Fungi are a diverse and ubiquitous group of organisms, neither plant nor animal but with characteristics seen in both; they possess a cell wall but gain nutrients from external sources (are heterotrophic). In a kingdom of their own, fungi occupy many environmental niches and perform many beneficial services for humans, including the fermentation of bread, cheese, wine, and beer, as well as the production of penicillin. As many as a million species of fungi are known to exist, but only about 400 are potential agents of human disease. Infections may result from introduction of exogenous organisms due to injury or inhalation, or during host disruptions that allow endogenous organisms such as the commensals to induce disease. Since fungi are ubiquitous in our environment, widespread fungal infections are often a sign of reduced immune competence in the host. In these cases, fungal agents may penetrate mucosal barriers and gain access to extracellular spaces deeper in the body (see Overview Figure 17-3, regions M and E).
Fungal diseases, or mycoses, are classified on the basis of three criteria: the site of infection, the route of acquisition, and level of virulence. These criteria and their subcategories are described in Table 17-3. Cutaneous infections include attacks on skin, hair, and nails; examples are ringworm, athlete’s foot, and jock itch. Subcutaneous infections are normally introduced by trauma and accompanied by inflammation; when inflammation is chronic, extensive tissue damage may ensue. Deep mycoses involve the lungs, the central nervous system, bones, and the abdominal viscera. These infections can occur through ingestion, inhalation, or inoculation into the bloodstream. A very rare and deadly outbreak of fungal meningitis in 2012 was linked to Exserohilum rostratum, a fungal contaminant in a preparation of corticosteroids used in epidural steroid injections, most often used to treat chronic back and joint pain.
| Site of infection: | Superficial | Epidermis, no inflammation |
| Cutaneous | Skin, hair, nails | |
| Subcutaneous | Wounds, usually inflammatory | |
| Deep or systemic | Lungs, abdominal viscera, bones, CNS | |
| Route of acquisition: | Exogenous | Environmental, airborne, cutaneous, or percutaneous |
| Endogenous | Latent reactivation, commensal organism | |
| Virulence: | Primary | Inherently virulent, infects healthy host |
| Opportunistic | Low virulence, infects immunocompromised host |
Virulence types can be divided into primary, indicating the rare agents with high pathogenicity, and opportunistic, denoting weakly virulent agents that primarily infect individuals with compromised immunity. Most fungal infections of healthy individuals are resolved rapidly, with few clinical signs. The most commonly encountered and best-studied human fungal pathogens are Cryptococcus neoformans, Aspergillus fumigatus, Coccidioides immitis, Histoplasma capsulatum, and Blastomyces dermatitidis. Diseases caused by these fungi are named for the agent; for example, C. neoformans causes cryptococcosis and B. dermatitidis causes blastomycosis. In each case, infection with these environmental agents is aided by predisposing conditions that include AIDS, immunosuppressive drug treatment, and malnutrition.
Physical barriers and agents involved in innate immunity control infection by most fungi. The presence of commensal organisms also helps control the growth of potential pathogens. This has been demonstrated by long-term treatment with broad-spectrum antibiotics, which destroy normal mucosal bacterial flora and often lead to oral or vulvovaginal infection with Candida albicans, an opportunistic fungal agent. Phagocytosis by neutrophils is a strong defense against most fungi, and therefore people with neutropenia (low neutrophil count) are generally more susceptible to fungal disease.
Resolution of infection in normal, healthy individuals is often rapid and initiated by recognition of common fungal cell wall PAMPs by PRRs, especially those in the C-type lectin receptor (CLR) family. The three most immunologically relevant cell wall components include β-glucans (polymers of glucose), mannans (long chains of mannose), and chitin (a polymer of N-acetylglucosamine). The importance of certain PRRs for resolving fungal infection has been demonstrated by the increased susceptibility to mycoses seen in individuals with particular alleles at the relevant genetic loci. For instance, certain molecular variants of dectin-1, a C-type lectin receptor (see Chapter 4), are associated with chronic mucocutaneous candidiasis. Toll-like receptors 2, 4, and 9, as well as complement receptor 3 (CR3), are also involved in the innate response to fungi. In sum, recognition of these fungal cell wall components leads to the activation of complement (via both alternative and lectin pathways) along with the induction of phagocytosis and destruction of fungal cells. The key role of CR3, which recognizes complement deposited on the β-glucans of fungal cells, was confirmed by the fact that mortality from experimental infections of mice with Cryptococcus increased after an antibody to CR3 was administered.
Like other microbes, fungi have evolved mechanisms to evade the innate immune response. These include production of a capsule, as in the case of C. neoformans, which blocks PRR binding. Another evasion strategy employed by this organism involves fungi-induced expulsion from macrophages after phagocytosis. Because this does not kill host cells it avoids induction of inflammation and further activation of immunologic attention.
The most convincing demonstration of acquired immunity against any infectious agent is the presence of memory, or protection against subsequent attacks following an infection. This protection is not always obvious for fungal disease because primary infection often goes unnoticed. However, positive skin reactivity (secondary recall responses) against fungal antigens are one indicator of prior infection and the presence of memory. For instance, a granulomatous inflammation response, like that seen against M. tuberculosis, also controls the spread of C. neoformans and H. capsulatum in most individuals, indicating the presence of acquired cell-mediated immunity. However, also like tuberculosis, the infectious organism may remain in a latent state within the granuloma, reactivating if the host becomes immunosuppressed.
The presence of specific antibodies is another sign of prior exposure and lasting immunity, and antibodies against C. neoformans are commonly found in healthy subjects. However, probably the most convincing argument for pre-existing immunity against fungal pathogens comes from the frequency of normally rare fungal diseases in patients with compromised immunity. Patients with AIDS suffer increased incidence of mucosal candidiasis, histoplasmosis, coccidioidomycosis, and cryptococcosis. These observations in T cell–compromised patients with AIDS, and data showing that B cell–deficient mice have no increased susceptibility to fungal disease, are strong indications that cell-mediated rather than humoral mechanisms of adaptive immunity likely control most fungal pathogens.
Strong TH1 responses and the production of IFN-γ, important for optimal macrophage activation, are most commonly associated with protection against fungi. Conversely, TH2-cell and TREG-cell responses, or their products, are associated with susceptibility to mycoses. This is apparent in patients displaying distinct T helper responses to coccidioidomycosis, where TH1 immune activity is associated with a mild, asymptomatic infection and TH2 responses result in a severe and often relapsing form of the disease. Although the role for other cell types is less certain, recently a regulatory role for TH17 cells in controlling adaptive immunity against fungi has been postulated, where these cells are hypothesized to help support TH1-cell and discourage TH2-cell activation.