Bacterial Toxins and the Clinical Picture
The pathogenic actions of bacteria ★★
| Action | Detail |
|---|---|
| Byproducts of bacterial metabolism — tissue destruction | Fermentation products — acids, gas · enzymes — hyaluronidase, DNAases, collagenase |
| Toxins | Exotoxins (§2) and endotoxins (§3) — the latter being the lipid A portion of lipopolysaccharide |
| Superantigen proteins | Activate T cells by binding simultaneously to a T-cell receptor and an MHC class II molecule on antigen-presenting cells, without requiring antigen |
- Name the pathogenic actions of bacteria. → Byproducts of metabolism (fermentation products, enzymes), toxins (exo- and endo-), superantigens
- Name three degradative enzymes. → Hyaluronidase, DNAase, collagenase
- What is the endotoxin, chemically? → The lipid A portion of lipopolysaccharide
Exotoxins ★★★
| Property | Exotoxin |
|---|---|
| Origin | Gram-positive bacteria (most), and some Gram-negative |
| Release | Secreted by living bacteria |
| Chemistry | Proteins, heat-labile (a few heat-stable) |
| Genetics | Coded on a plasmid or a lysogenic phage |
| Toxicity | High, with tissue specificity |
The A–B structure
| Subunit | Function |
|---|---|
| A subunit | Provides the toxic activity |
| B subunit | Mediates adherence to a host cell |
The three types of exotoxin
| Type | Action | Examples |
|---|---|---|
| Neurotoxin | Effects on nerve–muscle transmission | Tetanospasmin (Clostridium tetani) |
| Cytolytic toxin | Inhibition of protein synthesis, or causing cell lysis | Diphtheria toxin (protein synthesis) · pore-forming toxins such as streptolysin O · membrane-disrupting enzymes such as phospholipase C |
| Enterotoxin | Hyperactivation | Cholera toxin (Vibrio cholerae) · enterotoxin of Staphylococcus aureus |
Immunity to exotoxins — two examinable definitions
| Term | Definition | Application |
|---|---|---|
| Antitoxin | An antibody that specifically interacts with and neutralises a toxin | Treatment, or an urgent preventive measure |
| Toxoid | An exotoxin modified so that it is no longer toxic but is still able to induce antibody formation | Vaccine |
Both words are about the same toxin, and the difference is who makes the antibody.
A toxoid is the toxin with its poison removed and its antigenicity intact. You inject it, the patient makes antibody, and the protection is slow to arrive but lasts years. That is active immunisation — the tetanus and diphtheria components of every childhood schedule.
An antitoxin is ready-made antibody. You inject it, protection is immediate, and it fades in weeks. That is passive immunisation — what you give the patient with a dirty wound who is already at risk, or the suspected case of diphtheria or botulism.
Which is why the slide labels them vaccine and urgent preventive measure. Prevention in advance, versus rescue now.
- Where do exotoxins come from and how are they released? → Mostly Gram-positive bacteria (some Gram-negative); secreted by living bacteria
- What are they chemically, and where are they coded? → Proteins, mostly heat-labile; coded on a plasmid or lysogenic phage
- A and B subunits? → A provides toxic activity; B mediates adherence to the host cell
- Name the three types with examples. → Neurotoxin (tetanospasmin) · cytolytic toxin (diphtheria toxin, streptolysin O, phospholipase C) · enterotoxin (cholera toxin, staphylococcal enterotoxin)
- Antitoxin vs toxoid? → Antitoxin is antibody that neutralises a toxin, used for treatment or urgent prevention (passive). Toxoid is exotoxin made non-toxic but still antigenic, used as a vaccine (active)
Endotoxin ★★★
Endotoxin is the lipid A portion of lipopolysaccharide — the outer membrane component described in Unit 2 §4. It is therefore a property of Gram-negative bacteria only, and it is released when the cell is lysed, not secreted.
Its mechanism is indirect. Lipid A binds to specific receptors — CD14 and TLR4 — on macrophages, B cells and others, and stimulates the production and release of acute-phase cytokines. Those cytokines are the endogenous pyrogens that produce fever.
This is the single most important sentence about endotoxin, and it is the reason it behaves so differently from an exotoxin.
Tetanospasmin has a target: it cleaves a specific protein at the nerve terminal. Lipid A has no such target. It simply engages TLR4 — the receptor your innate immune system evolved specifically to detect Gram-negative bacteria — and the resulting cascade of TNF-α, IL-1 and IL-6 does the damage.
