Ensoniq Logo Pre-1993
8.1 Colonisation and virulence #
8.1.1 The microbiota #
Skin, mouth, gut, upper airway, and vagina are colonised. Blood and internal tissues are not. Colonisation is multiplication without damage. Disease is damage, from the microbe, its toxin, or the host response. Germ-free animals have poorer intestinal defences and need more dietary energy, because the fermentation of polysaccharide is missing.
The community occupies niches, which is colonisation resistance, and makes acetate, propionate, and butyrate for the gut epithelium. It contributes vitamin K. Amounts are not quoted. Skin staphylococci, oral streptococci, vaginal lactobacilli, and a colonic community rich in Bacteroides and firmicutes are the usual picture; percentages are not, because they shift with diet and with the method of counting. A dysbiosis is a shift associated with disease. It does not by itself prove cause. Loss of colonisation resistance, then C. difficile, does. The education of immunity is immunology.
8.1.2 Pathogens and virulence factors #
A primary pathogen damages a host whose defences were intact: M. tuberculosis, Shigella, influenza virus. An opportunist waits for a breach: Pseudomonas in a burn, Candida after antibacterial drugs, Cryptococcus when T-cell immunity fails, S. epidermidis on plastic. E. coli is either, by strain and site. A virulence factor is a component whose loss reduces disease.
| Class | Job | Examples |
|---|---|---|
| Adhesin | sticks the organism down | P fimbriae; haemagglutinin; streptococcal M protein |
| Capsule | blocks phagocytosis or complement | pneumococcus; Cryptococcus |
| Injection | delivers proteins into a host cell | type III systems of Salmonella, Shigella, Yersinia |
| Toxin | poisons a specific reaction | AB toxins; pore-forming haemolysins; superantigens |
| Antigenic variation | retires the previous surface | trypanosome coat; gonococcal pilin; influenza drift |
| Exoenzyme | opens tissue or cuts a defence molecule | hyaluronidase; IgA protease |
The type III injectisome is a relative of the flagellar basal body. Effectors rearrange actin or paralyse phagocytosis. Quorum sensing often times adhesins early and toxins late, when the population is large enough for the products to matter.
8.2 Toxins and the molecular postulates #
8.2.1 Exotoxin, endotoxin, and the AB pattern #
| Exotoxin | Endotoxin | |
|---|---|---|
| Who | Gram-positive or Gram-negative | Gram-negative only |
| Chemistry | protein | lipid A |
| Heat | usually labile | stable |
| Gene | often phage or plasmid | chromosomal |
| Toxoid | often possible | no |
| Action | a specific, often catalytic, lesion | systemic inflammation via TLR4 |
| Examples | diphtheria, cholera, tetanus, Shiga | E. coli, Salmonella, meningococcus |
Cytokines from macrophages, including IL-1 and TNF, are the inflammatory path and are immunology. A Gram-positive infection is not endotoxic in this sense. Lysing a heavy Gram-negative load can briefly raise circulating lipid A.
Membrane toxins such as streptolysin O collapse ion gradients. Superantigens, such as toxic-shock toxin, bind MHC class II and T-cell receptors off the peptide groove and fire many T-cell clones at once. An AB toxin uses B to deliver an enzyme, A, so one molecule modifies many targets.
Diphtheria toxin is made only if a phage carries tox, and only when iron is scarce enough for the iron-binding repressor to let go. B binds heparin-binding EGF-like growth factor. A ADP-ribosylates diphthamide on elongation factor 2, and translocation stops. The bacterium stays local; the toxin does not. Cholera toxin, also phage-encoded, is AB5. B binds ganglioside GM1. A ADP-ribosylates Gs, kills its GTPase, and leaves adenylate cyclase on. High cyclic AMP drives the chloride channel CFTR, and water follows. The diarrhoea is secretory, without invasion. Botulinum and tetanus toxins are zinc proteases of SNARE proteins: one blocks acetylcholine at the neuromuscular junction (flaccid), the other blocks inhibition in the cord (spastic). Shiga toxin removes an adenine from 28S rRNA. Same organisation, different chemistry. No production and no dose are described. A toxoid is a protein spoilt as a catalyst and kept as an antigen.
