to allergens is particularly important when trying to prevent asthma symptoms at all times of the day and night and there have been several attempts to provide relief by filtering out allergens from the air that a sleeping person is breathing.
Prof Warner pointed to other research suggesting night time allergen exposure has the greatest impact on symptom severity, possibly because of changes in circulating hormone levels and immune responsiveness prompted by the body's internal clock, or circadian rhythm.
None of those attempts were conclusively found to provide relief from symptoms.

The new treatment is a machine made by the Swedish company Airsonnett that simply provides a flow of cooled, filtered air around the sleeping person - the Protexo. This airflow seems to prevent allergens being breathed in by the sleeping person and thus prevents asthma triggers.  Symptom reports by the patients are lower and clinical tests show key clinical markers for asthma have reduced.

Comparing this machine with identical dummy machines has conclusively shown that they work, and they work as well as the two drugs that are currently used to provide relief. This is the first time a treatment strategy that does not involve drugs has been shown to work as well as this.

This non-invasive technique could be useful for a wide range of patients including those who suffer from allergy to molds such as Aspergillus (often the most severe cases of asthma). The machines are not currently available for use in the home but their cost is already far less than the average spend on keeping asthmatic patients stable so they should be cost effective in the home once available.

Thursday, 17 November 2011

Expert Assessments for Off-Label Medicine use

Medications are subject to tight regulation in most parts of the world whereby a particular drug, the group of patients it is used on and they way it is administered must be approved by a governing body prior to its marketing for use. Once authorised the specifics of its use (age group, dose, route of administration etc.) are written into the pack notes for reference by doctors and these form a useful check for the doctor that he/she is using the drug correctly.

In a field of rare diseases such as aspergillosis there is often a serious lack of fully tested and authorised medications for use by doctors. This leads directly to the use of medications which are not authorised to treat the disease, or are not authorised for use in a particular patient group or for use in a particular way - this is referred to as off-label use. This is completely legal in many countries as long as it is carried out by doctor as phsicians have the legal power to do so - they are however doing so without the authorised guidelines and must use their own experience and judgement.

For example the current approval in the US for the use of the antifungal voriconazole is as follows:

Vfend [voriconazole] has been approved by the FDA for the treatment of deadly fungal infections. The medication is indicated for the primary treatment of acute invasive aspergillosis.
The approval in the EU by the European Medicines Agency is very similar. Note that no mention is made of treating chronic aspergillosis, a purpose for which it is used every day by many patients. Likewise itraconazole is not approved for use in allergic broncho-pulmonary aspergillosis (ABPA), or severe asthma with fungal sensitivity (SAFS) for which it has proven benefit.

The central problem seems to be that formal approval is so complicated it takes a very long time to be granted, even when there are excellent cases for approval.

This situation is less than ideal and the UK NHS have decided to begin providing expert assessments for off-lable drug use via the National Institute for Clinical Excellence (NICE). The principle will be to provide a summary based on current available evidence which doesn't replace formal guidence but will support local decision making. Read more here.

Wednesday, 16 November 2011

Aspergillosis and Congenital Immune Deficiencies - What we learn

Some of the many genetic deficiencies of our immune systems
Children with congenital immune deficiencies have been born having lost specific parts of their immune system and are thus vulnerable to infection by a number of infecting microrganisms.
At first thought we might think that such children are infected by any passing germ, and as such they become infected by the first microrganism that comes their way but this is not the case. Some immune deficiencies predispose children to one type of infection by a particular micro-organism and while others do not seem to be vulnerable to that 'bug' and instead are predisposed to other infections.

Why is this? Each genetic deficiency effects different parts of the immune system leaving some parts still active, so by looking at the species that can most commonly infect we can gain information on which parts of the immune system are most important for resisting each infecting organism and the types of infection. This principle is summarised in some detail in a recent paper by Bustmante et.al. where they review the patterns of fungal infections in children with congenital immune deficiencies.

Those parts of the immune system that are revealed to be particularly important for resisting infection by Aspergillus are phagocytes (mutated in Chronic Granulomatous Disorder, CGD) and more specifically their ability to produce superoxide ions. This presumably is one part of our immune systems that Aspergillus is partucularly sensitive to. This discovery of an Aspergillus infection of the lung of a young child and a clinical presentation of a granuloma seems to be a strong enough to point to a diagnosis of CGD if it is not already susected, so close is the association between this pathogen, infection of young children and CGD.

Another genetic defect strongly associated with serious Aspergillus infection is Hyper IgE syndrome. Here we see mutations in STAT3, a gene responsible for turning other genes off and on. This is a particularly complicated disorder as STAT3 respnonds to stumili from many different genes - it is a kind of central signalling post for a whole variety of systems, one of which is the immune system. Its involvement in our immune system is illustrated by one of the first noted featured of this syndrome - sufferers overexpress at least one part of their immune system - the IgE part. Normally a fast response system for infection IgE is designed to be produced quickly and then just as quickly fade away as more procise parts of the immune system take over the job of fighting the infection - it could be partly described as a broadly effective attack on infection that buys our bodies enough time for the slower but more effective parts of our immune systems to become fully activated.

