The journey of the deadly mushrooms / Jennifer Fraser

A strange fungal infection in the United States and Canada poses a new threat to human health

In 2001, dead dolphins whose lungs were filled with large amounts of yeast washed up on the southeastern shores of Vancouver Island in British Columbia, Canada. The swollen organs were many times heavier than their normal weight and there was almost no room for air in them. The vets working on the island had never seen anything like it. The cats and dogs of the area also had difficulty breathing. In the cats, the disease caused a particularly gruesome symptom: sores on their heads that were created after the fungal infection gnawed at the walls of the skull and a gap in it was perforated. At the same time, several people on the island, located west of the Canadian coast, fell ill with an unknown respiratory disease. They coughed incessantly, their strength was dwindling and their sleep was disturbed. Chest X-rays revealed frightening foci in the lungs or brain. However, a biopsy of the tissues revealed that it was not cancer, but yeast, unicellular fungi that do not form webs or multicellular structures.

Despite the differences in symptoms, the cause of the suffering of the pets, dolphins and humans was the same: Cryptococcus Gatti (Cryptococcus gattii), a fungus that had never been observed on the island before, and the explanation was that it only survives in tropical and subtropical climates. The fungus was found around Vancouver Island, but no one knew where it came from or how long it had been there. And what is most worrying, no one knew how many would get the disease and how far this invader would go.

And there were good reasons for concern.

Fungi are an ancient scourge that has plagued plants for a long time. In the eastern United States and elsewhere they became famous for their ability to fell towering elm and chestnut trees. But recently epidemics of fungal infection have begun to appear with alarming frequency among animals. Reports of disease-causing fungi spreading like possessed mansions have come from forest ponds in South America, where the skin of frogs covered in fungus stops the action of white, to caves in the eastern United States, where shivering bats covered in mold fall from cave ceilings. Fungi that infect humans used to be known mostly as the source of inspiration for bad and ridiculous commercials dealing with annoying and unimportant skin infections, rather than something that causes very serious diseases. Our formidable immune system and warm body temperature, far higher than most fungi can tolerate, have ensured that most people in generally good health will easily fend off serious fungal attacks.

There were a few exceptions: in the US diseases transmitted by inhalation of air, such as coccidioidomycosis in the southwest of the country And histoplasmosis, common in the Midwest and Southwest, has always been quietly lurking in healthy people. For reasons that are not fully understood, coccidioidomycosis broke out on a scale eight times greater than usual in 1999 and 2011. As expected, in recent decades, fungal infections have increased among millions of people whose immune systems have been damaged by HIV or by the action of drugs that suppress the immune system, given after transplants or as a treatment for certain diseases. When the body's defense systems are neutralized, disease-causing pollutants thrive unhindered. However, attacks of fungi affecting many healthy people at the same time were rare and were mainly caused by fungi in their normal habitats that were randomly encountered in favorable environmental conditions for reproduction.

the mushroom K. Gatti is a different story. Until its appearance on Vancouver Island, it had occasionally infected single healthy people in other places, but never before had it caused an outbreak, or a wave of unexpected infections. Its appearance in Canada likely marks a jump into new territory with a much cooler climate, where these single-celled creatures have inexplicably become much more violent. From the beginning of the outbreak to the end of 2012, 337 residents of British Columbia were reported to have been affected by the infection, two-thirds of them residents of Vancouver Island, says Eleni Galanis, an epidemiologist at the Center for Disease Control of British Columbia. In 2005 it started K. Gatti Infecting people also in more southern places, in the northwest of the USA, on the shores of the Pacific Ocean. Since then, at least 100 people have been infected in the area, and 25% to 30% of them have died. "That's a pretty high mortality rate for an environmental fungus," says Joseph Heitman, head of Duke University's Center for Infectious Diseases. Although these are not AIDS patients, in about half of them the immune system was weakened due to the administration of drugs or due to the effect of the disease itself, and many of the others had common medical problems, such as diabetes and diseases of the lungs, kidneys or heart, which can weaken the immune system but to a lesser extent. But about 20% or more were healthy before the infection. "Many of these patients were perfectly healthy, spent a lot of time outside, and suddenly they became very sick," Heitman adds.

