KS

Pathogens and Pathogenesis – Core Vocabulary

Infection–Immunity Interplay

  • 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).

Basic Vocabulary & Core Definitions

  • 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.

Associations Between Organisms

  • 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.

Normal (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.

Classes of Pathogens

  • 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).

Progression of Infectious Disease (Clinical/Epidemiological)

  • Infection (entry + colonisation + spread).

  • Incubation period (asymptomatic).

  • Acute period (peak symptoms: fever, chills).

  • Decline (symptoms subside).

  • Convalescence (return to normal) or death.

Stages of Microbial Pathogenesis

  1. Entry via portal.

  2. Attachment/adhesion to cells or tissues.

  3. Infection (colonisation + growth; localised or systemic).

  4. Expression of symptoms (tissue damage).

Portals of Entry

  • 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.

Portals of Exit

  • 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.

Adhesion & Colonisation Mechanisms

  • 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.

Virulence Factors

Passive Defences

  • 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.

Active Defences – Extracellular Enzymes

  • 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.

Toxins

Exotoxins (secreted proteins)
  1. 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).

  2. 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.

  3. Superantigens: non-specific T-cell activation ⇒ cytokine storm (e.g. S. aureus enterotoxins, TSST-1).

  4. Enterotoxins: act on intestine; fluid secretion ⇒ vomiting/diarrhoea (S. aureus, C. perfringens, B. cereus, V. cholerae, E. coli, Salmonella enteritidis). Often pore-forming.

Endotoxin (Lipid A of LPS)
  • 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).

Host Factors Influencing Pathogenesis

  • 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.

Environmental Factors

  • Temperature, UV exposure, presence of inorganic/organic substances modify pathogen survival & host resistance.

Detailed Disease Case Studies

Botulism (Clostridium botulinum)

  • 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).

Diphtheria (Corynebacterium diphtheriae)

  • 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.

Staphylococcus aureus Infections

  • 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.

Two Main Routes to Disease Expression

  • 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.

Mathematical Insight: Exponential Growth Potential

  • 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).

Summary of Factors Affecting Pathogenesis

  • 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.

Diagrammatic Overview of Invasion vs. Toxicity

Exposure → Adherence → Invasion → Colonisation & Growth
          ↘ (toxins)          ↘ (invasiveness)
             Toxicity             Tissue spread
                            → Tissue damage / Disease

Key Reading & Exam Preparation

  • 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.