The Inhabited Body
Companion Primer

Primer Chapter 4: The Fungal Kingdom — Your Closest Strangers

This chapter is part of the companion primer to The Inhabited Body. It introduces the kingdom Fungi — what they are, how they live, how they differ from bacteria, plants, and animals, and why their biology matters for understanding the human mycobiome. Later chapters in the main book will explore their specific roles at different body sites.

Not a Plant, Not an Animal

For most of recorded history, fungi were classified as plants. It is easy to see why. Mushrooms sprout from the ground. Moulds grow on bread. Neither runs away when you approach. Carl Linnaeus, who gave us modern taxonomy, placed fungi firmly in the plant kingdom in the eighteenth century, and there they remained for the better part of two hundred years.

This was a mistake — and not a small one.

Fungi do not photosynthesise. They have no chloroplasts, no chlorophyll, no capacity whatsoever to capture energy from sunlight. Every fungus that has ever lived has obtained its energy by breaking down organic matter produced by other organisms — or, in some cases, by directly parasitising a living host. In this sense, fungi eat more like animals than they grow like plants.

But the most surprising correction came from molecular biology. When researchers in the 1990s began comparing DNA sequences across the major kingdoms of life, they discovered something that upended centuries of intuition: fungi are more closely related to animals than they are to plants [baldauf1993?]. You share a more recent common ancestor with the mould on your shower curtain than that mould shares with the grass in your garden.

The evidence for this relationship is now overwhelming. Fungi and animals both belong to a supergroup of eukaryotic life called the Opisthokonta — named for the single, rear-mounted flagellum (from the Greek opisthen, "behind," and kontos, "pole") found in the swimming cells of ancestral members of the group [REF:cavalier-smith1987]. Chytrid fungi still produce flagellated spores that swim with this characteristic posterior tail. Animal sperm cells do the same. Plants, by contrast, belong to an entirely different branch of the eukaryotic tree.

The last common ancestor of animals and fungi is estimated to have lived roughly one billion years ago, most likely as a single-celled, flagellated organism in an aquatic environment [parfrey2011?]. From that shared starting point, the two lineages diverged spectacularly — one branch developing nervous systems, muscles, and internal skeletons; the other evolving into networks of filaments that digest the world from the outside in. But at the molecular level, the kinship is still visible. Fungi and animals share key metabolic enzymes, signalling pathways, and gene families that are absent in plants. Both store surplus energy as glycogen rather than starch. And both build important structural molecules from chitin — in fungi, it forms the cell wall; in animals, it forms the exoskeletons of insects and crustaceans.

This evolutionary closeness has a practical consequence that matters enormously for medicine: because fungal cells are biochemically similar to animal cells, it is much harder to develop drugs that kill fungi without also harming the patient. Antibacterial drugs exploit the many differences between bacterial and human cells — different ribosomes, different cell wall chemistry, different membrane structures. Antifungal drugs have far fewer differences to exploit. This is one of the reasons that fungal infections remain disproportionately difficult to treat, particularly in immunocompromised patients, and why the repertoire of clinically available antifungal drugs is so much smaller than the antibiotic arsenal.

What Is a Fungus?

Defining "fungus" with a crisp one-sentence definition is harder than it sounds, because the kingdom encompasses an extraordinary range of forms. But most true fungi share a recognisable set of features.

They are eukaryotes. Like animal and plant cells, fungal cells have a nucleus enclosed by a membrane, along with other membrane-bound organelles including mitochondria and an endoplasmic reticulum. This places them squarely in the domain Eukarya, alongside all the other complex-celled organisms, and distinguishes them from the bacteria and archaea that dominate the rest of the microbiome.

They have cell walls made of chitin and glucan. This is one of the defining chemical signatures of the kingdom. Plant cell walls are built from cellulose; bacterial cell walls are built from peptidoglycan. Fungal cell walls are built from a scaffold of chitin (a tough polymer of N-acetylglucosamine — the same molecule found in crab shells) reinforced with β-glucans (polymers of glucose with characteristic β-1,3 linkages) and coated with a layer of mannoproteins [gow2017?]. The cell wall typically accounts for about 40 per cent of the total cell volume — it is not a thin skin but a massive, load-bearing structure that protects the cell from osmotic stress and environmental insult.

Think of it as a building analogy: the chitin fibres are the steel reinforcing bars; the β-glucan matrix is the concrete that surrounds them; and the mannoprotein coat is the painted plaster on the outside. Together, they create a structure that is rigid enough to maintain shape, yet flexible enough to allow growth.

