Endotoxin And Exotoxin – What Are The Definitions And Differences?

Microbiomes are found in literally every area of our planet, in our lives, both inside and outside of our bodies. 

These microbiomes are capable of producing toxins that are a huge reason for infections. There are two different categories of these toxins- Endotoxins and Exotoxins. 

These toxins vary dramatically in their danger to us and their toxicity levels. Exotoxins are often the most deadly in many cases compared to endotoxins. In simple terms, the main difference between these two toxins is how bacteria produce them. 

In this article, we will be discussing the definition of both endotoxins and exotoxins, along with a more in-depth discussion of the major differences between these two. 

What Are Endotoxins? Definition

Mainly produced by Gram-negative bacteria, endotoxins are toxins that have escaped from the exterior cell wall of a bacteria after the bacteria has died. These intricate compounds can be toxic to varying degrees. 

Endotoxins are also known as lipopolysaccharides (LPS) and are among the most typical pyrogens. A pyrogen is any substance that has the possibility of causing a fever. 

The term ‘endotoxin’ was first coined in the 1890s by Richard Pfeiffer during his research into the Vibrio cholera bacterium- the bacteria that is responsible for cholera.

He discovered during his research that the toxin was produced in the wall of the bacteria cell, and when the bacteria was killed the toxin remained. 

An LPS, or endotoxin, is responsible for the organization and construction of the cell wall in gram-negative bacteria and is part of its outer membrane. Endotoxins are made up of 

a hydrophilic (water dissolvable) polysaccharide and a hydrophobic (water repellent) segment. This hydrophobic component is also known as lipid A or a lipid moiety. 

Whilst these LPS are parts of the outer wall of the gram-negative bacteria, they are synthesized inside the bacterial cell in the cytoplasmic matrix, also known as the cytosol. 

Once synthesized, they are carried to the cell membrane. 

Within an endotoxin, the polysaccharide is linked to the hydrophobic lipid A, and lipid A is what is responsible for the toxic effects. 

What Are The Symptoms Of Endotoxins?

Listed below are some examples of the symptoms caused by exposure to airborne endotoxins: 

• Fever
• Septic Shock
• Nausea
• Hypotension
• Shivering
• Cough
• Shortness of breath
• Wheezing
• Chest tightness

These key signs and symptoms differ massively depending on exposure levels, period of exposure, the overall health of the person affected, and what particular endotoxin it was.

Some people who are exposed to the same endotoxin for example may just get a wheezing chest, whilst another person who has acute exposure could suffer from a high fever and septic shock. 

Different endotoxins are varied due to the different chemical structures of the gram-negative bacteria that they are found in. This structure of the endotoxin greatly affects the level of toxicity.  

What Are The Two Types Of Endotoxins?

The word endotoxin is used to describe a pyrogen that is produced by gram-negative bacteria, a pyrogen being any substance that has the possibility of causing a fever.

Another term that is commonly used in lieu of endotoxin is lipopolysaccharide. 

Endotoxins can be found in the outer walls of various bacteria such as E.coli, Salmonella shigella, and Haemophilus influenzae. 

The endotoxins or lipopolysaccharides can be divided into two principal categories: smooth lipopolysaccharides, and rough lipopolysaccharides. 

Smooth Lipopolysaccharide

A smooth lipopolysaccharide is also known as an sLPS or a wild-type LPS. This type of endotoxin consists of three main things: lipid A, complete core oligosaccharides, and the O-antigen.

The O-antigen is a huge component of these wild-type LPS and consists of individual chains attached to the core polysaccharide. The O antigen gives the lipopolysaccharide additional protection from the antimicrobial effects of antibiotics. 

Examples Of Smooth Lipopolysaccharide

One species that has smooth lipopolysaccharides in its outer membrane is various members of the Brucella genus. This includes Brucella suis, Brucella melitensis, and Brucella abortus. 

Rough Lipopolysaccharide 

Rough lipopolysaccharides do not contain the O-antigen. Instead, they are just made up of the lipid A and the core oligosaccharides.