Today there are clear signs that the outbreak of the disease caused by the fungus will continue to spread south. Immunologist Arturo Casdovall of the Albert Einstein College of Medicine thinks this guard will eventually reach Florida. The events in British Columbia and the Northwestern United States set a milestone in the history of human diseases: this is the first known outbreak of a disease whose cause is A fungus that suddenly developed increased violence. And another historical landmark: this happened in a place where the organism was not known at all before. the story of K. Gatti Thus poses a disturbing prediction: healthy people can no longer assume that they are immune to dangerous outbreaks of fungi that have suddenly turned violent. In fact, as global warming increases, we may be inviting more such attacks.

Anywhere and without the possibility of arrest

Those insights were still far in the future, in June 2001 on Vancouver Island, when public health officials faced the surprise attack. For disease researcher Murray Fife, then working at the British Columbia Center for Disease Control, the first sign that something was wrong was a phone call from the province's veterinarian, who reported an unusual increase in cryptococcal infections among dogs and cats on the island. Local doctors confirmed the existence of a similar increase in humans, and tests showed that the culprit was not the usual species, Cryptococcus neoformans (Cryptococcus neoformans), but another biological species, K. Gatti. The team raided the center's culture collection to test the possibility thatK. Gatti Infected people on Vancouver Island forever and was only misidentified as K. neoformans. This turned out to be true for some infections starting in 1999 but not in the years before that. Fife, now in charge of public health and medicine at the Vancouver Island Health Authority, took several approaches to pinpoint exactly where the fungus was hiding. One direction was to establish a team of researchers to look for new patients on the island and all over British Columbia. The team interviewed patients and owners of infected pets, collected details of symptoms, looked for common characteristics and risk factors, such as previous illnesses and travel to distant places, and even inquired whether the victims had eucalyptus trees growing in their yards. The fungus was discovered on these trees in Australia, where people have occasionally been infected with the fungus for years. They marked the location of the patients on maps and compared the patients and people who did not get sick, according to a method called case-control studies, to identify differences or trends.

to trace the traces of K. Gatti In Nature, Fife turned to Karen Bartlett from the University of British Columbia, an expert on the behavior of airborne biological particles, such as fungal spores, or other particles that reach the respiratory tract of organisms. Since the fungus was found on eucalyptus trees in Australia, she began her work by taking samples from trees that grew on Vancouver Island. But the platforms that Bartlett made from these and other trees and from the ground did not bring up anything.

The study of the control cases did not yield results either. No environmental factor was found, such as gardening, pruning trees or laying surfaces of bark pulp, It seems to increase the risk of the islanders. The patients were scattered randomly from north to south along the east coast of the island without one distinct focus. Furthermore, not all patients had traveled in the period preceding the illness to Australia or to an exotic place from which they could have brought the fungus.

The investigators faced a dead end. Their frustration lasted six months. The breakthrough came when several patients were found who did not live on Vancouver Island but traveled to visit it. Few of them visited Rathrevor Beach Park. A team of samplers was sent to the park in early 2002. In the end, one of the samples, taken from Douglas fir, a biological species common in that area, was found to have the presence of K. Gatti. No one expected the apparently exotic fungus to hide in native trees. Bartlett's team isolated 57 samples of the fungus from 24 trees in the park belonging to several native biological species. By the end of that summer, Bartlett had discovered the fungus in the soil, in the air, and on trees in the city of Victoria, which stands at the southern end of the island, and up the east coast to the Campbell River, and westward from there, in the center of the island. The majority of Vancouver Island's population lives in this area, so the researchers believed that most likely all residents will be exposed, or have already been exposed, and there is nothing to be done about it.

