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Toxins are microbial substances that are able to induce damage to host cells, an immunogenic or allergic response, and/or fever. Fever is an abnormal rise in body temperature often associated with acute microbial infections. As toxins are released from the microorganism, either during normal cell metabolism or on cell death, they can have dramatic effects on a susceptible host away from the actual site of infection or microbial growth; in some cases, the toxins can remain present despite the removal or inactivation of the microorganism. Although many toxins may be inactivated by various biocidal processes used to control microorganisms, in some cases toxins are considered heat and/or chemical resistant and require special consideration.

Many toxins are potent poisons and are important factors in the pathogenic nature of bacteria, fungi, and algae (Table 1.15).

Many toxins are macromolecules, in particular, proteins, polysaccharides, and LPSs, but can also include chemical toxins, as in the cases of many fungal and algal toxins. They can be classified in many ways, including by their sites of activity (e.g., neurotoxins, affecting neural tissue, and enterotoxins, affecting the small intestine), their structures, and their mechanisms of action.

TABLE 1.15 Examples of bacterial, fungal, and algal toxins

Toxin class and producing microorganism	Toxin	Effect or disease
Bacterial exotoxins
Campylobacter jejuni	Enterotoxin, cytotoxin	Food-borne illness; cell toxicity
Clostridium botulinum	Neurotoxins	Paralysis (relaxed muscles); botulism
Clostridium tetani	Neurotoxin	Paralysis (tensed muscles); tetanus
Escherichia coli (some entero-pathogenic strains)	Enterotoxins	Food poisoning, including diarrhea
Bacillus anthracis	Three-protein-component toxin (protective antigen, lethal factor, and edema factor)	Anthrax
Vibrio cholerae	Enterotoxin	Cholera
Corynebacterium diphtheriae	Two-protein-component toxin	Diphtheria
Bacterial endotoxins
Escherichia coli, Shigella, Salmonella	Endotoxin	Fever, diarrhea, inflammation
Fungal toxins
Aspergillus flavus	Aflatoxins	Hepatic disease and known carcinogens; often associated with contaminated foods and feeds
Penicillium rubrum	Rubratoxins	Liver and kidney toxicity; often associated with contaminated foods and feeds
Stachybotrys spp.	Mycotoxins (e.g., trichothecenes)	Respiratory effects, headaches, flu-like illness, allergic reactions; associated with water-damaged buildings
Algal toxins
Gonyaulax	Saxitoxins	Food-borne illness (associated with shellfish)
Microcystis	Hepatoxins	Liver damage; associated with contaminated water

Bacterial toxins are categorized as exotoxins when they are actively produced and released from the bacterial cell during growth and as endotoxins when they are a normal part of the cell wall structure but are toxic when released following damage to the cell wall or on cell death.

The most widely studied bacterial exotoxins are proteins (ranging in size from 50 to 1,000 kDa) that are released from actively growing gram-positive and gram-negative bacteria. As proteins, they are generally heat sensitive, although some have been shown to survive heat treatment processes. Many exotoxins are potent poisons at relatively low concentrations and are important virulence factors in bacterial diseases, such as anthrax, tetanus, cholera, and food poisoning. Their toxic effects can include cell damage (AB toxins), cell lysis (cytotoxic toxins), and an inflammatory response (superantigen toxins). Examples of exotoxins and their effects on host cells are given in Table 1.16.

By definition, endotoxins can be any cell-bound toxin that is released upon cell damage or cell death, although the term is generally used to refer to the LPS component of the cell walls of gram-negative bacteria, including E. coli, Salmonella, Shigella, and Pseudomonas (see section 1.3.4.1). LPS contains a lipid portion (known as lipid A) that forms part of the external surface of the outer membrane, which is linked to an external polysaccharide (containing a core and an O-polymer of sugars) (Fig. 1.15). The exact fatty acid and sugar structures of LPS vary among gram-negative species. In general, the polysaccharide can contain various types of sugars and the lipid A portion consists of fatty acids attached to a disaccharide of N-acetylglucosamine phosphate.

TABLE 1.16 Common examples of bacterial exotoxins

Type	Example	Microorganism	Effects
AB toxins (component toxins that cause cell damage)	Diphtheria toxin	Corynebacterium diphtheriae	Inhibition of protein synthesis
Tetanus and botulism toxins	Clostridium tetani, Clostridium botulinum	“Neurotoxins”; block neurotransmitters
Cholera toxin	Vibrio cholerae	“Enterotoxin”; secretion of fluids from small intestine
Cytotoxic toxins (cause cell lysis)	α, β, and γ toxins	Corynebacterium perfringens	Cell lysis, including damage to cell membrane
α toxin	Staphylococcus aureus	Cell lysis
Superantigen toxins (cause an immunological response and inflammation)	Toxic shock syndrome toxin	Staphylococcus aureus	Septic shock
Erythrogenic toxin	Streptococcus pyogenes	Scarlet fever rash

Endotoxins can have a variety of biological activities when introduced directly into the blood and are therefore an important consideration in various pharmaceutical, medical-device, and water purification applications. LPS is pyrogenic (fever causing) and induces an inflammatory response, which can lead to septic shock, diarrhea, and, under some circumstances, death. The polysaccharide component is considered responsible for fever and inflammation, while the lipid A component is linked to the toxicity effect on host cells. Overall, the toxic effects of LPS are considered to be less than those of exotoxins. Endotoxins are notably heat resistant.

FIGURE 1.15 The general structure of lipopolysaccharide. The lipid A component is integrated into the outer membrane of the gram-negative cell wall, with the polysaccharide portion extending to the outside of the cell.

Mycotoxins are produced by fungi, in particular, molds like Aspergillus, Fusarium, Stachybotrys, Penicillium, and Chaetomium. They are usually produced during the late exponential and/or stationary phase of growth and, like other secondary metabolites (e.g., antibiotics), provide competitive advantages to the fungus in its environment. They can be associated with the vegetative mold, its spores, or surrounding mold growth. Most of these toxins are chemical in nature, and they include aflatoxins, ochratoxins, trichothecenes, and gliotoxins; an example of a fungal aflatoxin is shown in Fig. 1.16.

FIGURE 1.16 Typical fungal aflatoxin structure.

Mycotoxins also have multiple effects on target cells, including membrane damage, cell death, and free-radical damage. Aflatoxins have been particularly associated with food and feed (grain) contamination and have been shown to be carcinogenic. Some fungal cell wall components (like β-1,3-glucan) are also considered toxins and can cause allergic reactions, including coughing and other respiratory effects.

Many algae also produce toxins, which are often associated with contaminated water. These include hepatoxins (in particular, from blue-green algae), neurotoxins, cytotoxins, and endotoxins (similar to gram-negative bacteria, the LPS from the outer membrane of the algal cell wall).