The next pandemic could be due to fungi against which we are powerless

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While the COVID-19 pandemic is not over and an epidemic of monkeypox is spreading around the world, worrying the leaders of the affected countries, epidemiologists fear another threat, microscopic fungi. The latter could cause a new pandemic much more terrifying than those caused by viruses, given the little knowledge we have of them and their ability to adapt to our weak therapeutic measures. Despite their presence by our side for a long time, scientists believe that they currently represent a real public health challenge in the face of strong selective pressures, climate change and an ever-growing human population.

Only 120,000 of the approximately five million fungal species have been identified — of these, only a few hundred are known to harm humans. But environmental and climatic changes, as well as the overuse of fungicides in agriculture, have contributed to the creation of infectious “super agents”, capable of escaping our limited therapeutic arsenal.

According to GAFFI (Global Fund for Action Against Fungal Infections), in recent years, fungal diseases cause approximately 1.6 million deaths per year and more than one billion people suffer from serious fungal diseases. Tom Chiller, a medical epidemiologist at the US Centers for Disease Control and Prevention (CDC), tells National Geographic : “ What continually worries us in the fungal world is the potential of fungi to cause human disease. There’s a lot of things we don’t even understand “.

Indeed, microscopic fungi can cause serious disorders and infections, in particular aspergillosis, which has been on the increase for several years, and which raises new questions for the scientific community. Notably Aspergillus fumigatus, which thrives in house dust and decaying plant matter. It can cause complications in people with respiratory problems or a weakened immune system. Inhaling the spores can lead to infection of the lungs and bronchial tubes, which can be fatal in some cases.

While infections caused by bacteria are the most common and best known, the aging of the population and the increase in the number of immunocompromised people — as a result of disease, treatment — has created a window of unprecedented opportunities for microscopic fungi. Thus, antifungals now represent a greater expenditure than antibiotics and antifungal strategies should, in the years to come, be placed at the center of many public health strategies. But why be afraid of mushrooms?

Far too rapid evolution and far too weak a therapeutic arsenal

Although the mutation rate in fungi is generally lower than that of bacteria or viruses, they can evolve at an extremely rapid rate, causing infections that are increasingly difficult to treat with antifungals. Amelia Barber, a microbiologist at the Hans Knöll Institute in Germany, published a study in 2020 on a case of infection in which the fungus Candida glabrata had two particular mutations allowing it to adapt extremely well, and quickly, to new environments and to become much more virulent.

The fungus Aspergillus fumigatus, responsible for severe infections in humans. © Getty Images

This virulence is what makes invasive fungal infections so dangerous, as opposed to superficial varieties such as thrush. Such mutated and aggressive fungi excrete tissue-destroying toxins, which they can then feed on — much the same way they break down organic matter as part of an ecosystem’s nutrient cycle. They enter a cycle of self-sufficiency, creating the nutrients they need to thrive.

Unfortunately, current therapeutic strategies are ineffective. Helpless against this infection, the body can trigger an extreme reaction of the immune system which is sepsis. It is a life-threatening organ dysfunction resulting from the body’s dysregulated response to infection, the most severe form of which is septic shock. This exacerbated body response affects the functioning of vital organs in an acute manner, and can lead to longer-term functional sequelae. Resistance only makes things worse: the mortality rate is 25% higher when an antifungal-resistant pathogen is involved.

Species extinction due to fungi, leading to disproportionate antifungal measures

Besides this direct impact on human health, fungal diseases can also damage plants and crops, leading to significant losses in agricultural activities and food production.

Animal pathogenic fungi threaten bats, amphibians and reptiles with extinction. Not to mention forests in Europe and North America that have been decimated by Dutch elm disease, a fungus spread by beetles, according to the National Geographic. Saturating the vascular system of trees, the infection deprives them of water until they wilt and die. And by wanting to save these crops, we have triggered a phenomenon of resistance in fungi.

