Fungi Read online

  None of the dermatophyte infections are life threatening, and most respond to treatment with antifungal agents. Fluconazole is a popular medicine that is directed against an enzyme used to produce ergosterol, which is an essential component of the fungal cell membrane. It has relatively few side effects because animal membranes contain cholesterol rather than ergosterol. This specificity is the goal of antifungal drug discovery, because many of the medicines that are effective against fungi have damaging side effects. Terbinafine hydrochloride (Lamisil) is another medicine which is active against an earlier step in the pathway of ergosterol synthesis than fluconazole. It is very useful when it is applied to the skin to treat athlete’s foot and other types of ringworm, but is associated with liver problems when it is taken orally for many months to treat stubborn toenail infections (onychomycosis).

  Trichophyton species are very common skin residents even when there is no obvious ringworm infection, which means that they may operate as commensals, causing no benefit or harm to the host, as well as pathogens when they cause disease. Malassezia species, which are not considered to be dermatophytes, span the continuum of symbioses from mutualism (if the fungus curbs the growth of damaging microorganisms), to commensalism, and parasitism (when they cause dermatitis). Many of the microorganisms that flourish in our microbiome behave in this malleable fashion in their interactions with the human body. Fungi that live in the genitourinary tract and digestive system can cause more serious diseases than the members of the skin microbiome. The yeast called Candida albicans is the most important of these fungi.

  Candida and opportunistic infections

  Candida is a normal member of the gut microbiome and also grows in the mouth and in the female genitourinary tract. When these normal commensal relationships are disrupted, it causes superficial infections in the mouth and vagina, referred to as oral and vulvovaginal candidiasis. Oral candidiasis or ‘thrush’ is also common in babies and in adults with suppressed immune systems. More serious infections occur when the yeast spreads to internal organs causing systemic candidiasis.

  The infection process begins when Candida adheres to the surface of host cells. Contact initiates a developmental switch in the fungus, which converts itself from budding yeasts into filamentous hyphae. The hyphal form is associated with the penetration of the host tissues. This occurs in two ways. The first mechanism involves some molecular trickery in which the fungus secretes molecules called invasins that cause host cells to take up the living pathogen. The alternative approach seems more direct, with the hyphae penetrating the underlying tissues by secreting enzymes to weaken proteins and applying turgor pressure as a source of physical force to push their way in (Chapter 2). As the infection develops, Candida can produce layered communities of yeasts and hyphae in tissues and on the surface of catheters. These are called biofilms. Biofilms can make it more difficult to treat an infection because the cells that are buried beneath the surface are protected from antifungal agents. In the severest infections, Candida spreads through the bloodstream causing fever, shock, kidney failure, and widespread clotting and bleeding (disseminated intravascular coagulation). Candidiasis caused by Candida albicans is the most common infection acquired in hospitals.

  Proponents of the ‘yeast syndrome’ and ‘Candida complex’ misrepresent scientific facts about this fungus, suggesting that it is responsible for all manner of complaints including anxiety, fatigue, headaches, weight gain, and depression. These often high-profile alternative health practitioners recommend dietary changes and various nutritional supplements to get rid of Candida and restore good health. People are misled by the real problems associated with superficial candidiasis into believing that the mere presence of the yeast is damaging. Candidiasis is a significant problem for many women, but suggestions for eradicating the fungus are misplaced and create a false sense of insecurity about our intimate relationships with microorganisms. Fungi grow on us, inside us, and are all around us. Whether we like it or not, fungi accompany us throughout our lives and help decompose our bodies when we die.

  Candida and Malassezia are part of everyone’s microbiome. Other fungi are detected on some people and not on others. In general, the immune system is exceedingly effective in limiting the growth of fungi beyond the skin. This is evident from the diversity of fungi that can invade our tissues when the immune defences are impaired. Rare systemic mycoses develop when vulnerable patients are colonized by fungi that live as saprotrophs in the environment. Zygomycete fungi that rot fruits and cause food spoilage in kitchens produce potentially lethal infections called mucormycoses in immunocompromised patients. Burn patients and people with uncontrolled diabetes are also vulnerable to these fungi. Colonies of filamentous hyphae invade soft tissues in the nasal passages and can grow within the walls of blood vessels and spread to the brain. Antifungal agents can be used to slow the progression of the disease, but mucormycoses are very difficult to treat. Aspergillus fumigatus, which thrives in the warmth of compost heaps, is another opportunist that starts as a lung infection (aspergillosis) and can spread throughout the body. Similar infections are caused by multiple species of fungi whose invasive hyphae are blackened with melanin pigment.