8.2.2 Molecular Koch’s postulates #
Falkow (1988) asked the classical questions of a gene. It should be associated with pathogenic strains and absent from harmless relatives. Disrupting it should reduce virulence. Restoring it should bring virulence back. Expression during infection is a practical fourth test. Two redundant toxins hide each other: losing one does not drop virulence. A gene essential in every condition cannot be deleted cleanly, so the test never sees it. A list of genes found in a pathogen is not yet a list of virulence factors. Pathogenicity islands, with a base composition unlike the rest of the chromosome, are the scar of acquisition. The same horizontal transfer that moves resistance moves these blocks.
8.3 Epidemiology and the first barriers #
8.3.1 Reservoir, transmission, and R0 #
The reservoir is where the organism maintains itself: people, including healthy carriers; animals, which makes a zoonosis (rabies, avian influenza A, plague in rodents); or the environment (C. tetani in soil, Legionella in water). The source of one case need not be the long-term reservoir. Contact includes direct touch and droplets that fall within about a metre. Airborne spread uses particles that stay suspended. Vehicles are food, water, and objects. A biological vector multiplies the pathogen or carries a necessary stage (Anopheles, the tick of Borrelia). A mechanical vector only transports it. Vertical spread crosses placenta, birth canal, or milk. Break reservoir, exit, transmission, entry, or susceptibility, and that chain stops.
Sporadic means scattered cases; endemic, a steady background; epidemic, a rise above it; pandemic, spread across continents. The words measure incidence, not severity. R0 is the mean number of secondary cases one case would produce in a fully susceptible population. It is not a constant of the species, and no number is given here. Above one, introduction can grow; below one, chains die. The effective reproduction number is the same idea once some people are immune. In a simple well-mixed model the immune fraction that stops spread is 1 − 1/R0. It is not evaluated for a named disease: that would invent an R0, and real contact is not well mixed. How a person becomes immune is immunology.
8.3.2 Innate barriers and evasion #
Skin is dry, salty, shed, and already occupied. Mucus, cilia, tears, and urine flush surfaces. Stomach acid kills many swallowed cells; urease is Helicobacter‘s local answer. Lysozyme cuts peptidoglycan. Defensins pore membranes. A pathogen of an intact host has an answer to at least one of these, or it enters through a wound.
Complement, phagocytes, and inflammation are the next layer and are immunology. Evasion maps onto structures already met. Capsules block uptake and complement. IgA protease removes the mucosal antibody. Antigenic variation retires the previous response. Intracellular life hides the cell from antibody, if the phagosome can be survived or remodelled. Modified lipid A can miss TLR4. Siderophores steal iron the host has bound. None of this is invisibility in general. Antibodies, T cells, and vaccines as immune events are the handover. A drug acts while it is present. A vaccine changes the host, which may remember for life.
8.4 Key terms, summary, and self-check #
Key terms. Colonisation; opportunist; primary pathogen; virulence factor; type III secretion; exotoxin; endotoxin; AB toxin; toxoid; molecular Koch’s postulates; reservoir; zoonosis; R0; herd immunity; colonisation resistance.
Summary. Colonisation is not disease. Primary pathogens do not wait for a breach; opportunists do. Virulence factors stick, hide, inject, poison, or change coat. Endotoxin is heat-stable lipid A. Exotoxins are proteins, often on phages. Diphtheria toxin ADP-ribosylates EF-2; cholera toxin ADP-ribosylates Gs. Falkow’s three tests ask whether a gene is necessary and sufficient for virulence. R0 is an idea about spread in a susceptible population and is not given a number. Skin, acid, mucus, and lysozyme are the barriers; the adaptive system behind them is immunology.
Self-check.
1. How can E. coli be both normal microbiota and a pathogen?
2. Give one chemical, one heat, and one genetic difference between diphtheria toxin and LPS.
3. What does each A subunit do, diphtheria and cholera, and why are the symptoms unlike?
4. State Falkow’s three criteria. Why do two redundant toxins defeat the inactivation test?
5. What is R0, why is no value quoted, and which link does a vaccine break that a filter does not?
—
—
—