Indeed, in the face of these infections, the disproportionate use of fungicides, especially azoles, has quadrupled over the past 10 years, says Marin Brewer, a plant pathologist at the University of Georgia, in National Geographic. Agricultural fungicides often employ similar strategies to their pharmaceutical analogues, when fungi become immune to one they also develop resistance to others. Brewer and his colleague, Michelle Momany, recently proved this by testing samples ofAspergillus fumigatus of patients who had never received antifungal treatment. They discovered resistant strains, known so far only in the agricultural world.

In the Netherlands, this resistance reaches up to 20% of cases in certain hospitals and the therapeutic strategy there had to be modified in order to systematically identify the strains before initiating treatment or using amphotericin B as first-line treatment. In France, this figure has never exceeded 2% and does not call into question the use of voriconazole in first intention nor its prophylactic use in certain immunocompromised patients, or whose aspergillosis is chronic.

It should be noted that fungicides, such as azoles, bind to an enzyme involved in the assembly of ergosterol, a molecule related to cholesterol in humans and an important component of the fungal cell membrane. Without it, the membrane leaks and disintegrates, killing the infectious agent. Concretely, the fungi thwart current fungicides in two steps. First, they change the shape of the target enzyme so that the drug no longer recognizes it. Then they increase the production of the enzyme to ensure that enough ergosterol is produced to keep the fungal cells intact.

Only three fungicides currently exist, and some fungi like candida auris are resistant to all three, threatening the entire world.

candida aurisa global threat due to climate change

The mushroom candida auris, resistant to antifungal drugs, has been spreading in hospitals around the world for a decade. If left unchecked, it could cause more deaths than cancer. According to the CDC, nearly half of patients who have so far contracted yeast infection from candida auris died within 90 days.

candida auris was originally discovered in Japan in 2009, in the ear of a 70-year-old woman. He then seemed harmless. Then, from 2012, it materialized almost simultaneously on three continents, emerging as a direct result of climate change. Then, it was gradually observed independently in different places around the world. The US Centers for Disease Control and Prevention (CDC) added it to the list of germs that pose an “urgent threat” to health. This fungus has acquired the ability to resist high temperatures, while adapting to the excessive use of fungicides in agriculture. The mechanism of this adaptation to heat is unknown at present and is the subject of ongoing studies.

Faced with these threats, the reinforced and systematic monitoring of fungal infections would help to control the transmission of these infections. Additionally, remarkable progress has been made in the development of fungal vaccines for human use. In animal studies, protection against all major medically important mycoses has been achieved using vaccines composed of live attenuated and killed fungi, crude extracts, recombinant subunit formulations and vaccines based on ‘nucleic acid.

Three vaccines have been tested in humans, demonstrating the feasibility of conducting clinical trials targeting at-risk populations. Although many scientific and logistical hurdles remain, there is reason to be optimistic about the availability of clinically approved fungal vaccines.

Do not confuse everything, but respect nature and live together

Finally, fungi have been present for thousands of years all around us — in water, on trees, in the ground, in the air — on us and inside our bodies. They are often described as the “fifth kingdom of life on Earth”; they are neither plants nor animals, neither microbes nor protozoa. Their spores can survive extreme temperatures, radiation, and even outer space.

It is not possible to eradicate fungi, if that were possible! They are of significant importance in the medical sector. Penicillin, for example, was developed from a fungus. Some elements of mushrooms are essential nutrients that can prevent cancer.

Besides bacteria, fungi are important as decomposers in the soil food web. Their strands — or hyphae — also physically bind soil particles together, which helps water penetrate the soil and increases the soil’s ability to hold it.

Last point: mushrooms could help fight against pollution. Some species, such as the oyster mushroom, produce enzymes that digest petroleum hydrocarbons. Some can absorb heavy metals like mercury and even digest polyurethane plastics.

As Momany concludes for National Geographicthe rapid acquisition of azole resistance in Aspergillus in the Netherlands serves as a cautionary tale: “ Aspergillus isn’t even a plant pathogen – it’s just ubiquitous in soil. But because it was in the environment when crops and flowers were sprayed with azole, the pathogen quickly developed resistance to it. “.

Learning to cohabit with the biodiversity of our planet is becoming a more than vital and crucial issue in the face of accelerating climate change, making the threat of new pandemics weigh even more heavily.

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