The fact that Aspergillus can infect children that cannot control production of IgE might be another clue that IgE control is important for our resistance to Aspergillus, but as several (many) other genes are also involved we cannot yet come to such a clear conclusion.

These defects are giving us clues as to how Aspergillus and many other fungal infections (e.g.  Candida) can get past our normally efficient immune systems. The study of the defects will give us more clues in the future, and hopefully also give us ways to better treat children with these disorders.

Friday, 11 November 2011

Newsbite: MycAssay Shows Promise for the Rapid Detection of Invasive Aspergillosis

MycAssay (Lab21) was utilised among a mixed population of 158 patients with underlying haematological or critical illness, in order to assess its reliability and performance compared with clinical diagnosis and conventional diagnostic tests.

Analysis of bronchoalveolar lavage samples showed that MycAssay Aspergillus offers sensitive and specific detection capabilities, performing better than other assays and showing marked superiority to culture-based methods. more...

Tuesday, 8 November 2011

Aspergillus Catches a Cold

Can Aspergillus catch the equivalent of 'flu? Apparently it can as reported in a new paper published recently.  Several Aspergillus fumigatus isolates have been shown to be infected with mycovirus. They were 'cured' of infection and then re-infected to prove that there was a virus passing between the different isolates. Once 'cured' the fungus had a different growth rate and appearance. When re-infected they took on the same appearance that they had had prior to 'curing'.

On left - 'cured'           On right virally infected

Interestingly those isolates that were infected showed a number of physical changes including poorer growth - they grew less well in several different types of growth media, so this suggests that the virus disables the fungus to some extent.

We know that mycovirus' cannot infect humans so perhaps here is a potential route for treatment of people with chronic infections by Aspergillus fumigatus? One thought is that if we could use these viruses to infect the fungus growing in the lungs or sinus' of people living with aspergillosis then we might be able to reduce the pathogenicity or virulence of the resident fungus with little damage to the host? This may help us resist the infection.

Another possibility is to genetically engineer a mycovirus so as to make it a deadly agent we could use against the fungus. The virus can only infect the fungus so the toxin would only be present in the fungus and not in the surrounding tissues of the human host - this is particularly attractive in the case of fungi that have become resistant to antifungal drugs as there is no known resistance in fungi to mycovirus infection and it would represent the opening of a whole new route of attack against the fungus.

Does this sounds a bit unlikely? Not really. In fact there are already extensive research efforts underway to do precisely this and to try to selectively transport antifungal toxins into fungi using mycovirus - see van de Sande et. al. 2011. Who knows? perhaps using a natural pathogen of fungi will help us overcome many of their defences, reduce our exposure to toxic drugs and act as the 'magic bullet' of the future to help us fight off these insidious invaders.

Monday, 7 November 2011

Obituary: The contribution of John Pateman to Fungal Genetics

1965 Photo of Pateman's colleagues taken by himself
Professor John Arthur Pateman FRS died on 18th May 2011. He was a PhD student of John Fincham at Cambridge University.
Professor Pateman played a large part in our understanding of fungal genetics, in particular the process by which gene products from two separate fungal nuclei can complement each other within the cell to partially restore wild-type function - known as complementation. His work in the 1950's and 60's helped define what we know as a gene.
For information on more figureheads of Aspergillus research, refer to our Hall of Fame.

Thursday, 3 November 2011

Newsbite: The First Case of Onychomycosis due to Aspergillus nomius

Onychomycosis (infection of the nails) accounts for more than 50% of nail disorders and is commonly caused by the fungi Aspergillus flavus, A. terreus, A. niger, A. fumigatus and A. nidulans. Also commonly caused by the fungi Fusarium, Acremonium and Scopulariopsis, but never before recorded as an infection of the Aspergillus species nomius.
There were 48 species of Aspergillus recorded as being pathogenic out of over 700 recorded species names, this latest find increases that number to 49. more...

Wednesday, 2 November 2011

The Steph Smith Appeal: Pre-race relaxation

The Steph Smith Appeal: Pre-race relaxation: Saturday 15 th Oct On arrival at the rather unconventional Bagdogra airport we were hurried into an awaiting jeep by the race organisers. ...

Tuesday, 1 November 2011

Newsbite: Farmers Should Take Care Handling Contaminated Grain

At this time of year in some parts of the world there are large harvests of grain, including the US. In some areas the grain can become contaminated with aflatoxin after growth of Aspergillus in some parts of a field - it is difficult to predict where  as Aspergillus tends to infect crops that have become stressed, often by drought and/or insect damage.

Contamination is detected in most parts of the developed world by tests run by government agencies  responsible for ensuring food is of good quality and of course grain buyers can also run their own tests. If a farmer finds out he has a contaminated batch of grain he has a few options, depending on the extent of the contamination, but often the grain must be disposed of.

This report suggests that in the past the grain has been simply dumped outside - perhaps on a spare bit of land or in a landfill site. The report warns that this makes the contaminated grain highly available to wildlife for whom the toxic grain is fatal. Adding to the problem is the large number of hungry migrant birds passing through many areas at the time of year. Farmers are being asked to ensure that any contaminated grain is not available to passing wildlife. more...

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