These core oligosaccharides are progressively shorter than those found in smooth lipopolysaccharides. Rough lipopolysaccharides are also called R species. 

Examples Of Rough Lipopolysaccharide

Also within the Brucella genus, Brucella ovis and Brucella canis are both examples of rough lipopolysaccharides that do not contain the O antigen.  

Whilst both rough and smooth lipopolysaccharides contain lipid A, the varieties of the lipopolysaccharides that do not contain the O-antigen (rough lipopolysaccharides) are found to be less contagious and easier to treat than smooth lipopolysaccharides that contain the O antigen. 

What Are The Attributes Of Endotoxins? 

As stated above, endotoxins, or lipopolysaccharides, are usually present on the surface of gram-negative bacteria. Though not all of these endotoxins are pathogenic or virulent.

This is dependent on their structure, and whether or not they are a rough lipopolysaccharide or a smooth (wild-type) lipopolysaccharide. 

Whilst all of these compounds contain the lipid A segment which is responsible for the level of toxicity in the bacteria, the way that it can compromise our immune system and trigger immunogenicity is down to the structuring of the polysaccharides. 

Whilst these bacteria that have endotoxins in their outer membrane can release small amounts of the toxins, it is generally less concentrated, and therefore less virulent than the release of exotoxins. 

What endotoxins do is enhance the absorbent nature of the outer cell membrane, which can permit hydrophilic (water dissolvable) molecules of very low weight to permeate the bacteria.  

Here, lipopolysaccharides enhance the permeability border, only permitting hydrophilic molecules of low molecular weight to pass through.

Though not as eager to release their toxins as exotoxins, smooth or wild-type endotoxins can encourage the bonding of the bacteria to the host cells, thus contributing to infection, making them more virulent and dangerous than their rough lipopolysaccharide counterparts. 

What Are Exotoxins? Definition

Exotoxins are toxins that are released by a living bacterial cell, rather than an endotoxin which is only released when a bacteria dies. Exotoxins are present in both gram-negative and gram-positive bacteria. 

These exotoxins are a part of the bacteria’s defense system and prevent them from being captured and killed by leukocytes in the body. Leukocytes are a part of the body’s immune system and help to fight off bacteria and infection. 

Depending on the different bacteria, exotoxins can be either protein or non-protein in variety, though most exotoxins are proteins, and they are usually diffusible. 

Exotoxins are highly concentrated and powerful, and they can wreak serious damage to the host cells in the body by hindering the day-to-day cellular production within the host, along with other primary functions.

As with most other molecules, exotoxins are made in the cytoplasmic matrix, otherwise known as the cytosol. Once synthesized, these toxins are then released into the outer environment. 

These bacteria can also make their way into the host cells where they live as intracellular pathogens.

Once there, these toxins are continuously synthesized, secreted, and released into the host- thus making them much more virulent and toxic than endotoxins that are only released after the bacteria is dead. 

Whilst there are many different bacteria that constantly secrete and release exotoxins, some of these exotoxins are only released after the cellular disruption or lysis of the bacterial cell, in the same way, that endotoxins are only released after the breakdown of bacteria (when it dies).

This is when the cell membrane is broken down to release intercellular material into the host. 

Unlike endotoxins, which only really have two different main structures (rough and smooth), both of which involve the toxins being in the outer cellular membrane, exotoxins come in a wide variety of formats and have some major disparities in their molecular structure. 

What Are The Symptoms Of Exotoxins?

Unlike endotoxins, each type of exotoxin responds wildly differently, meaning there is no standard list of symptoms associated with them. 

There are three main types of exotoxins that all work in different ways to damage the host. 

Type I toxins, otherwise known as superantigens, cause symptoms by triggering a host’s immune responses, and cause severe immune reactions that can seriously diminish the way the immune system functions.

An example of a Type I exotoxin is Toxic Shock Syndrome TSS. 

Symptoms of Type I Toxins

• Fever
• Rash
• Cappliery leaks and hypotension
• Excessive stimulation of Type I toxins can lead to the production of inflammatory cytokines. 

