Virulence Factors of Eukaryotic Pathogens

Although fungi and parasites are important pathogens causing infectious diseases, their pathogenic mechanisms and virulence factors are not as well characterized as those of bacteria. Despite the relative lack of detailed mechanisms, the stages of pathogenesis and general mechanisms of virulence involved in disease production by these pathogens are similar to those of bacteria.

Fungal Virulence

Pathogenic fungi can produce virulence factors that are similar to the bacterial virulence factors that have been discussed earlier in this chapter. In this section, we will look at the virulence factors associated with species of Candida, Cryptococcus, Claviceps, and Aspergillus.

Candida albicans is an opportunistic fungal pathogen and causative agent of oral thrush, vaginal yeast infections, and cutaneous candidiasis. Candida produces adhesins (surface glycoproteins) that bind to the phospholipids of epithelial and endothelial cells. To assist in spread and tissue invasion, Candida produces proteases and phospholipases (i.e., exoenzymes). One of these proteases degrades keratin, a structural protein found on epithelial cells, enhancing the ability of the fungus to invade host tissue. In animal studies, it has been shown that the addition of a protease inhibitor led to attenuation of Candida infection (K. Fallon et al. “Role of Aspartic Proteases in Disseminated Candida albicans Infection in Mice.” Infection and Immunity 65 no. 2 (1997):551–556.). Similarly, the phospholipases can affect the integrity of host cell membranes to facilitate invasion.

The main virulence factor for Cryptococcus, a fungus that causes pneumonia and meningitis, is capsule production. The polysaccharide glucuronoxylomannan is the principal constituent of the Cryptococcus capsule. Similar to encapsulated bacterial cells, encapsulated Cryptococcus cells are more resistant to phagocytosis than nonencapsulated Cryptococcus, which are effectively phagocytosed and, therefore, less virulent.

Like some bacteria, many fungi produce exotoxins. Fungal toxins are called mycotoxins. Claviceps purpurea, a fungus that grows on rye and related grains, produces a mycotoxin called ergot toxin, an alkaloid responsible for the disease known as ergotism. There are two forms of ergotism: gangrenous and convulsive. In gangrenous ergotism, the ergot toxin causes vasoconstriction, resulting in improper blood flow to the extremities, eventually leading to gangrene. A famous outbreak of gangrenous ergotism occurred in the Rhine Valley in 857 AD (Source note: the source says this outbreak “occurred in Eastern Europe during the 5th century AD”; the earliest documented outbreak of gangrenous ergotism is the 857 AD outbreak in the Rhine Valley (Bové, “The History of Ergot of Rye I,” PubMed 19847980; Annales Xantenses).) due to the consumption of rye contaminated with C. purpurea. In convulsive ergotism, the toxin targets the central nervous system, causing mania and hallucinations.

The mycotoxin aflatoxin is a virulence factor produced by the fungus Aspergillus, an opportunistic pathogen that can enter the body via contaminated food or by inhalation. Inhalation of the fungus can lead to the chronic pulmonary disease aspergillosis, characterized by fever, bloody sputum, and/or asthma. Aflatoxin acts in the host as both a mutagen (a substance that causes mutations in DNA) and a carcinogen (a substance involved in causing cancer), and has been associated with the development of liver cancer. Aflatoxin has also been shown to cross the blood-placental barrier (C.P. Wild et al. “In-utero exposure to aflatoxin in west Africa.” Lancet 337 no. 8757 (1991):1602.). A second mycotoxin produced by Aspergillus is gliotoxin. This toxin promotes virulence by inducing host cells to self-destruct and by evading the host’s immune response by inhibiting the function of phagocytic cells as well as the pro-inflammatory response. Like Candida, Aspergillus also produces several proteases. One is elastase, which breaks down the protein elastin found in the connective tissue of the lung, leading to the development of lung disease. Another is catalase, an enzyme that protects the fungus from hydrogen peroxide produced by the immune system to destroy pathogens.

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Protozoan Virulence

Protozoan pathogens are unicellular eukaryotic parasites that have virulence factors and pathogenic mechanisms analogous to prokaryotic and viral pathogens, including adhesins, toxins, antigenic variation, and the ability to survive inside phagocytic vesicles.

