Infection and immunity are inseparable; humans and microbes form a “chimerical community”.
Immune system continually restrains microbial load to a survivable limit.
New concepts
Microbiota = sum of internal + external microbes inhabiting the body.
Microbiome = aggregate of their genomes.
Gnotobiology
Raising mammals under germ-free or controlled-flora conditions.
Uses genetically-modified models to dissect immune development, disease aetiology, cancer links.
Key review: Falk et al., MMBR 62:1157 (1998).
Health = optimal structural & functional state dictated by genetics/physiology/biochemistry.
Disease = dysfunction; deviation from primary design.
Pathogenesis = mechanisms by which an aetiological factor produces disease (pathos + genesis).
Epidemiology = study of occurrence, distribution, control of diseases at population level.
Etiological factor = primary independent cause of disease.
Pathogen = microbe that causes disease; Host = organism harbouring pathogen.
Pathogenicity = ability to cause disease.
Virulence = degree of pathogenicity; often expressed as infectious dose: few cells ⇒ high virulence.
Attenuation = laboratory passage of pathogen lowers virulence, basis of live vaccines (e.g. measles, mumps, rubella, yellow fever).
Balanced pathogenicity concept – evolutionary moderation benefits both pathogen & host; overly lethal strains eliminated when hosts die.
Parasitism – one benefits, other harmed (e.g. measles, typhoid, TB; all viruses).
Symbiosis – mutual benefit (rumen flora, vitamin B production by gut bacteria).
Commensalism – one benefits, other unharmed; normal flora termed commensal flora.
Skin: ≈10^{12} bacteria; mouth: ≈10^{10}; alimentary canal: ≈10^{14} (recent recalculation 3.72\times10^{13} human cells).
Uneven “island” distribution on skin. Examples:
Skin: Pityrosporum spp., Candida albicans, Staphylococcus spp., Pneumocystis carinii.
Intestine: Escherichia coli, Sarcina ventriculi, Pseudomonas aeruginosa.
True (primary) pathogens – readily overcome defences (Clostridium botulinum, Vibrio cholerae, Yersinia pestis, Mycobacterium tuberculosis; HIV, HBV).
Opportunistic pathogens – cause disease when defences decline (Staphylococcus spp., P. aeruginosa, Candida albicans). Predisposing conditions: malnutrition, chemotherapy, chronic disease, genetic defects, antibiotic therapy.
Domains of life containing pathogens: Viruses, Bacteria, Fungi, Protozoa, emerging Archaea.
Archaea: methanogens implicated in endodontic infections, periodontitis, obesity (Vianna et al. 2006; de Macario & Macario 2009).
Infection (entry + colonisation + spread).
Incubation period (asymptomatic).
Acute period (peak symptoms: fever, chills).
Decline (symptoms subside).
Convalescence (return to normal) or death.
Entry via portal.
Attachment/adhesion to cells or tissues.
Infection (colonisation + growth; localised or systemic).
Expression of symptoms (tissue damage).
Skin (intact barrier but breaches allow arthropod-borne viruses, staphylococci, B. anthracis, T. pallidum, Y. pestis, Plasmodium).
Respiratory tract mucosa – most common; inhale ≈8 microbes/min (\approx10^4/day).
Defences: mucociliary escalator; alveolar IgG/IgA; microbes with attachment proteins (influenza haemagglutinin binding neuraminic acid; Mycoplasma pneumoniae; Bordetella pertussis).
Some suppress cilia (B. pertussis, H. influenzae, P. aeruginosa).
Gastro-intestinal mucosa – food/water route; flow rate critical (slower ⇒ more growth).
Surviving bile: Salmonella, Shigella, E. coli, Proteus, Pseudomonas, Enterococcus faecalis.
H. pylori colonises stomach mucus; V. cholerae produces mucinase.
Giardia lamblia uses ventral adhesive disc.
Urogenital tract – urine sterile but supports growth; pathogens: E. coli, N. gonorrhoeae, Chlamydia, HIV, HSV.