Type II toxins are responsible for damaging the host cells, with the inflammatory response of the system furthering the damage. There are subtypes of Type II exotoxins that will be examined further in the article. 

Type III toxins interfere with the primary function of the host cell. A type III exotoxin again differs massively in its symptoms and range of infectiousness throughout the body. It comes in two main parts.

The A component is responsible for deactivating the host cells’ function, whilst the B component binds the exotoxin to the receptor of the host cell, thus determining the type of effect it will have on the body. 

More symptoms will be discussed in these individual types of exotoxins, as they vary massively across the board, depending on how they interact and damage the host cells. 

What Are The Three Main Types of Exotoxins?

As mentioned, there are three types of exotoxins. These exotoxins are produced by both Gram-negative and Gram-positive bacteria.

They are Type I (superantigens), Type II (membrane-disrupting toxins), and Type III (A-B toxins). Within these types, there are also many, many subtypes that will briefly be covered. 

Type I Toxins

Type I toxins are also called superantigens. These exotoxins affix themselves to the surface receptors of the host cells, making the body think that it is getting signals from other parts of the body.

These cell surface receptors are interfered with so that the body no longer responds the way it should, as it thinks it is getting stimuli that it is not receiving from the surrounding proteins in other host cells. 

Rather than entering the cells, they bind themselves to the surface of the cells, interfering with their receptors and triggering certain responses from the body. 

How Do Type I Toxins Work?

Type I toxins are also called superantigens. This is because, unlike other antigens, they are capable of avoiding the antigen-presenting stage of the body’s immune response.

It does this by linking the T-cell receptors (TCR) to the Major histocompatibility complex (MHC) class II molecules. 

This also allows the type I toxins to protect themselves from being surrounded and degraded by the rest of the immune system. 

Compared to other antigens, type I toxins are capable of cross-linking the Major Histocompatibility Complex Class II and T cell receptors which allows them to bypass the antigen-presenting phase of the immune reaction.

This likewise prevents the toxin from being engulfed and degraded. 

The result of this is that the superantigens create a huge immune response from the host, which can cause far more damage to the body. 

As the T-cells are stimulated to produce more and more, this triggers the production of interleukin 2 (IL2) as the immune system is activated.

Interleukin 2 is therefore an indicator of the immune response in the body, which in turn, triggers the production of even more T-cells. 

Some of the body’s responses to a high concentration of IL2 in the bloodstream are diarrhea, extreme tiredness, and spiking fever. 

For some circumstances, this increased level of interleukin 2 can also increase the levels of interleukin 1 and 8, which are both inflammatory cytokines.

This increase in inflammatory cytokines can result in organ failure, shock, and other seriously dangerous side effects. 

Examples Of Type I Toxins

Some examples of type I toxins include:

• Enterotoxigenic E. coli (ETEC)
• Toxic shock syndrome toxin (TSST-1)
• Staphylococcal enterotoxins (SE)
• Streptococcal pyrogenic exotoxins (SPE)

Type II Toxins

Type II toxins are also known as membrane disruptors. These exotoxins work by causing severe damage to the membranes of the host cells.

As the host cells are damaged, their programmed reaction is to alert other cells of an invasion and they release danger-associated molecular patterns (DAMPs) that secure themselves to pattern-recognition receptors (PRRs) inducing the release of inflammatory cytokines in an attempt to repair themselves. 

As with Type I toxins, the function is to create an inflammatory response by getting the host cells to trigger the release of inflammatory cytokines into the bloodstream.

How Do Type II Toxins Work?

There are many different subtypes of Type II toxins, though they all fit under the umbrella of being membrane-damaging. That is, they work by disrupting the host cells’ outer membrane to trigger an immune response from the host.

This heightened response then causes more serious damage to the rest of the cells and can have deadly implications in some varieties. 

There are many types of exotoxin pathogens that carry more than one type II toxin, all working in a different way to damage the cell membrane and trigger an immune response. 

All of these various membrane damaging toxins work with different mechanics to change the structure of the cell membrane. 

Clostridium perfringens bacteria, also commonly known as food poisoning bacteria, is responsible for food poisoning, gastrointestinal disease, gas necrosis, and affiliated necrotic conditions in humans and other mammals.