They are heterotrophs. Fungi cannot make their own food. They obtain carbon and energy by secreting digestive enzymes into their environment and then absorbing the resulting small molecules across their cell membranes — a strategy called absorptive nutrition (sometimes called osmotrophy). In effect, fungi digest their food externally before absorbing it, which is the reverse of what animals do: we swallow first and digest later. A useful analogy is to imagine dissolving your meal in acid outside your body and then soaking up the nutrients through your skin.

Their membranes contain ergosterol. Animal cell membranes use cholesterol to regulate membrane fluidity and stability. Fungal membranes use a related but structurally distinct molecule called ergosterol [REF:naranjo-ortiz2019]. This difference is one of the few biochemical handles that antifungal drugs can grip: the azole class of antifungals (fluconazole, voriconazole, itraconazole) works by blocking the enzyme that synthesises ergosterol, destabilising the fungal membrane while leaving human cholesterol production largely intact. The polyene antifungal amphotericin B goes further — it binds directly to ergosterol molecules in the membrane, punching holes that cause the cell to leak and die. The specificity is imperfect, however, which is why amphotericin B is notorious among clinicians for its toxicity: at high doses, it can also interact with human cholesterol, damaging kidney and liver cells. The old clinical nickname for the drug — "ampho-terrible" — reflects this narrow therapeutic window.

Shape-Shifters: Yeasts, Moulds, and Mushrooms

Fungi come in three basic body plans, but many species can switch between them depending on environmental conditions — a flexibility that is central to their success, both as ecological recyclers and as human pathogens.

Yeasts

Yeasts are single-celled fungi. Each cell is a small, rounded or oval unit, typically 3 to 10 micrometres in diameter — larger than most bacteria, but still microscopic. Yeasts reproduce primarily by budding: a small daughter cell grows as an outgrowth from the mother cell, gradually enlarging until it pinches off and becomes independent. Some yeasts can also reproduce sexually, forming spores under specific environmental conditions.

The most familiar yeast is Saccharomyces cerevisiae — baker's yeast, brewer's yeast — the organism that gives bread its rise and beer its alcohol. It was also the first eukaryotic organism to have its entire genome sequenced, in 1996, making it one of the most thoroughly studied organisms in biology [goffeau1996?]. But in the context of the human microbiome, the yeasts that matter most are different species: Candida albicans, a commensal resident of the gut and mucous membranes that can become an aggressive pathogen when the immune system falters; Malassezia, the dominant fungal genus on human skin; and Saccharomyces boulardii, a yeast that has been studied as a probiotic — though as we will discuss in the main book, the evidence base for fungal probiotics is considerably thinner than the marketing suggests.

Moulds

A mould is a fungus that grows as a network of branching, thread-like filaments called hyphae (singular: hypha). Each hypha is a cylindrical tube, typically only a few micrometres wide, enclosed by a rigid cell wall. As the hypha grows — always at its tip — it extends into new territory, secreting enzymes ahead of itself to digest whatever substrate it is growing on. When many hyphae branch and interweave, they form a tangled mat called a mycelium (plural: mycelia), which is the main body of the organism.

A mycelium can be enormous. The largest known organism on Earth is a single individual of Armillaria solidipes (the honey fungus) in Oregon's Blue Mountains, whose mycelium extends over roughly 9 square kilometres and is estimated to be several thousand years old. What you see when you spot a mushroom in the forest is not the organism itself — it is a temporary reproductive structure, like a flower on a plant. The real organism is the vast, hidden mycelium beneath the soil.

In the human body, the moulds of greatest medical importance include Aspergillus species (particularly Aspergillus fumigatus, a major cause of invasive pulmonary aspergillosis in immunocompromised patients), Mucor and Rhizopus (agents of the devastating infection mucormycosis, which gained worldwide attention during the COVID-19 pandemic), and various Fusarium species.

Mushrooms

Mushrooms are the large, visible fruiting bodies produced by certain fungi — specifically, by members of the phyla Basidiomycota and some Ascomycota — for the purpose of sexual reproduction and spore dispersal. The cap-and-stem structure that most people picture when they think of a mushroom is essentially a sophisticated spore-launching platform. Some mushrooms release billions of spores per day, carried by air currents to colonise new habitats.