  Other systemic infections

  More common systemic mycoses are produced by a small number of opportunists whose life cycles alternate between distinctive growth phases in the soil and in animal tissues. The most important diseases caused by these fungi are cryptococcosis, histoplasmosis (Ohio valley disease), blastomycosis, and coccidioidomycosis (valley fever). Cryptococcosis is caused by Cryptococcus neoformans and Cryptococcus gattii. These are species of basidiomycete yeasts that infect the nervous system. Outside the body Cryptococcus grows in the form of filamentous colonies in bird droppings. Human infections begin when spores or yeast cells produced by this saprotrophic phase are inhaled deep into the lung. In the mucous lining of the lung the fungus is consumed by macrophages and other cells of the immune system programmed to destroy microorganisms. But the fungus subverts this defence mechanism by sidestepping digestion inside the macrophages and using the host cells as vehicles for spreading around the body and into the bloodstream. Transmission from the bloodstream into the brain may involve uptake by another population of macrophages that have been aptly described as Trojan horses.

  Once inside the brain tissues, Cryptococcus forms abscesses and produces a severe form of meningitis. Amphotericin B is the antifungal drug used against the most serious cases of cryptococcosis. Rather than inhibiting ergosterol synthesis like fluconazole, amphotericin B works by binding to ergosterol after it has been incorporated into the fungal membrane. This damages the membrane, making the fungal cells leaky. Unfortunately, amphotericin B also attaches to cholesterol, weakening the membranes of human cells and causing kidney damage. The way that Cryptococcus avoids destruction by macrophages may have evolved from ancient interactions with soil microorganisms that enabled the fungus to avoid digestion by amoebae. Based on this theory, the pathogenic behaviour of the fungus may be rooted in ecological relations that evolved long before the origin of mammals.

  Histoplasma capsulatum is another fungus with distinctive saprotrophic and pathogenic phases. Like Cryptococcus, Histoplasma grows in soil enriched with bird droppings. It is also found in soil on the floors of caves that are fertilized with bat guano. The fungus grows in the lungs and only causes any serious symptoms when the immune system is compromised. AIDS patients, for example, are susceptible to rare cases of systemic disease when Histoplasma spreads to the spleen, liver, and adrenal glands. The common name of Ohio Valley disease comes from the concentration of cases along the Ohio and Mississippi river valleys. Blastomycosis is a similar illness caused by Blastomyces dermatitidis. It is distributed across a wide region that includes the Eastern United States and Canadian provinces as far west as Manitoba. Another species, Coccidioides immitis, is a soil fungus in the southwestern United States and northern Mexico that grows in the lung and can spread to other tissues and produc
e brain inflammation. Outbreaks of the disease have been linked to soil disturbance caused by farming, construction projects, and earthquakes, which release Coccidioides spores into the air. The common name for this mycosis is valley fever.

  Most serious cases of fungal infection occur in people with compromised immune systems, but disease outbreaks do occur occasionally in people with apparently healthy immune systems. Immune responses to fungi range from mechanisms of general exclusion to attacks upon specific pathogens engaged in an ongoing infection. The skin and the mucous-covered surfaces of the lungs, gut, and genitourinary tract provide the first obstacles to fungal invasion. In addition to acting as physical barriers, antimicrobial compounds secreted by these tissues and resident commensal microorganisms interfere with pathogen growth. If these obstacles are breached, a series of innate or non-specific immune mechanisms destroy the foreign cells.