It is one of the most commonly found forms of Type II toxins. It contains alpha, kappa, epsilon, and iota toxins. 

Clostridium perfringens can be found on raw meat, animal intestines, and in the environment. Clostridium perfringens spores can survive in high temperatures, and as it is an exotoxin.

It can germinate and spread its toxins whilst it is alive, not when it dies. Between the temperatures of 54-140 degrees Fahrenheit, the bacteria continue to grow. If that food is consumed, live bacteria are eaten. 

The alpha-toxin requires zinc for activation, after which it then binds to the surface of the host cell to decrease the blood flow to the surrounding tissue. As alpha toxins are lecithinase, it means they break down the lecithin in the cell membrane. 

The beta toxin in C. perfringens works by increasing the blood pressure with the presence of catecholamine, resulting in necrosis of the cells.

This particular toxin is deadly, and is usually found in strains in piglets, and young farm animals and is not common in strains across most developed nations. 

The epsilon toxin creates microscopic holes in the cell membrane, leading to leakage of potassium ions and other fluid. This toxin is rare in humans due to gut flora though is common in animals and can lead to pulpy kidney disease and lamp dysentery. 

Examples Of Type II Toxins

• Cytotoxin, Exotoxin U, Pyocyanin, and Phospholipase – all of which are Pseudomonas aeruginosa toxins
• Clostridium perfringens – these bacteria contain alpha toxins, kappa toxins, iota, and epsilon toxins.
• Leukotoxins – Leukotoxin binds active LFA-1(a key T-cell integrin) and causes lysosomal mediated cell death.

Type III Toxins

Type III toxins are distinguished by their two main parts that both play different roles in the exotoxin. These parts are known as A (active) and B (binding), thus type III toxins are also called A-B toxins. 

These two-component protein complexes are released by several different pathogenic bacteria. 

How Do Type III Toxins Work?

Type III toxins work by interfering with the internal functioning of the host cells. The A component or ‘active’ portion enters the host cell and the B (binding) component binds the newly interfered host cell in place.

Examples Of Type III Exotoxins

Here are some examples of A B toxins that interfere with the function of host cells:

• Diphtheria exotoxin.
• Tetanus toxin (TeNT)
• Clostridium botulinum
• Shiga toxin (Stx)
• Choleragen (CTX)
• Anthrax lethal toxin and edema toxin.

Endotoxin Vs Exotoxin – Differences

As discussed, here are the main differences between endotoxins and exotoxins: 

Definition: Endotoxins are complexes that are released at the time of bacterial cell death. Exotoxins are excreted constantly by species of bacteria when their environmental conditions are met. 

Location in the cell: Endotoxins are located in the chromosomal genes of the cell, on the surface of the cell membrane. Exotoxins are released from the cell on plasmids. 

Effects: Endotoxins symptoms are fever, diarrhea, and vomiting. Exotoxins symptoms are either cytotoxic, enterotoxin, or neurotoxin dependent on the strain.

Vaccination: There are no efficacious vaccines for endotoxin. For many exotoxins, there are effective vaccines.

Immunogenicity: Endotoxins are weakly immunogenic whilst exotoxins are highly immunogenic.

Toxicity Levels: Endotoxins are moderately toxic, whereas Exotoxins can be highly toxic. 

Production: Endotoxins are produced after gram-negative bacteria have disintegrated. Exotoxins are produced in living gram-positive and negative bacteria. 

Final Notes

In summary, endotoxins are released from bacteria when it dies, whereas exotoxins immediately release their toxins into the surrounding environment. Endotoxins are produced by bacteria such as E.coli, Salmonella, and Shigella to name a few. 

Exotoxins are produced by bacteria such as Clostridium botulinum and Corynebacterium diphtheria, with Clostridium botulinum being the deadliest toxin in the world. Exotoxins are the most potent type of toxin and exposure to many usually results in death. 

After reading this article, you should have a better understanding of how both of these types of toxins function, how dangerous they are, and the many subtypes of toxins within these two main groups. 

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