More worrying news followed. Data collected between 2002 and 2006 later showed that the rate of infection in the population of Vancouver Island was 27.9 infections per million: a rate three times higher than the rate of infection of humans in the tropical north of Australia. It is certainly possible that the North Americans encounter a much more violent strain, although the lack of previous exposure may also explain the infection pattern; If the fungus is a new guest, only few of the population, if any, have already encountered it and could develop immunity against it at an earlier stage in their lives. Tests done on the organism revealed disturbing findings. It is resistant to fresh water. It can survive in salt water. It survives in the air. It can survive for years in mud on shoe soles. A parallel research paper showed thatK. Gatti is in motion. In 2004, people from the mainland of British Columbia who had never been to Vancouver Island began to get sick. Statistical models have shown that the organism prefers relatively warm winters, low altitudes and dry conditions. Areas in the south seemed like fertile ground for him. In February 2006, an elderly man suffering from leukemia came to his doctor and complained of a cough. The elderly man, who lives in the San Juan Islands west of the coast of Washington state, was treated with steroids that suppress the immune system before his application. An X-ray of his chest revealed a focus of K. Gatti. Genetic analysis by Heitman in collaboration with Kieren Marr, a physician-researcher then working at the Fred Hutchinson Center for Cancer Research in Seattle, revealed that the fungus was identical to the strain found on Vancouver Island. Although the man lives a few kilometers from the maritime border with Canada, he has not traveled to Canada since. The mushroom came to him.

why now

Although already in the middle of the previous decade, the researchers realized that there was almost nothing that could be done to stop the spread of the fungus In North America, they were still preoccupied with the question of how long the fungus had existed in British Columbia and Northwestern America, where it came from, and what caused it to suddenly infect so many people. They found clues to the answers by analyzing her DNA sequence.

The genetic research revealed that the fungus may have been found around Vancouver Island for several decades before 1999, Heitman says. DNA analysis of the main strain of K. Gatti located on the island, marked VGIIa, and found to be responsible for 90% of infections on Vancouver Island, found a particular genetic sequence identical to 30 or more parallel segments of DNA found in a sputum sample taken from a man in Seattle in 1971. His travel history is unknown, and he may have visited Vancouver Island. Regardless, this evidence probably shows that the VGIIa strain has been present on the northwest coast of America for at least 40 years. In the years since the outbreak, scientists in North America have found less violent strains of the mushroom which do not cause eruptions, so it is possible that the VGIIa segment is the product of evolution that took place there. but K. Gatti It could also have come from Africa, Australia or South America, where the species is also endemic.

A second strain of the fungus, labeled VGIIb, is indistinguishable from the strain now common in Australia. Researchers later realized that it caused disease on Vancouver Island in 1999 along with VGIIa and that it accounted for 10% of the infections in the first outbreak. Australia may be the origin of this strain. Oregon now has both varieties, and a third has been added: VGIIc. The latter spread unexpectedly in Oregon in 2005, but it is not known whether it is found there or elsewhere.

Also of concern is the fact that the two strains VGIIa and VGIIc found in samples from mice in Heitman's lab are the most virulent forms of Cryptococcus the lab has ever studied. This and other findings indicate, according to Heitman, that it may have been some kind of mating between unspecified strains of the fungus that produced the two strains and gave them their increased virulence. Asexual reproduction encourages the formation of diversity among the offspring by mixing the DNA of the parents and creating new combinations. In fungi, the act of mating itself generates mutations that can yield new traits. The putative outbreaks of fungal sex could just as easily have occurred in North America or in the fungus's common habitats of Australia, South America or Africa, where researchers have yet to find the parent fungus.

It is also not known if the strains that broke out came from outside the continent, and if so, if they made their way to North America separately or together. The scientists can think of many scenarios for their arrival: the importation of plants, soil or animals or long-distance migration by wind or ocean currents - all these have been suggested. The fungus could hitch a ride on a ship's ballast water. Infected dolphins could cross the Pacific Ocean on their own, releasing the organism onto land, or pass it on to scavengers after their bodies washed ashore. Mud on car wheels or shoes can carry the fungus from one place to another. The journey or journeys that brought the mushrooms to North America could have taken place 10,000 years ago, or 43 years ago.

