Pathogenesis of Bacterial Infection
How do they make you sick? ★★
The lecture frames the whole subject as a contest between two sides, and every later question about pathogenesis is an elaboration of this slide.
| Side | What it brings |
|---|---|
| The organism | Virulence factors (biochemical, structural and genetic) · the number of infecting bacteria · the route of entry |
| The body | Resistance |
Bacterial disease production is therefore the damage produced by the bacteria plus the consequences of the innate and immune responses to the infection. The length of the incubation period is the time required for the bacteria and/or the host response to cause sufficient damage to initiate discomfort or interfere with essential functions, and the signs and symptoms are determined by the infection and by the importance of the affected tissue.
Read that definition again: disease is bacterial damage plus the consequences of your own immune response.
That second clause is the one students skip, and it is doing most of the work. The fever, the malaise, the hypotension of Gram-negative sepsis, the granuloma of tuberculosis, the carditis of rheumatic fever — none of those is the organism damaging tissue directly. All of them are your immune system's response, which is either proportionate and protective, or excessive and lethal.
It is also why the affected tissue matters more than the organism. The same amount of inflammation is trivial in skin, uncomfortable in a joint, and fatal in the meninges.
- What three things does the organism bring? → Virulence factors, number of infecting bacteria, route of entry
- What does the body bring? → Resistance
- Define bacterial disease production. → Damage produced by the bacteria plus the consequences of the innate and immune responses
- What determines the incubation period? → The time for the bacteria and/or host response to cause enough damage to cause discomfort or interfere with essential functions
The glossary ★★★
Twelve terms, and any of them could be a Section I item — the paper draws four-mark definitions from exactly this kind of slide.
| Term | Definition |
|---|---|
| Carrier | A person or animal with asymptomatic infection that can be transmitted to another susceptible person or animal |
| Adherence (adhesion, attachment) | The process by which bacteria stick to the surface of host cells. A major initial process after bacteria enter the body |
| Infection | Multiplication of an infectious agent within the body |
| Invasion | The process whereby bacteria, animal parasites, fungi and viruses enter host cells or tissues and spread in the body |
| Microbiota | Microbial flora harboured by normal, healthy individuals |
| Nonpathogen | A microorganism that does not cause disease; may be part of the normal microbiota |
| Pathogen | A microorganism capable of causing disease |
| Pathogenesis | How a disease develops |
| Pathogenicity | Disease-causing ability of microorganisms |
| Virulence | The quantitative ability of an agent to cause disease. Virulence involves adherence, persistence, invasion and toxigenicity |
| Toxigenicity | The ability of a microorganism to produce a toxin that contributes to the development of disease |
| Superantigen | Protein toxins that activate the immune system by binding to MHC molecules and T-cell receptors, stimulating a large number of T cells to produce massive quantities of cytokines |
Students lose marks on this pair constantly, and the slide gives the discriminator away.
Pathogenicity = disease-causing ability. A quality. Either an organism can cause disease or it cannot.
Virulence = the quantitative ability to cause disease. A degree. Two strains may both be pathogenic while one is far more virulent.
The word quantitative is the answer. And the four components — adherence, persistence, invasion, toxigenicity — are the four things you can measure.
An ordinary antigen is chopped up, presented in the groove of an MHC molecule, and recognised by perhaps 1 in 10 000 T cells with a matching receptor.
A superantigen skips all of that. It clamps the outside of MHC class II to the outside of the TCR β chain — without requiring antigen — and so activates every T cell bearing that Vβ family: up to 20% of all T cells at once.
The result is not immunity but a cytokine storm — fever, rash, capillary leak, hypotension, multi-organ failure. That is toxic shock syndrome, caused by TSST-1 of Staphylococcus aureus and the pyrogenic exotoxins of Streptococcus pyogenes. Remember it for the cocci unit.
- Define a carrier. → A person or animal with asymptomatic infection transmissible to another susceptible person or animal
- Pathogenicity vs virulence? → Pathogenicity is the disease-causing ability; virulence is the QUANTITATIVE ability, involving adherence, persistence, invasion and toxigenicity
- Define infection and invasion. → Infection: multiplication of an agent within the body. Invasion: entry of organisms into host cells or tissues and spread in the body
- Define a superantigen. → A protein toxin that binds MHC and the TCR directly, without antigen, activating a large number of T cells to release massive cytokines
- Define toxigenicity. → The ability of a microorganism to produce a toxin contributing to disease
Normal flora and its medical significance ★★★
“The medical significance of normal flora” is named on the lecture's summary slide — a brief-answer question in waiting.