Mushrooms are not significant members of the human microbiome. We mention them here only to complete the picture of fungal diversity and to make a point: the kingdom Fungi is much more than the moulds and yeasts that colonise the human body. It includes organisms that range from single-celled yeasts a few micrometres across to mycelial networks that span kilometres — a range of scale that rivals anything in the animal or plant kingdoms.

Dimorphism: The Switch

Some of the most clinically important fungi are dimorphic — they can switch between a yeast form and a mould form depending on their environment. Candida albicans, the most common fungal pathogen of humans, is a textbook example. In its yeast form, C. albicans exists as harmless, rounded, budding cells on the mucosal surfaces of the gut, mouth, and vagina. But when conditions change — a shift in pH, a weakened immune response, a disruption of the competing bacterial community — it can switch to a hyphal form, extending invasive filaments that penetrate tissue, evade immune cells, and cause disease [sudbery2004?].

This morphological switching is not merely a change of shape. It is accompanied by changes in gene expression, surface proteins, and virulence factors. The hyphal form expresses adhesins that help it stick to human cells, secretes enzymes that degrade tissue, and forms biofilms — structured microbial communities encased in a self-produced matrix — on medical devices such as catheters and prosthetic heart valves. Understanding what triggers the yeast-to-hypha transition, and how to prevent it, remains one of the central questions in medical mycology.

How Fungi Feed: Decomposers, Mutualists, and Parasites

The way an organism obtains its food determines its ecological role. Fungi fall into three broad nutritional strategies, and understanding these helps explain why they are found in almost every habitat on Earth — including the human body.

Saprotrophs: The Recyclers

Most fungi are saprotrophs (from the Greek sapros, "rotten") — they decompose dead organic matter. Fallen leaves, dead wood, animal carcasses, food scraps: saprotrophic fungi secrete cocktails of powerful enzymes — cellulases, ligninases, proteases, lipases — that break down complex organic molecules into simpler compounds that the fungus can absorb. Without saprotrophic fungi, dead plant material would accumulate indefinitely and the global carbon cycle would grind to a halt. Fungi are the only organisms on Earth that can efficiently decompose lignin, the tough structural polymer that gives wood its rigidity. Before fungi evolved this ability — roughly 300 million years ago — dead trees simply piled up rather than rotting. This is the period that gave us the vast coal deposits of the Carboniferous era.

Mutualists: The Partners

Some fungi form intimate partnerships with other organisms from which both partners benefit. The most ecologically important of these are the mycorrhizae (from the Greek myco, "fungus," and rhiza, "root") — associations between fungi and plant roots that have existed for at least 450 million years, since the earliest land plants colonised the terrestrial environment. In a mycorrhizal partnership, the fungal mycelium extends into the soil far beyond the reach of the plant's own roots, absorbing water and mineral nutrients (particularly phosphorus) and delivering them to the plant. In return, the plant provides the fungus with sugars produced by photosynthesis. The vast majority of land plants — roughly 90 per cent of species — form mycorrhizal associations, and many cannot survive without them.

Lichens are another form of mutualism: composite organisms formed by a fungus (usually an ascomycete) living in intimate association with a photosynthetic partner — either a green alga or a cyanobacterium. The fungus provides structure and protection; the photosynthetic partner provides food. Lichens can colonise bare rock, arctic tundra, and desert surfaces where neither partner could survive alone.

In the human body, the relationships between fungi and their host are more complex and ambiguous — often described as commensalism (the fungus benefits; the host is apparently unaffected) rather than true mutualism. Whether gut fungi actively benefit their human hosts — for example, by training the immune system or competing with pathogens — is an active area of research that we will examine in Chapter 10 of the main book.

Parasites and Pathogens

Some fungi obtain their nutrition from living hosts, causing disease in the process. Fungal pathogens infect plants, insects, amphibians, and mammals. In humans, fungal infections range from superficial and merely annoying (athlete's foot, ringworm, dandruff) to invasive and life-threatening (invasive aspergillosis, disseminated candidiasis, cryptococcal meningitis).

Globally, fungal diseases are estimated to kill more than 1.5 million people each year — a toll that rivals tuberculosis and exceeds malaria in some estimates — yet they receive a fraction of the research funding and public attention [bongomin2017?]. This neglect is slowly changing, in part because the COVID-19 pandemic brought fungal superinfections — particularly mucormycosis in India and invasive aspergillosis in intensive care patients — to sudden and devastating public visibility.