So the effects are non-specific and identical whatever the organism: fever, leukocyte changes, hypotension, disseminated intravascular coagulation, and septic shock. No tissue specificity, because the tissue being acted on is your own immune system.
It also explains the clinical trap: giving a bactericidal antibiotic to a patient with Gram-negative sepsis lyses the organisms and releases more lipid A, which can transiently worsen the shock.
- What is endotoxin chemically, and which bacteria have it? → The lipid A portion of LPS; Gram-negative bacteria only
- How is it released? → On lysis of the cell — not secreted
- Which receptors does it bind? → CD14 and TLR4 on macrophages, B cells and others
- What does it then cause? → Production and release of acute-phase cytokines — the endogenous pyrogens — giving fever, hypotension, DIC and septic shock
⭐ Exotoxin versus endotoxin ★★★
“Please describe the differences between exotoxin and endotoxin.” — 7 marks, 2020 Section III. The lecture asks the same question on its own slide. Answer it as a table.
| Exotoxin | Endotoxin | |
|---|---|---|
| Source | Mostly Gram-positive, some Gram-negative | Gram-negative only |
| Chemistry | Protein | Lipopolysaccharide — the lipid A portion |
| Location and release | Secreted by living bacteria | Part of the cell wall; released on lysis |
| Heat stability | Heat-labile (mostly, ~60 °C) | Heat-stable (withstands 160 °C for 2–4 h) |
| Toxicity | High, with tissue specificity — distinct clinical syndromes | Relatively low, non-specific — the same syndrome whatever the organism |
| Effects | Specific — neurotoxic, cytolytic or enterotoxic | Fever, leukocyte changes, hypotension, DIC, septic shock |
| Antigenicity | Strong — stimulates antitoxin | Weak — no effective neutralising antitoxin |
| Toxoid | Can be made into a toxoid — vaccine | Cannot |
| Genetics | Coded on a plasmid or lysogenic phage | Chromosomal — an integral wall component |
The seven that carry the marks: source (Gram-positive mostly vs Gram-negative only) · chemical nature (protein vs lipopolysaccharide/lipid A) · release (secreted by living cells vs released on lysis) · heat stability (labile vs stable) · toxicity and specificity (high and tissue-specific vs low and non-specific) · antigenicity (strong, produces antitoxin vs weak) · toxoid (can be made vs cannot).
If space allows, close with one line of consequence: because endotoxin cannot be made into a toxoid and is not neutralised by antibody, there is no vaccine against Gram-negative endotoxic shock — whereas tetanus and diphtheria are wholly preventable. That sentence shows you understand the table rather than having memorised it.
- Give seven differences between exotoxin and endotoxin. → Source · chemistry · release · heat stability · toxicity and specificity · antigenicity · toxoid formation
- Which is heat-stable? → Endotoxin — it withstands 160 °C for 2–4 hours
- Which produces antitoxin? → Exotoxin — it is strongly antigenic
- Why is there no vaccine against endotoxic shock? → Endotoxin is weakly antigenic and cannot be converted into a toxoid
Immunopathogenesis ★★
In many cases the symptoms are produced by excessive innate, immune and inflammatory responses triggered by the infection. The lecture gives three grades.
| Response | Result |
|---|---|
| Limited and controlled | A protective antibacterial response — fever and malaise |
| Systemic and out of control | Life-threatening symptoms associated with sepsis and meningitis |
| Autoimmune responses | See below |
The worked example is streptococcal. The M protein of S. pyogenes antigenically mimics heart tissue; its antibodies cross-react with and initiate damage to the heart — rheumatic fever. Alternatively, immune complexes are deposited in the kidney glomeruli — post-streptococcal glomerulonephritis.
- Name the three grades of immune response to infection. → Limited and controlled (protective, fever and malaise) · systemic and out of control (sepsis, meningitis) · autoimmune
- How does M protein cause rheumatic fever? → It antigenically mimics heart tissue, so anti-M antibodies cross-react with and damage the heart
- What is the other streptococcal immune complication? → Post-streptococcal glomerulonephritis, from immune complexes deposited in the glomeruli
Sources of infection ★★★
| Source | Detail |
|---|---|
| Exogenous infection | From a patient · an animal with bacterial infection · a carrier — a person or animal harbouring a specific infectious agent without discernible clinical disease, serving as a potential source of infection |
| Endogenous infection | From the patient's own flora — including nosocomial infection |
Hospital-acquired infection — an infection that develops within a hospital.