However, there is at least one clue to solving the question of how long the mushrooms have been in the American Northwest. The genetic diversity of fungi found for a long time in one place tends to increase. The three strains of the fungus causing outbreaks in the region are phylogenetic, meaning that all individuals of a single strain, b, a or c, are very similar to each other. "If it had been here for 100,000 years, we would have expected to find much greater diversity in the population, and we don't see that kind of diversity," says Heitman. "From my point of view, this may be the strongest argument by virtue of suggesting that [these fungi] may have actually arrived here 50 or 70 years or 100 years ago" and not thousands of years earlier.

As for why the fungus hasn't caused outbreaks until recently even though it's been around for at least 40 years, one possible answer is climate change. The average temperature on Vancouver Island has risen by one or two degrees Celsius in the past 40 years, Bartlett says. "It doesn't sound like much, but it can make a huge difference for single-celled creatures," she adds. In each of the years 1991, 1993, 1996 and 1998 the summer temperatures were higher than average on Vancouver Island. Higher temperatures may have allowed the subtropical organism, which previously only existed on the brink of survival, to begin to thrive. As the Earth warms, Casdwell says, heat-loving disease-causing fungi can expand their distribution, invading habitats that were previously unfriendly to them. And it is already known that since 1960, fungi that cause diseases in plants have been moving towards the poles at a particularly brisk pace of about 7.5 kilometers per year on average in response to climate change. Meanwhile, warmer climates may encourage other fungi to develop tolerance to warmer temperatures. The complex fungal genome, larger than that of bacteria and viruses, gives its owner a variety of response options to stress, enabling adaptation to heat. Even slight increases in heat tolerance may allow fungi that were on the verge of being able to cause disease to tolerate our high body temperature and multiply in it, instead of dying after invading it. If such scenarios do occur, there is bad news for humans, who rely on high body temperature as a mainstay of defense against fungi.

In addition to climate warming, in the late 90s we witnessed accelerated development of the eastern side of Vancouver Island. Forests were cut down, a long highway was paved, and the land was excavated and turned into construction purposes. Turning the land and cutting down trees could have released the organism and spread it from its small niche into the wider world, Bartlett notes. The appearance of K. Gatti As a disease generator in this area it could have been the result of a random combination of factors that acted at the same time: several years of relatively warm winters and dry summers; turning the land; And the fact that the area is popular with both tourists and retired people, who tend to be more susceptible to infection than younger people.

foreseeable threats

To a large extent, we have nothing but ourselves to blame for the development of this myriad of disease-causing fungi that threaten plants, animals and humans - and not just because we have a significant part in climate change. Humans determinedly helped them escape from their previous limited abode through international trade. It is very likely that international trade spread the potato caraway from Ireland to Europe, the chestnut caraway to North America and the skin infection fungus chytridiomycosis to amphibians all over the world. Our addiction to shipping across the globe has effectively created a mushroom matchmaking service. The fungi as a group are passionate sexual creatures. When humans bring together fungi that have lived apart due to geographic barriers, but are still able to mate, the resulting pairings can produce new, more virulent strains capable of infecting organisms their ancestors could not harm, or thriving in new environments. The continuation of the trade or its expansion will increase the chances of introducing existing pathogens to unprotected hosts and of the emergence of new pathogens due to fungal matings.

Although there is almost nothing that can be done to stop the spread of K. Gatti, we can take steps to reduce the chances of fungi running rampant and wreaking havoc on innocent populations, and to be prepared when an outbreak occurs. It is advisable to start improving the diagnosis of fungal diseases and their follow-up. Since fungal diseases are not common in healthy people, doctors usually ask for tests to detect them, and this leads to a delay in diagnosis and the development of symptoms that are more difficult to treat after diagnosis. Currently, the diagnostic methods for many fungi are not specific or sensitive enough and may be too expensive in poor countries. The World Health Organization has not prepared a plan to prevent infection with fungi, and only a few public health bodies, apart from the American Centers for Disease Control and Prevention, conduct systematic monitoring of infection with fungi.

Another line of defense may be increasing the safety of plant and animal transfer. Since many human pathogens also live in the soil and on plants, increased supervision of the import of such substances, strict inspection of cargoes of agricultural crops or animal products for fungi known to cause human diseases, for example, or closer inspection of customs at airports On shoes or equipment covered in mud, or the prohibition of the introduction of plant material by tourists as is customary in Austria and New Zealand - all these will help not only in preventing diseases, but also in reducing the risk of unwanted pairings between mushrooms.