Protozoans often have unique features for attaching to host cells. The protozoan Giardia lamblia, which causes the intestinal disease giardiasis, uses a large adhesive disc composed of microtubules to attach to the intestinal mucosa. During adhesion, the flagella of G. lamblia move in a manner that draws fluid out from under the disc, resulting in an area of lower pressure that facilitates adhesion to epithelial cells. Giardia does not invade the intestinal cells but rather causes inflammation (possibly through the release of cytopathic substances that cause damage to the cells) and shortens the intestinal villi, inhibiting absorption of nutrients.

Some protozoans are capable of antigenic variation. The obligate intracellular pathogen Plasmodium falciparum (one of the causative agents of malaria) resides inside red blood cells, where it produces an adhesin membrane protein known as PfEMP1. This protein is expressed on the surface of the infected erythrocytes, causing blood cells to stick to each other and to the walls of blood vessels. This process impedes blood flow, sometimes leading to organ failure, anemia, jaundice (yellowing of skin and sclera of the eyes due to buildup of bilirubin from lysed red blood cells), and, subsequently, death. Although PfEMP1 can be recognized by the host’s immune system, antigenic variations in the structure of the protein over time prevent it from being easily recognized and eliminated. This allows malaria to persist as a chronic infection in many individuals.

The virulence factors of Trypanosoma brucei, the causative agent of African sleeping sickness, include the abilities to form capsules and undergo antigenic variation. T. brucei evades phagocytosis by producing a dense glycoprotein coat that resembles a bacterial capsule. Over time, host antibodies are produced that recognize this coat, but T. brucei is able to alter the structure of the glycoprotein to evade recognition.

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Helminth Virulence

Helminths, or parasitic worms, are multicellular eukaryotic parasites that depend heavily on virulence factors that allow them to gain entry to host tissues. For example, the aquatic larval form of Schistosoma mansoni, which causes schistosomiasis, penetrates intact skin with the aid of proteases that degrade skin proteins, including elastin.

To survive within the host long enough to perpetuate their often-complex life cycles, helminths need to evade the immune system. Some helminths are so large that the immune system is ineffective against them. Others, such as adult roundworms (which cause trichinosis, ascariasis, and other diseases), are protected by a tough outer cuticle.

Over the course of their life cycles, the surface characteristics of the parasites vary, which may help prevent an effective immune response. Some helminths express polysaccharides called glycans on their external surface; because these glycans resemble molecules produced by host cells, the immune system fails to recognize and attack the helminth as a foreign body. This “glycan gimmickry,” as it has been called, serves as a protective cloak that allows the helminth to escape detection by the immune system (I. van Die, R.D. Cummings. “Glycan Gimmickry by Parasitic Helminths: A Strategy for Modulating the Host Immune Response?” Glycobiology 20 no. 1 (2010):2–12.).

In addition to evading host defenses, helminths can actively suppress the immune system. S. mansoni, for example, degrades host antibodies with proteases. Helminths produce many other substances that suppress elements of both innate nonspecific and adaptive specific host defenses. They also release large amounts of material into the host that may locally overwhelm the immune system or cause it to respond inappropriately.

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Summary

• Fungal and parasitic pathogens use pathogenic mechanisms and virulence factors that are similar to those of bacterial pathogens
• Fungi initiate infections through the interaction of adhesins with receptors on host cells. Some fungi produce toxins and exoenzymes involved in disease production and capsules that provide protection of phagocytosis.
• Protozoa adhere to target cells through complex mechanisms and can cause cellular damage through release of cytopathic substances. Some protozoa avoid the immune system through antigenic variation and production of capsules.
• Helminthic worms are able to avoid the immune system by coating their exteriors with glycan molecules that make them look like host cells or by suppressing the immune system.

Key terms

• mycotoxin — biologically active product of pathogenic fungi that causes adverse changes in the host cells.
• carcinogen — agent that causes cancer.

