by Tim Vernimmen

August 13, 2016

from Sci-Hub Website

We overlook

a mushrooming threat at our peril,

finds Tim Vernimmen

Some are tasty, others are a nuisance.

That's probably how most of us think of fungi. Few people would consider them to be killers. But perhaps we should.

Fungi are on the march. New varieties are emerging and infecting everything from crops to amphibians. Some of this is down to the ease of international travel, which is spreading hardy spores to new locations.

Then there's our disruption of natural environments, which creates opportunities for fungi to evolve.

Now, some researchers are worried we could be about to reap the spores we've sown:

might we have unleashed a killer?

Neil Gow, a medical mycologist at the University of Aberdeen, UK, was co-organizer of a conference held at London's Royal Society earlier this year to assess the growing fungal threat in areas from animal welfare to food security to ecosystem stability.

He's keen not to overstate the threat to human health - but not to downplay it either.

"I don't think a fungal pandemic is imminent: as far as we know, humanity has never been struck by one," he says.

That is not to say fungi don't kill people.

"More people die from invasive fungal infections than from malaria, a disease we hear much more about."

Even now, about a dozen fungal species (Hidden Killers - Human Fungal Infections) kill in total around 1.5 million people every year.

Fungal disease is a significant contributor to AIDS deaths, for example - and yet the threat is often overlooked.

"Fungal and bacterial infections may give similar symptoms, leading to misdiagnosis," says Gow. "So in many cases, patients with fungal infections are initially treated for bacterial infections instead."

Fungi comprise a whole kingdom of organisms in their own right, separate from plants and animals, and far less studied.

This hugely diverse group of up to 5 million species includes mushrooms, yeasts, moulds and crop-destroying rusts and smuts.

Most of the time, we happily coexist even with the killer varieties - you may be inhaling them right now, or they may be living in or on your body. But occasionally they turn rogue.

Take Candida albicans, which causes most fungal infections in humans.

Candida cannot survive without living on us or other animals.

"There's no evidence that it's doing us any good, but it usually doesn't harm us either," says Gow, who studies Candida.

Yet sometimes the unassuming resident gets a bit too comfortable and multiplies so fast that it causes the infection commonly known as thrush.

How and why this happens is the focus of intense research.

Usually, our white blood cells and other defences do a good job of keeping the fungus under control.

"But anything that tips the odds the other way," says Gow, "such as low numbers of white blood cells or antibiotics that wipe out other microflora, may cause a local outbreak."

This can be very aggravating - just ask one of the 100 million women worldwide who suffer at least four episodes of vaginal thrush a year.

"More people die from invasive fungal infections

than from malaria may cause a local outbreak."

Most people recover without complications, because the fungus seldom thrives in the blood.

"The bloodstream of a healthy human is quite robust to infections," says Gow.

But Candida does overcome the defences of hundreds of thousands of people each year to enter their blood - and at least half of them die.

How can this be?

"In a way, fungal infections are the disease of the diseased," says Gow.

 

"People who are vulnerable after an accident or invasive surgery, or whose immune system has been weakened or suppressed after an organ or stem cell transplant, may be unable to fend off a fungal attack.

 

Candida is very opportunistic."

A handful of fungi kill some 1.5 million people each year.

They include Candida, Cryptococcus and Aspergillus
 

EYE OF SCIENCE/SCIENCE PHOTO LIBRARY
DAVID SCHARF/SCIENCE PHOTO LIBRARY

E. GUEHO/SCIENCE PHOTO LIBRARY
 

To work out a way to help the immune system nip Candida in the bud, Gow and his colleagues are investigating how the fungus interacts with our white blood cells.

"It's a titanic struggle on a microscopic scale," he says.

Candida uses camouflage and can shed tiny bits of cell wall to avoid being caught.

Even when it does end up inside a white blood cell, it's not game over.

"The fungus can evade digestion by reducing the acidity inside the cell compartment where it's held, and it even scavenges some of the cell's food," says Gow, "which is why it's often able to keep growing until the white blood cell bursts open."

Another potentially deadly fungus, Cryptococcus, can cause meningitis by lurking in a white blood cell until it crosses the usually impenetrable blood-brain barrier. It then forces the cell to eject it.

Unlike Candida, Cryptococcus is not a fungus native to us - instead, it usually grows on rotting plant material in the soil.

"Though most of us have been exposed to it by the age of 6, the chance that a particular Cryptococcus cell has encountered a human before is absolutely minuscule," says Robin May at the University of Birmingham, UK.

Yet Cryptococcus has recently achieved something once considered almost impossible:

it has infected and killed previously healthy people.

First discovered in Vancouver, Canada, over a decade ago, a particular strain of Cryptococcus, C. gattii, spread across the Pacific Northwest of the US, killing hundreds along the way.

How does a fungus living on plant matter manage to survive inside a healthy human body?

By accident, argues Robin May.

"There is obviously very little evolutionary pressure on Cryptococcus to find a way to survive in humans," says May.

However, the fungus is preyed upon by amoebas in the soil, and their mode of attack is quite similar to that of white blood cells.

That might give the fungus a head start. This means it can occasionally thrive inside the body, harming its host in the process.

Like Gow, May doesn't think a fungal pandemic is just around the corner.

"Fungi have very complex life cycles, and they tend to grow and evolve much slower than bacteria or viruses do."

The fact that fungi don't depend on us for their survival cuts both ways, though.

"It means that they probably aren't trying very hard to conquer us. But also that they couldn't care less if we were all to die."

Given that there has only been a single outbreak of C. gattii, it's difficult to establish what led to it.

May surmises that the strain had been around for some time, and that a very hot and dry summer may have contributed to its spread.