  Chemical signatures that are common to all fungi alert the innate immune system. These include molecules that form the walls of yeast cells and filamentous hyphae. Recognition triggers an inflammatory response in which neutrophils, macrophages, and other kinds of white blood cells attack and destroy the pathogens. The innate response also involves the uptake and disassembly of yeasts, hyphae, and spores by dendritic cells. Dendritic cells process molecules released during the disintegration of the fungi and display these antigens on their surfaces. This action by the dendritic cells triggers the adaptive immune system that provides a specific response to a particular fungus. Antigen presentation activates T cells that coordinate the destruction of the fungal cells in other parts of the body. Populations of T cells called CD4+ helper T cells are vital to the operation of the adaptive immune system. Low levels of these T cells in AIDS patients and people coping with other forms of immune damage are an indicator of their susceptibility to opportunistic infections.

  A form of pneumonia caused by a yeast called Pneumocystis jiroveci illustrates the importance of immunodeficiency in fungal infection. Pneumocystis pneumonia, or PCP, was an exceedingly rare illness before the beginning of the AIDS epidemic in the 1980s. Cases of this infection were so unusual that requests by physicians in California and New York for the antibiotic called pentamidine used to treat PCP were one of the first indications of the new epidemic. Reports of Kaposi’s sarcoma, a rare form of cancer caused by a herpes virus, were another sign of an emerging disease that crippled the immune system. Eighty per cent of AIDS patients developed PCP before effective HIV medications were developed and it remains a major cause of death among AIDS patients today.

  Our understanding of the biology of the fungi that cause opportunistic infections has advanced in ways that were not imagined a few decades ago. Molecular genetic experiments, the sequencing of whole genomes, and advances in microscopy have revealed masses of information about the operation of these microorganisms. On a clinical level, however, the modern exploration of pathogenic fungi has been disappointing. The quest for the molecular determinants of virulence has shown how Candida sticks to host cells and how Cryptococcus evades the immune defences, but these discoveries have not led to new treatments. The pace of antifungal drug discovery has been sluggish and the emergence of Candida strains that are resistant to fluconazole is a troubling development. The most serious mycoses continue to be treated with amphotericin B that was introduced in the 1950s. The most definitive approaches to treating these illnesses are likely to come from therapies that resolve the underlying immunological deficiencies that invite opportunistic infection.

  Infections of other animals

  Fungi that infect humans produce similar diseases in our mammalian relatives. Ringworm is common among domesticated dogs and cats, candidiasis and cryptococcosis occur in pets and farm animals, and coccidioidomycosis is encountered in a wide range of zoo animals. Aspergillosis is the most common respiratory infection in birds and a few of the human mycoses also occur in reptiles. Populations of wild animals are also prey to these fungi. Marine biologists have reported outbreaks of cryptococcosis and coccidioidomycosis among porpoises and dolphins, sea lions, and sea otters. The spread of highly virulent mycoses among single animal groups has become a major concern in our time. These include chytridiomycosis, caused by Batrachochytrium dendrobatidis, which affects one-third of amphibian species, white-nose disease (Pseudogymnoascus destructans) that has killed six million bats in North America, and marine aspergillosis of sea fan corals in the Caribbean caused by Aspergillus sydowii. Degradation of the environment by human activities may be a factor in some of these epidemics, with climate change, ozone depletion, and multiple pollutants implicated in various studies. Each of these diseases is so complex, however, that it has been impossible to identify a single cause.

  The rapid spread of unusual fungal diseases is a new and disturbing phenomenon, but mycoses are a normal part of animal life and death. Just as all animals engage in mutualistic and commensal symbioses with fungi (Chapter 4), pathogenic fungi affect every species. Pathogenic interactions are very evident among the insects. Insects and spiders are attacked by Cordyceps species that penetrate their exoskeletons, invade their soft tissues, and break out from the dead animal with club-shaped fruit bodies. Cordyceps militaris infects the larvae and pupae of moths and butterflies, and transforms the host into masses of white hyphae. This process is referred to as mummification. If the insect dies in soil or rotting wood, the fungus is recognized from its orange clubs protruding into the air. The largest of the fruit bodies are the size of pencil stubs. The infectious ascospores of Cordyceps militaris are long filaments. These are ejected into the air flowing around the top of the club and fragment into multiple infectious particles.