Practice

Describe virulence factors unique to fungi and parasites

Compare virulence factors of fungi and bacteria

Explain the difference between protozoan parasites and helminths

Describe how helminths evade the host immune system

This section is adapted from Microbiology, Section 15.4: Virulence Factors of Eukaryotic Pathogens by Nina Parker, Mark Schneegurt, Anh-Hue Thi Tu, Philip Lister, Brian M. Forster, and OpenStax, © OpenStax, licensed under CC BY-NC-SA 4.0. Access the original for free at openstax.org. Changes: this module has no figures and no feature boxes; nothing was vendored or rendered as a callout. All six of the module’s Multiple Choice, Fill in the Blank, and Short Answer exercises reach a Practice item: both Multiple Choice items keep their source order, options, and keys; both Fill in the Blank items are rendered as textin with their printed keys (“protease and phospholipase,” an unordered pair whose accept list carries the reversed order (grading already folds the comma, so only the reversed-order spellings are listed); “protease”); both unkeyed Short Answer questions are selfchecks in Practice — the Aspergillus virulence-factors question (no single sentence answers it — the module names four separate factors across several sentences) and the helminth immune-evasion question “Explain how helminths evade the immune system” (its model answer and rubric cover all four of the module’s mechanisms: size, tough cuticle, glycan surface mimicry, and active suppression such as S. mansoni’s antibody-degrading proteases). This Short Answer’s stem is close to the body Check Your Understanding bullet “Describe how helminths avoid being destroyed by the host immune system,” but the two are rendered as separate items, per the rule that no source exercise is ever dropped or folded: the body bullet is a multiplechoice keyed narrowly to the module’s own glycan-mimicry sentence, with three distractors built from this module’s own fungal and protozoan mechanisms (Cryptococcus’s capsule, T. brucei’s antigenic variation, Aspergillus’s gliotoxin), none of which the module ever attributes to helminths, while the Short Answer’s selfcheck covers the full breadth of the question. Of the module’s four body Check Your Understanding bullets, three (both fungal-section bullets and the one protozoan-section bullet) are selfchecks with model answers and rubrics assembled only from this module’s own sentences — none is answerable from a single sentence — and the fourth (helminth section) is the graded multiplechoice described above. The ## Practice block holds 15 items across the section’s four objectives (floor: 12), because the source exercise set alone (six items) falls well short of the floor: nine items are author-written from this module’s own sentences to fill the “compare fungi and bacteria” and “protozoan versus helminth” objectives, which the source’s exercise sets do not test directly — the mycotoxin/exotoxin analogy, the Cryptococcus-capsule/phagocytosis analogy, and the opening paragraph’s “similar to bacteria” cloze (Compare virulence factors of fungi and bacteria); a true/false item on unicellular versus multicellular cellularity, an item on which parasite group survives inside phagocytic vesicles, and a selfcheck comparing protozoan antigenic variation with the helminth section’s several evasion strategies (Explain the difference between protozoan parasites and helminths); and an item on S. mansoni’s antibody-degrading proteases, an item on helminths overwhelming the immune system with released material, and a selfcheck on a helminth’s size and tough cuticle (Describe how helminths evade the host immune system) — none of these nine duplicates the module’s own Check Your Understanding or Short Answer questions, and each is traced in the source ledger to the single sentence it is built from. ## Key terms is compiled from the module’s two defined terms (mycotoxin, carcinogen); both definitions are taken verbatim from the book’s Glossary appendix, and neither is sentence-derived. Footnotes: all three of the module’s footnotes are rendered as inline parenthetical citations after the sentences they support, author names, titles, journals, volumes, issues, years, and pages kept verbatim; none carries a bare access URL or a DOI. No cross-references to other sections or modules appear in this module — confirmed by a direct grep of the CNXML for <link (zero matches), so the parent’s run-wide cross-reference-routing rule has nothing to apply to here. No one-word source typos. One claim-pass correction (erratum 610): the source dates the famous gangrenous-ergotism outbreak to “Eastern Europe during the 5th century AD,” but the earliest documented outbreak is the 857 AD outbreak in the Rhine Valley (Bové, “The History of Ergot of Rye I,” PubMed 19847980; Annales Xantenses); the page reads “the Rhine Valley in 857 AD” with the source’s wording noted beside it. No item, hint, or model answer on the page depends on the outbreak’s date or location.