Conjunctiva – lysozyme tears; pathogens: Chlamydia trachomatis (trachoma), enteroviruses, adenovirus 8.
Placenta – vertical transmission.
Parenteral route – injections, surgery, insect/arthropod vectors.
Often mirror entry sites: respiratory droplets, saliva, sputum, feces, urine, blood, semen, vaginal secretions, breast milk, skin flakes, tears, ear wax.
Controlling exit (e.g. isolation) limits spread.
Adhesins (lectins) on pili/fimbriae bind host sugars (E. coli, N. gonorrhoeae).
Non-pili adhesins: Yersinia, Mycoplasma pneumoniae, B. pertussis.
Lipoteichoic acid + F protein mediate S. pyogenes binding.
Biofilms: multi-species polysaccharide matrices (dental plaque: 300\text{–}400 species; catheter infections).
Invasins: Shigella, Salmonella, Yersinia bind M cells, trigger uptake.
Motility example: Treponema pallidum corkscrew penetration.
Polysaccharide capsule – blocks phagocytosis (S. pneumoniae, B. anthracis). <10 encapsulated pneumococci can kill mice; 10^4 needed after hyaluronidase digestion.
Cell-wall components e.g. mycolic acid (Mycobacterium) impede phagocytosis & antibiotics.
Hyaluronidase: digests host cement → spread (streptococci, staphylococci, clostridia).
Collagenase (\kappa-toxin): destroys collagen (C. perfringens – gas gangrene).
Streptokinase: dissolves fibrin clots (S. pyogenes).
Coagulase: forms fibrin clots shielding S. aureus.
Proteases, nucleases, lipases degrade host macromolecules.
Cytolytic/hemolysins: phospholipases, pore formers (C. perfringens \alpha-toxin lecithinase; streptolysin O; leukocidins).
Hemolysis patterns on blood agar: \alpha (green, partial), \beta (complete), \gamma (none).
A–B toxins: separate binding (B) & active (A) subunits.
Diphtheria toxin: B binds receptor; A inactivates EF-2 ⇒ halts protein synthesis; one molecule kills one cell.
Botulinum toxin: B (heavy chain) targets cholinergic nerve endings; A (light chain) endopeptidase cleaves SNAREs ⇒ blocks ACH release ⇒ flaccid paralysis.
Superantigens: non-specific T-cell activation ⇒ cytokine storm (e.g. S. aureus enterotoxins, TSST-1).
Enterotoxins: act on intestine; fluid secretion ⇒ vomiting/diarrhoea (S. aureus, C. perfringens, B. cereus, V. cholerae, E. coli, Salmonella enteritidis). Often pore-forming.
Present in outer membrane of Gram (–) bacteria; released on lysis.
Cascade: binds macrophage/B-cell receptors ⇒ induces IL-1, TNF-α, IL-6, prostaglandins.
Low dose: fever, vasodilation, immune activation.
High dose / bacteremia: high fever, hypotension, disseminated intravascular coagulation (DIC), lymphopenia, shock, death.
Virulence role in N. meningitidis, Brucella, Francisella tularensis, N. gonorrhoeae (requires capsule + fimbriae + LPS for virulence).
Age: neonates & elderly more susceptible.
Stress: physical exertion, climate change, dehydration.
Nutrition: poor diet lowers infectious dose threshold.
Compromised hosts (hospitalised, immunosuppressed) prone to nosocomial infections.
Innate barriers
Skin: keratinised layer + sebum (fatty & lactic acids, pH ≈5).
Mucociliary escalator.
Gastric acid pH ≈2.
Normal flora \approx10^{10}\,/\text{g} intestine outcompete invaders.
Lysozyme in tears, kidney filtrate; β-lysins in blood disrupt bacterial membranes.
Temperature, UV exposure, presence of inorganic/organic substances modify pathogen survival & host resistance.
Anaerobic Gram(+) spore-former; produces A–B neurotoxin (150–165 kDa).
One gram can kill 10^7 people.