Effects of bacterial infection
| Effect | Detail |
|---|---|
| Inapparent infection | The presence of infection in a host without recognisable clinical signs or symptoms |
| Apparent infection | With clinical signs and symptoms |
| Inflammation | By bacteria or toxins |
| Spread of infection | Local, or generalised — through blood or lymphatic spread, or through natural passages |
- Exogenous vs endogenous infection? → Exogenous: from a patient, an infected animal or a carrier. Endogenous: from the patient's own flora
- Define a carrier. → A person or animal harbouring a specific infectious agent without discernible clinical disease, and serving as a potential source of infection
- Define nosocomial infection. → Hospital-acquired infection — one that develops within a hospital
- Define inapparent infection. → Infection in a host without recognisable clinical signs or symptoms
Blood invasion — five terms that are constantly confused ★★★
The lecture's summary slide names bacteraemia, septicaemia, toxaemia and endotoxaemia as definitions to learn, and adds pyaemia on the diagram. They differ in what is in the blood and whether it is multiplying.
| Term | Definition |
|---|---|
| Bacteraemia | Presence of bacteria in the blood. No multiplication. Derived from a septic focus |
| Septicaemia | Circulation and multiplication of bacteria and their toxins |
| Toxaemia | The presence of bacterial exotoxins in the blood |
| Endotoxaemia | The presence of bacterial endotoxins in the blood |
| Pyaemia | Development of multiple small abscesses in different sites and organs due to the arrest of septic emboli |
What is in the blood? Bacteria — the first two and pyaemia. Toxin — toxaemia and endotoxaemia. Which toxin? Exotoxin is toxaemia; endotoxin is endotoxaemia. Done.
Is it multiplying? This is the only thing separating bacteraemia from septicaemia. In bacteraemia the organisms are merely passing through, shed from a focus elsewhere — which is why brushing your teeth causes a transient bacteraemia and nothing happens. In septicaemia they are multiplying in the blood, and the patient is critically ill.
Pyaemia is the odd one out: it is not defined by what is in the blood but by what the blood delivers — septic emboli lodging and forming abscesses in multiple organs.
- Bacteraemia vs septicaemia? → Bacteraemia: bacteria present in blood, NOT multiplying, from a septic focus. Septicaemia: circulation AND multiplication of bacteria and their toxins
- Toxaemia vs endotoxaemia? → Exotoxins in the blood vs endotoxins in the blood
- Define pyaemia. → Multiple small abscesses in different sites and organs due to the arrest of septic emboli
Revision
The lecture's summary slide — ten definitions across Units 5 and 6
Normal flora · opportunistic pathogen (Unit 5) · antitoxin · toxoid · nosocomial infection · bacteraemia · septicaemia · toxaemia · endotoxaemia · carrier (this unit). Plus the medical significance of normal flora, the conditions causing opportunistic infections, virulence of bacteria and clinical characteristics of bacterial infections.
⭐ The exotoxin/endotoxin table, compressed
| Exotoxin | Endotoxin | |
|---|---|---|
| Source | Mostly G+ | G− only |
| Chemistry | Protein | LPS — lipid A |
| Release | Secreted, living cell | On lysis |
| Heat | Labile | Stable |
| Toxicity | High, tissue-specific | Low, non-specific |
| Antigenicity | Strong → antitoxin | Weak |
| Toxoid? | Yes | No |
- Give seven differences between exotoxin and endotoxin. → Source, chemistry, release, heat stability, toxicity/specificity, antigenicity, toxoid formation
- Name the three types of exotoxin with examples. → Neurotoxin (tetanospasmin) · cytolytic (diphtheria toxin, streptolysin O, phospholipase C) · enterotoxin (cholera, staphylococcal)
- Define antitoxin and toxoid. → Antibody neutralising a toxin (treatment/urgent prevention) vs exotoxin made non-toxic but antigenic (vaccine)
- Define the five blood-invasion terms. → Bacteraemia (present, not multiplying) · septicaemia (circulating and multiplying) · toxaemia (exotoxin) · endotoxaemia (endotoxin) · pyaemia (multiple abscesses from septic emboli)
- How does endotoxin act? → Lipid A binds CD14 and TLR4 on macrophages, releasing acute-phase cytokines — the endogenous pyrogens — giving fever, hypotension, DIC and shock