Fungal Reproduction: Spores, Sex, and Survival

Fungi reproduce by both asexual and sexual means, and many species alternate between the two depending on environmental conditions. Understanding the basics of fungal reproduction helps explain why fungi are so successful at colonising new environments, including the human body.

Asexual Reproduction

Most fungi can reproduce asexually — that is, without the genetic mixing that comes from sex. The simplest method is budding, as seen in yeasts: a new cell simply grows from the surface of an existing one. In filamentous fungi, asexual reproduction more commonly involves the production of spores — tiny, lightweight cells that are released into the environment and can survive hostile conditions until they find a suitable place to germinate and grow.

Asexual spores come in various forms. Aspergillus produces chains of spores called conidia (singular: conidium) at the tips of specialised structures, releasing thousands of them into the air. A single Aspergillus fumigatus colony can produce billions of conidia, and every human being inhales several hundred of them each day. In healthy individuals with intact immune systems, these spores are cleared by alveolar macrophages in the lungs without incident. In patients whose immune systems are compromised — by chemotherapy, organ transplantation, high-dose corticosteroids, or advanced HIV — the spores can germinate in lung tissue, producing invasive hyphae that destroy the surrounding parenchyma.

Sexual Reproduction

Sexual reproduction in fungi involves the fusion of genetic material from two compatible individuals, producing offspring with new genetic combinations. The details vary enormously across the kingdom, but the general pattern involves three steps: first, the fusion of two cells (plasmogamy); then, the fusion of their nuclei (karyogamy); and finally, meiosis — the reductive cell division that shuffles the genetic deck and produces haploid spores.

For the non-specialist reader, the key takeaway is this: sexual reproduction generates genetic diversity, which helps fungal populations adapt to new challenges — including, in the clinical setting, the selective pressure of antifungal drugs. Drug-resistant strains of Candida auris, which has emerged as a globally significant pathogen in the last decade, owe some of their adaptability to mechanisms of genetic exchange and recombination [lockhart2017?].

The Major Phyla: A Brief Tour

The kingdom Fungi is currently divided into approximately 19 phyla, a number that continues to shift as molecular phylogenetics reveals new relationships [tedersoo2018?]. For the purposes of this primer, we will focus on the groups most relevant to human biology.

Ascomycota — The Sac Fungi

The Ascomycota is the largest phylum of fungi, containing roughly 64,000 described species — more than half of all named fungi. The name comes from the ascus (plural: asci), a sac-like structure in which sexual spores are produced. This is an enormously diverse group. It includes yeasts (Saccharomyces, Candida, Pichia), moulds (Aspergillus, Penicillium, Fusarium), the organisms that produce truffles and morels, and most lichen-forming fungi.

For the human microbiome, the Ascomycota is the most important phylum. Candida albicans and its relatives, Aspergillus fumigatus, and Pneumocystis jirovecii (the cause of a devastating pneumonia in AIDS patients — itself an organism that was misclassified as a protist until molecular studies placed it firmly among the ascomycetes) are all members of this group.

Basidiomycota — The Club Fungi

The Basidiomycota contains roughly 32,000 described species and includes most of the organisms that produce conspicuous mushrooms, bracket fungi, and puffballs. The name comes from the basidium (plural: basidia), a club-shaped structure on which sexual spores are produced.

In the human microbiome, the most significant basidiomycete is Malassezia — a genus of lipid-dependent yeasts that dominate the fungal community on human skin. Malassezia is associated with seborrhoeic dermatitis, dandruff, pityriasis versicolor, and may play a role in atopic eczema. Despite being one of the most abundant organisms on the human body surface, Malassezia was historically difficult to study because its strict requirement for exogenous lipids made it hard to grow in standard laboratory culture media — another example of how technical limitations have shaped what we know about the microbiome. The genus Cryptococcus, which causes cryptococcal meningitis (a leading killer of people with advanced HIV infection), is also a basidiomycete.

The "Basal" Lineages

Below the Ascomycota and Basidiomycota (which together form a clade called the Dikarya, meaning "two nuclei," because their cells often contain two genetically distinct nuclei for a period before sexual fusion), there are a number of earlier-diverging fungal lineages. These include the Mucoromycota (which contains the agents of mucormycosis — Mucor, Rhizopus, Rhizomucor) and the Chytridiomycota (aquatic fungi that retain the ancestral posterior flagellum). These groups are less frequently encountered in the human microbiome but are not absent from it, and the mucormycosis agents can cause catastrophically aggressive infections in diabetic and immunocompromised patients.