Microorganisms that live on or in human bodies and ordinarily do not cause human disease.
⭐ The three medical significances
| Significance | Mechanism |
|---|---|
| 1 · Antagonism | Competition for receptors on host cells · competition for nutrients · metabolic or toxic products |
| 2 · Nutritional function | e.g. Lactobacillus casei in the intestine and mouth improves digestion; gut flora supply vitamin K |
| 3 · Immunity | Continuous low-level stimulation matures and maintains the immune system |
Two cautions from the same slides. The flora becomes dangerous when it enters normally sterile sites of the body. And the Human Microbiome Project (HMP) is the study cataloguing the comprehensive human microbiota and its roles in health and disease. cfu (colony-forming unit) is the unit used to estimate the number of viable bacteria or fungal cells in a sample.
| Definition | |
|---|---|
| Colonisation | Microorganisms do not interfere with normal body function, whether they colonise for a short period or permanently |
| Disease | When the interaction between microbe and human leads to a pathologic process characterised by damage to the human body, resulting from microbial virulence factors or the host's immune response |
If the flora's first significance is antagonism — holding the receptors, eating the nutrients, poisoning the neighbourhood — then removing the flora removes a defence.
Give a broad-spectrum antibiotic and you clear the colonic flora. The receptors are now free, the nutrients unclaimed, and Clostridioides difficile, which was present in small numbers and resistant to the drug, expands unopposed. The result is pseudomembranous colitis.
Same logic, different site: Candida after antibiotics, or Candida vaginitis after the lactobacilli are lost. One mechanism, three clinical pictures.
- Define normal flora. → Microorganisms living on or in human bodies that ordinarily do not cause disease
- Name the three medical significances. → Antagonism · nutritional function · immunity
- Name the three mechanisms of antagonism. → Competition for host-cell receptors, competition for nutrients, metabolic or toxic products
- Colonisation vs disease? → Colonisation does not interfere with normal body function; disease is a pathologic process damaging the body, from virulence factors or the host response
- What is a cfu? → Colony-forming unit — the unit estimating the number of viable bacterial or fungal cells in a sample
Opportunistic pathogens ★★★
An agent capable of causing disease only in immunosuppressed and debilitated persons. They are typically members of the patient's own normal flora. Examples: Staphylococcus aureus and Escherichia coli.
⭐ Under what conditions will opportunistic pathogens cause disease?
- Alteration of colonisation sites — the organism reaches a site it does not belong in
- Declination of the host's immune defence
- Dysbacteriosis
The state in which the proportion of bacterial species and the number of the normal flora colonising a certain site of a host present large-scale alteration.
- Define an opportunistic pathogen. → An agent causing disease only in immunosuppressed and debilitated persons, typically a member of the patient's normal flora
- Give two examples. → Staphylococcus aureus and Escherichia coli
- Name the three conditions causing opportunistic infection. → Alteration of colonisation sites · declination of host immune defence · dysbacteriosis
- Define dysbacteriosis. → Large-scale alteration in the proportion of species and number of normal flora colonising a site
Initiating the infectious process ★★
- Entry into the human body
- Colonisation, adhesion and invasion
- Pathogenic actions of bacteria — Unit 6
Entry — the modes of transmission
The lecture names the gastrointestinal tract, trauma, contact — direct and indirect — and animal bite.
Colonisation and adhesion
Bacteria attach or adhere to host cells, establishing a primary site of infection. The named adherence factors are pili, lipoteichoic acid (LTA) and M protein — the last two being streptococcal, which is why they return in the cocci unit.
From there the organism may multiply and spread directly through tissue, or via the lymphatic system to the bloodstream — bacteraemia — and then multiply in a particularly suitable tissue.