  Related species that infect adult insects modify the behaviour of their prey, stimulating them to climb to the top of grass stalks or to crawl on to leaves. As the infection proceeds, the fungus sprouts from the dead insect and its fruit bodies are in a perfect position to ensure wind dispersal. The biochemical mechanism used by the fungus to control the behaviour of the host has not been solved. A particularly fascinating species of Ophiocordyceps that parasitizes ants has been studied in tropical rainforest in Thailand. After infection, the ants develop convulsions and adopt a ‘drunkards walk’. These symptoms are observed in ants that have fallen from their preferred habitat high in the tree canopy. In the humid atmosphere of the forest understorey, these ‘zombie ants’ crawl on to saplings and bite into the main vein on the underside of leaves. This is synchronized to the elevation of the sun, or to a related environmental variable like temperature or humidity, because the infected ants always bite leaf veins around noon. Meanwhile, the fungus destroys the muscles controlling the mandibles, which locks the insect in its ‘death grip’. The insects live for up to six hours after they bite into a leaf, twitching their legs but unable to release themselves. After a few days, the fruit body of the fungus erupts from the head of the ant and discharges its filamentous spores (Figure 26). Characteristic bite marks have been found on 48 million-year-old fossilized leaves showing that this sophisticated relationship between fungi and ants is a very ancient form of parasitism.

  26. Ophiocordyceps unilateralis on rainforest ant.

  Allergens, hallucinogens, and poisons

  Fungi have adverse effects on animal health besides their role as pathogens. Asthma is a serious global health problem that affects 300 million people and is implicated in 250,000 deaths each year. Fungi are a significant cause of asthma. The frequency of asthma symptoms fluctuates in response to seasonal changes in the concentration of airborne spores, and hurricanes and other climatic events worsen the problem through their widespread effects on spore dispersal. Allergy to fungi results from interactions between the immune system and proteins carried on the surface of the commonest kinds of spores. Dendritic cells in the lungs process spore fragments in the same way that they handle pathogens, but the cascade of immunological reactions in people with allergies results in the release of histamine and other inflammatory compounds that produce the
symptoms of asthma and allergic rhinitis (called hay fever when it is seasonal).

  There has been a lot of anxiety, particularly in the United States, about the purported toxicity of fungi that grow in flooded homes. The spores of some of these indoor fungi, including a black-pigmented ascomycete called Stachybotrys chartarum, carry toxins that can cause a range of symptoms if they are absorbed in high concentrations. Most of the available evidence suggests that people that inhale spores of this fungus in water-damaged buildings are not exposed to levels of these mycotoxins that can cause illness. Nevertheless, the inhalation of large quantities of allergenic spores in these circumstances is a serious public health issue. Fungal growth inside buildings is indicated if the concentration of spores in indoor air exceeds the concentration measured in outdoor air on the same day. The detection of different kinds of fungi in indoor and outdoor air is another sign of the active growth of fungi inside buildings. Stachybotrys and the other microscopic fungi that can thrive in flooded buildings are referred to as indoor ‘moulds’, but this term, like ‘mildew’ and ‘toadstool’, has no precise scientific meaning.

  Ergotism, resulting from the consumption of rye bread contaminated with ergot, was a major threat to public health in the Middle Ages. The ergot fungus, Claviceps purpurea (Chapter 4), is an ascomycete pathogen that infects the flowers of cereals and replaces the seeds with hard black nuggets called sclerotia. Rye flour milled from infected crops was responsible for documented outbreaks of ergotism in France and other European countries between the 6th and 12th centuries. Symptoms of poisoning included severe burning sensations in the limbs due to the constriction of blood vessels, convulsions, and hallucinations. Gangrene resulting from vasoconstriction was often lethal and the affliction became known as St Anthony’s Fire. Ergotamine is one of the poisonous alkaloids in ergot. Ergotamine in combination with caffeine is prescribed as a treatment for migraine headaches today. Ergotamine is also used to synthesize lysergic acid, which is a precursor of the drug LSD or ‘acid’. The hallucinogenic effects of LSD were discovered in 1943 by Albert Hofmann who was investigating the pharmacological properties of ergot extracts. Another ergot alkaloid, ergometrine, is used to ease delivery of the placenta and to prevent bleeding after childbirth.