More money should be invested in the development of new and improved anti-fungal drugs. A big obstacle here is our proximity to them: we are almost first cousins ​​in the family tree of life. The fungi and animals diverged later in evolution than any other large group of organisms. Although due to this closeness the yeasts are excellent models for studying the biology of mammals, but it makes it very difficult when they infect humans. "The fact that they are [so close to us] is a huge problem because a large part of their intracellular mechanisms are shared with us," says Heitman, "therefore it is more difficult to find unique targets for the action of antifungal drugs." The effectiveness of the drugs we have is usually quite modest in reducing mortality from invasive fungal disease, and they may cause toxic side effects or adverse drug interactions. Few antifungal agents are currently in development. Antifungal vaccine components are another line of defense. But few of them have reached the stage of a clinical trial, and there is currently no vaccine available for humans. The development of anti-fungal ingredients may be a good insurance policy should the worst happen, and they could help many who are already at increased risk of getting a fungal disease.

to the story of K. Gatti Accompanied by an ominous footnote. VGIIa and VGIIb had already spread to Oregon, but VGIIc first appeared there in 2005, before the Vancouver Island strains, a and b, appeared in the US. Extensive tests of samples from Vancouver Island show that VGIIc was never there. Genetic analysis of the VGIIc strain from Oregon clearly shows that it is not the descendant of a simple mating between VGIIa and VGIIb. These observations suggest that there was not one outbreak of a new, more violent strain in the north-west of the continent, but two.

"This appears to be an outbreak within an outbreak, which may have different origins," Heitman recently wrote in a report to the Institute of Medicine. "It looks like two pebbles thrown into the pool one after the other and created concentric ripple circles, which are now spreading and crossing each other." In other words, the near-simultaneous eruption of VGIIa and b on Vancouver Island and that of VGIIc in Oregon may have been two events that happened almost together in an amazing coincidence, although both may have resulted from the same environmental conditions. Such eruptions were unknown before 1999, and now two have occurred back to back in just seven years. This discovery underscores one of the few certainties in this story of coughing people, moldy bats, and tarred trees: Underestimating the ability of fungi to migrate to new hosts and thrive in our warming and shrinking world is a very bad bet.

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in brief

In 2001, on Vancouver Island, British Columbia, Canada, it was discovered that an airborne yeast fungus causes apparently healthy people to become seriously ill. This is the first known case of a human disease-causing fungus suddenly becoming virulent in areas where it was previously unknown.

Locating the origin of the fungus turned out to be a difficult task. Eventually, researchers discovered that it was hiding in surprising places, and that it may have become violent due to climate change and land development work in British Columbia.

The outbreak is expected to continue. Improved diagnostic tools can help us prepare. Closer controls on the movement of plants and animals between countries and the development of better drugs and vaccines against fungi can also help.

on the notebook

Jennifer Frazer is a freelance science writer and blogger at The Artful Amoeba, one of Scientific American's blogs. She has written in the journals Nature, Grist and the Village News and won the Science Journalism Award of the American Association for the Advancement of Science.

More on the subject

Global Warming Will Bring New Fungal Diseases for Mammals. Monica A. Garcia-Solache and Arturo Casadevall in mBio, Vol. 1, no. 1; April 2010.

Sexual Reproduction, Evolution, and Adaptation of Cryptococcus gattii in the Pacific Northwest Outbreak. Joseph Heitman, Edmond J. Byrnes III and John R. Perfect in Fungal Diseases: An Emerging Threat to Human, Animal, and Plant Health. National Academies Press, 2011.

Hidden Killers: Human Fungal Infections. Gordon D. Brown, David W. Denning, Neil AR Gow, Stuart M. Levitz, Mihai G. Netea and Theodore C. White in Science Translational Medicine, Vol. 4, no. 165; December 19, 2012.

The article was published with the permission of Scientific American Israel