"The fungus likes humid soils, so perhaps the drought stimulated it to produce more spores, or simply provided conditions that helped them to blow around more," he says.

However, we don't have clear evidence for this and May notes that the summers of the past decade have all been fairly wet.
 

FUNGAL HELPERS
 

Although a few fungi can kill us, many provide indispensable services.

• Fungi play a crucial role in ecosystems by feeding off organic matter and recycling the nutrients for plants to use.
   

• Yeasts are vital in the fermentation of sugars to make alcohol and for leavening bread.
   

• Fungi produce antibiotics, most famously penicillin, and are used to make other drugs - even antifungals. They also synthesize complex compounds of commercial value, including ingredients for perfume.
   

• We can use fungi to tackle oil spills, break down pesticides and herbicides, and destroy neurotoxins used in chemical weapons.
   

• The birch polypore mushroom even makes a good hat.

This raises the question of whether other deadly new fungal strains might emerge as climate change takes hold.

That is difficult to answer because the impact on weather patterns is likely to be very variable, says May.

"But you might expect, for example, that Britain, which is a bit too cold for many fungi right now, may see an influx of fungus when temperatures rise."

Another concern is that although the warmth of our body protects us from many fungal infections, a warmer world may undo that by helping fungi to adapt.

"But I currently know of no studies showing that fungi from warm soils infect warm-blooded animals more easily," says May.

In any case, Cryptococcus copes just fine with being at 37°C.

Another fungus, called Aspergillus, can live in the heart of compost heaps at temperatures of 60°C.

Aspergillus spores are absolutely everywhere, says Jacques Meis of the Canisius Wilhelmina Hospital in Nijmegen, the Netherlands.

"Every breath you take, they're infecting you."

Garden-variety killer

In the early 1990s, Meis was a parasitologist working on malaria when a prominent Dutch hematologist sought his help.

"We can now treat blood diseases with bone marrow transplants or cycles of chemotherapy, but then patients literally die of garden-variety fungal infections," he told Meis.

Keeping Aspergillus at bay is a constant challenge.

"The fungus and its spores are really small and often very water-repellent, so they take off with the slightest air current and find their way through all but the finest air filters," says Meis.

They are also extremely hardy - the spores can survive acidity, dehydration, freezing and high heat. No wonder they're the most common eukaryote on the planet.

Eukaryotes - which include fungi but not bacteria or viruses - are organisms in which the cells contain a nucleus.

The fact that we, too, are eukaryotes makes it difficult to combat fungal pathogens.

"Some of the most effective medicines against fungal infections, such as amphotericin B, are quite toxic to our cells as well," says Meis.

So they are often combined with or replaced by another class of antifungal drugs, collectively known as azoles.

"The azoles block an enzyme that most fungi need to maintain their cell membrane," he says.

One deadly fungal strain has found a way into the human brain.

EDMOND BYRNES AND JOSEPH HEITMAN/DUKE UNIVERSITY
KOH OKAMOTO, SHUJI HATAKEYAMA ET AL.
 

You would expect fungi to develop resistance to these drugs in people receiving repeated or long-term treatment.

But lately, Meis has seen an increasing number of patients coming down with a resistant strain right away.

"We found this very odd at first," he says.

 

"But then it dawned on us that in the past decades, azoles have become very popular products."

They are now used to prevent fungal growth on crops, produce and flowers, and are an ingredient in many paints and coatings.

Aspergillus isn't the target of these azoles, but it is constantly exposed to them.

"There is no doubt that some of these applications are contributing to azole resistance in the clinic," says Meis.

 

"Because Aspergillus is quite literally all over the place and exchanges genes very quickly, resistance can spread across the world incredibly fast."

Meis doesn't expect companies to stop producing azoles or farmers to stop using them.

"I'm afraid the fact that Aspergillus targets only patients who are already weak will likely undercut any arguments in favor of reduced azole use," he says, "except if we can figure out which products are causing the biggest problems and why."

Deadly fungal disease is often not viewed with the seriousness it deserves because it mainly affects people that were "on the way out anyway", says medical mycologist David Denning at the University of Manchester, UK.

But that argument is very problematic, he says.

"The Cryptococcus gattii outbreak shows that there is always a risk that a fungus will one day find a way to infect healthy people as well."

In any case, it isn't true that weakened patients who contract a fungal disease are already bound to die of some other cause, says Denning:

our ability to keep severely ill people alive is constantly improving.

However, this means the number of people vulnerable to fungal disease will go on rising unless we tackle the problem.

"It would be a terrible shame if this progress and all we've invested in it were offset by fungal infections."

Yet that is what is happening, especially in the fight against HIV.

Antiretroviral cocktails are now highly effective, but many people with HIV live in poor countries where it can be difficult for them to take the drugs as prescribed.

A lapse in treatment can cause their white-blood-cell count to drop, at which point any fungus they're exposed to may turn invasive.

"About half of all AIDS deaths are the result of fungal infections," says Denning, "yet they're hardly addressed."

There are multiple reasons why the problem is going untackled.

"Diagnosis of fungal disease isn't straightforward - it is as good as impossible without access to a medical lab - and treatment with amphotericin B is intravenous and risky," says Denning.

But the task isn't impossible, and cracking it could be a big step towards achieving the UN's target of reducing annual AIDS-related deaths to below 500,000 by 2020.

"If we could treat 60 per cent of the HIV patients annually overcome by an invasive fungus, we could save at least 300,000 lives a year - typically 35- year olds, economically active, with husbands or wives and children who need them," he says.

 

"These people aren't on the way out. They are ill, and they need our help."