Types A, B, E, F infect humans.
Mechanism: toxin binds peripheral cholinergic synapses → light chain endopeptidase cleaves SNARE proteins → blocks \text{ACH} release ⇒ flaccid paralysis, respiratory failure.
Forms
Food-borne: home-canned foods, preserved fish. Incubation 1–2 days. Symptoms: dizziness, blurred vision, dry mouth, descending flaccid paralysis.
Infant: ingestion of spores (honey); spores germinate in low-acid gut.
Wound: contamination of traumatic wounds; longer incubation (≥4 days).
Diagnosis: mouse bioassay for toxin; EMG, Tensilon test; modern MALDI-TOF endopeptidase assay.
Treatment: equine antitoxin (early); gastric lavage/enema; surgical debridement; mechanical ventilation; antibiotics not recommended (may worsen paralysis).
Gram(+), club-shaped rods (Chinese letters); aerobic/facultative.
Diphtheria toxin (A–B) encoded by β-phage tox gene; iron represses expression.
Local infection: pharyngeal pseudomembrane.
Systemic absorption ⇒ cardiomyopathy, peripheral neuropathy.
Pathogenesis: B binds heparin-binding EGF receptor; A ADP-ribosylates EF-2 ⇒ halts translation.
One cell: ≈5000 toxin molecules/h; one molecule kills a host cell.
Treatment: immediate antitoxin; penicillin/erythromycin; toxoid vaccine (DTP); Schick skin test assesses immunity.
Gram(+), grape-like clusters; facultative anaerobe; golden colonies, \beta-hemolysis.
Reservoir: skin, mucosa of humans; common nosocomial pathogen.
Virulence arsenal
Coagulase, Protein A, carotenoids (antioxidant), capsule.
Enzymes: hyaluronidase, staphylokinase, lipases.
Toxins: >20 enterotoxins (A–E etc.), TSST-1 (enterotoxin F), exfoliatin (scalded-skin syndrome), hemolysins \alpha,\beta,\gamma,\delta, Panton-Valentine leukocidin (2-component S + F proteins).
Clinical syndromes
Local skin: folliculitis, sty, furuncle, carbuncle, impetigo, abscesses.
Systemic: septicemia, endocarditis, pneumonia, osteomyelitis.
Toxin-mediated: food poisoning (rapid vomiting + diarrhoea), toxic shock syndrome (tampon-associated; fever, rash, hypotension), scalded-skin/Ritter’s disease (neonates; epidermolysis).
Gangrene due to vascular occlusion in severe cases.
Toxicity – local/systemic damage via toxins (e.g. C. tetani tetanospasmin => spastic paralysis).
Invasiveness – extensive growth in tissues (e.g. encapsulated S. pneumoniae multiplying in lungs ⇒ pneumonia) even without potent toxins.
Ideal doubling every 20\,\text{min} ⇒ N = N_0 \times 2^{72} \approx 4.7\times10^{21} cells in 24 h (theoretical upper limit illustrating need for host barriers).
Pathogen: virulence determinants, adaptations (biofilms, motility, sporulation).
Host: age, genetics (e.g. immune deficiencies), stress, nutrition, concurrent infections.
Environment: temperature, UV, chemical exposures, hospital settings.
Exposure → Adherence → Invasion → Colonisation & Growth
↘ (toxins) ↘ (invasiveness)
Toxicity Tissue spread
→ Tissue damage / Disease
Bauman R.W. Microbiology with Diseases by Body System, 2nd ed. Pearson (2009).
Madigan & Martinko. Brock Biology of Microorganisms.
Strelkauskas et al. Microbiology: A Clinical Approach (2010).
Murray, Rosenthal & Pfaller. Medical Microbiology.
Mims’ Pathogenesis of Infectious Disease.
Colour Atlas of Infectious Diseases (Emond et al.).
Mock Exam Prompt: “Describe specific pathogenic factors of microbial pathogens, discussing biology, function, and roles in pathogenesis.” Focus on virulence factors & adaptations.