Invasiveness
- Invasion of the host's epithelium is central to the infectious process
- Through the junctions between epithelial cells — e.g. by invasive enzymes
- Through specific types of epithelial cell — e.g. Neisseria gonorrhoeae
- Capsule or slime layer
- Name the three stages of initiating infection. → Entry into the body · colonisation, adhesion and invasion · pathogenic actions of bacteria
- Name the adherence factors. → Pili, lipoteichoic acid (LTA) and M protein
- How does a bacterium invade epithelium? → Through the junctions between epithelial cells (invasive enzymes), through specific epithelial cell types (N. gonorrhoeae), aided by capsule or slime layer
⭐ The six virulence factors ★★★
“What factors determine bacterial pathogenicity?” is the lecture's own question, and “virulence of bacteria” is on its summary slide. This list is the skeleton of the 2019 brief answer on the virulence factors of Staphylococcus aureus (7 marks) — and of any similar question about any organism.
| Virulence factor | What it does |
|---|---|
| 1 · Adhesin | Binds to specific receptors on the cell surface and keeps the organisms from being washed away |
| 2 · Capsule | Shields the bacteria from immune and phagocytic responses |
| 3 · Invasin | Aids the bacteria to cross mucosal membranes and other tissue barriers |
| 4 · Degradative enzyme | Breaks down tissue, thereby promoting bacterial spread |
| 5 · Toxin | Directly harms tissue or triggers destructive biologic activities — Unit 6 |
| 6 · Mechanisms for escaping elimination by host defences | e.g. Protein A, intracellular survival, antigenic variation |
Adhesin — surface adhesins binding fibronectin and fibrinogen · capsule and slime layer, antiphagocytic · invasins · degradative enzymes — coagulase, hyaluronidase, staphylokinase, DNAase, lipase · toxins — haemolysins, leukocidin, exfoliative toxin, enterotoxin, TSST-1 (a superantigen) · escape mechanisms — Staphylococcal Protein A (SPA), which binds the Fc region of IgG and blocks opsonisation.
Then the diseases, in two groups: invasive — boil, carbuncle, wound infection, pneumonia, osteomyelitis, endocarditis, sepsis — and toxin-mediated — food poisoning, scalded skin syndrome, toxic shock syndrome.
SPA was itself set as a Section I term in 2020. Both papers, one organism — see the Cocci unit.
- Name the six virulence factors. → Adhesin · capsule · invasin · degradative enzyme · toxin · mechanisms for escaping host defences
- What does an adhesin do? → Binds specific host-cell receptors, keeping the organism from being washed away
- What does a capsule do? → Shields the bacteria from immune and phagocytic responses
- Invasin vs degradative enzyme? → Invasin crosses mucosal membranes and tissue barriers; degradative enzymes break down tissue to promote spread
Revision
The whole unit on one screen
| Question | Answer |
|---|---|
| Disease production? | Bacterial damage plus the consequences of innate and immune responses |
| Pathogenicity? | Disease-causing ability |
| Virulence? | The quantitative ability to cause disease — adherence, persistence, invasion, toxigenicity |
| Carrier? | Asymptomatic infection, transmissible to another susceptible host |
| Superantigen? | Protein toxin binding MHC and TCR without antigen, activating many T cells and massive cytokine release |
| Normal flora — 3 significances? | Antagonism · nutrition · immunity |
| Antagonism — 3 mechanisms? | Receptor competition · nutrient competition · metabolic or toxic products |
| Opportunistic pathogen? | Causes disease only in the immunosuppressed and debilitated; usually normal flora |
| 3 conditions for opportunistic infection? | Altered colonisation site · declining immunity · dysbacteriosis |
| Adherence factors? | Pili · LTA · M protein |
| ⭐ Six virulence factors? | Adhesin · capsule · invasin · degradative enzyme · toxin · escape mechanisms |
- List the six virulence factors and use them to answer an S. aureus question. → Adhesin, capsule, invasin, degradative enzyme, toxin, escape mechanisms — then coagulase, TSST-1, Protein A and the invasive vs toxin-mediated diseases
- Give the three medical significances of normal flora. → Antagonism, nutritional function, immunity
- Define opportunistic pathogen and dysbacteriosis. → Disease only in the immunosuppressed, usually from the patient's own flora; large-scale alteration in the proportion and number of normal flora at a site
- Why is virulence the harder word? → It is the QUANTITATIVE ability to cause disease, not the yes/no of pathogenicity