The Cell Wall as a Battleground

We return to the fungal cell wall — not because it is architecturally interesting (though it is) but because it is the primary interface between the fungus and the human immune system, and the principal target of most antifungal drugs. Understanding its structure helps explain both how our bodies detect fungal invaders and why treating fungal infections is so difficult.

The immune system detects fungi primarily through pattern recognition receptors on the surface of innate immune cells — macrophages, dendritic cells, and neutrophils. The most important of these, for fungi, is a receptor called Dectin-1, which recognises the β-1,3-glucan that forms the structural core of the fungal cell wall [brown2006?]. When Dectin-1 binds β-glucan, it triggers a cascade of inflammatory signals that recruit more immune cells and activate antifungal killing mechanisms. A related receptor, Dectin-2, recognises mannan structures on the outer surface of the wall.

But here is the catch: in many pathogenic fungi, the β-glucan layer is hidden beneath the outer coat of mannoproteins. This masking means that the immune system's primary sensor cannot see the target. Candida albicans, for instance, actively remodels its cell wall surface to conceal its β-glucan from Dectin-1, and only certain conditions — damage to the wall, exposure to antifungal drugs, or the probing of neutrophil enzymes — strip away the masking layer and expose the glucan underneath. This is a form of immune evasion, and it explains, in part, why some fungal infections are so difficult for the body to control.

The clinical classes of antifungal drugs map neatly onto the cell wall and membrane:

Notice that three of these four classes — azoles, allylamines, and polyenes — all converge on the same molecular target: ergosterol. They simply attack it at different points (synthesis versus the finished molecule in the membrane). Only the echinocandins target something entirely different (the cell wall glucan). That is essentially the entire clinical toolkit for systemic and serious fungal infections — four classes of drugs, but really only two molecular targets (ergosterol and β-glucan). Compare this to the dozens of antibiotic classes available for bacterial infections, and the vulnerability of the antifungal arsenal becomes starkly apparent. The recent emergence of Candida auris — a multidrug-resistant yeast first identified in 2009 that can resist all three classes simultaneously — has been described by public health agencies as a serious and urgent threat [lockhart2017?].

How Many Fungi? And How Little We Know

How many fungal species exist on Earth? As with bacteria, the honest answer is that we do not know. Current estimates range from 2.2 to 3.8 million species, with some analyses using environmental DNA data suggesting the number could be as high as 12 million [hawksworth2017?]. As of 2024, roughly 155,000 species have been formally described — meaning that somewhere between 92 and 97 per cent of all fungal species have never been given a name [hawksworth2017?].

This matters for the human microbiome because when researchers sequence fungal DNA from human body sites using ITS amplicon sequencing (the fungal equivalent of the bacterial 16S approach, as discussed in Chapter 4 of the main book), a substantial proportion of the sequences they recover cannot be confidently matched to any known species. The fungal reference databases — primarily UNITE (a curated database of ITS sequences) — are less complete than their bacterial counterparts, and the gap is closing slowly. The human mycobiome is still, in many respects, a partially mapped territory.

Why This Matters for the Microbiome Story

The key messages of this primer chapter — the ones to carry forward into the main book — are these:

Fungi are eukaryotes, not bacteria. They are vastly more complex at the cellular level than the bacteria that dominate most microbiome discussions. They have nuclei, organelles, and genomes that are orders of magnitude larger. They are, in evolutionary terms, our distant relatives.

Fungi are biochemically similar to human cells. This makes them hard to kill selectively — a fact that shapes every aspect of antifungal medicine.

The fungal cell wall is both a shield and a signal. Its β-glucan and chitin content defines the kingdom, provides the target for the major antifungal drugs, and serves as the primary molecular pattern by which the immune system detects fungal presence.

Most fungal diversity is undescribed. Our ability to identify and understand the fungi in the human body is limited by reference databases that are still under construction.

Fungi are a minority by numbers but not by influence. In most human body sites, fungi represent less than 0.1 per cent of the total microbial community by cell count. But their cells are much larger than bacterial cells, they interact with bacteria through cross-kingdom signalling, and they expand rapidly into niches vacated by bacteria during antibiotic therapy. Their influence on human health is disproportionate to their census numbers — a theme we will return to, at length, in Chapter 10.

In the next primer chapter, we will turn to the viruses — entities that are not cells at all, yet profoundly shape every microbial community in and on the human body.

References Cited in This Chapter

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