Pathogens and Pathogenesis – General View

Aim & Scope of Lectures

Provide an overarching framework for understanding microbial pathogenesis as the process leading from exposure to disease and (hopefully) convalescence.
Core components to master:
- Essential vocabulary (pathogen, host, pathogenicity, virulence, etc.)
- Major and minor pathogen-transmission routes and stages of pathogenesis
- Categories of virulence factors (passive vs active) and illustrative diseases
- Host variables (age, stress, genetic background, innate barriers) and environmental modulators
- Epidemiological context: distribution, outbreak investigation, public-health relevance.

Infection–Immunity Continuum & Microbiota Concepts

Human and microbial cells form a “chimerical community” locked in continuous competition.
The immunological goal: keep total microbial load & taxonomic spectrum below a threshold compatible with survival/fitness.
New definitions:
- Microbiota = total internal + external microbial cells associated with the body.
- Microbiome = aggregate of their genomes.
Gnotobiology (germ-free or defined-flora animal models) elucidates:
- Immune-system maturation
- Microbe–microbe & microbe–host interactions
- Etiology of infectious diseases & even cancer.

Health vs Disease: Binary States

Health – optimal structural & functional status dictated by genetics, physiology, biochemistry (symbolised by Michelangelo’s “David”).
Disease – any deviation from that baseline (illustrated by tetanus muscle spasms); includes infectious & non-infectious disorders.
Pathogenesis – mechanistic chain transforming etiological factor into clinical disease; applicable to cancer, diabetes, infections, etc.

Epidemiology Foundations

“Occurrence–distribution–control” of diseases in populations.
Dual nature:
- Practical: outbreak tracing, health promotion.
- Theoretical: statistics, geography, sociology, psychology, biology.
For novel diseases epidemiological data often precedes identification of agent or mechanism.

Primary Causal Factors (Etiologies)

Environmental (chemical/physical) | Microbial | Higher organisms | Genetic | Physiological.

Types of Bi-Organism Associations

Parasitism – one benefits, other harmed (measles, TB, typhoid, most viral infections).
Symbiosis – mutual benefit (rumen microflora, vitamin B₁/B₁₂ synthesis by gut bacteria).
Commensalism – one benefits, host unaffected (normal skin/intestinal flora).

Normal (Commensal) Flora Highlights

Skin “islands” detected by replica plating; typical residents: Pityrosporum spp., Candida albicans, Staphylococcus, Pneumocystis.
Intestine: \textit{E. coli},\; Sarcina\; ventriculi,\; Pseudomonas\; aeruginosa.

Pathogen Definitions & Categories

Pathogen – microbe capable of causing disease; host – organism harbouring it.
True pathogens: readily overcome defences (Clostridium botulinum, Vibrio cholerae, Yersinia pestis, HIV, HBV, M. tuberculosis).
Opportunists – harmless until defences fall (Staphylococcus spp., P. aeruginosa, C. albicans). Favoring host states: malnutrition, chemotherapy, HIV, diabetes, depression, etc.

Domains & Unusual Agents

Viruses – obligatory intracellular; Bacteria – surface or intracellular; Fungi – mostly free-living; Protozoa – low virulence, chronic; emerging Archaea – methanogens implicated indirectly (periodontitis, colon cancer, obesity).

Pathogenicity & Virulence Concepts

Pathogenicity – qualitative ability to cause disease.
Virulence – quantitative measure (e.g., infectious dose ID_{50}).
Attenuation by prolonged culture ⇒ live vaccines (yellow fever, MMR).
Balanced pathogenicity principle: excessive host killing decreases pathogen fitness; evolutionary drive toward moderation (e.g., TB spread from resistant Europeans to naïve populations increased severity).

Natural History of an Infectious Disease (Epi timeline)

Incubation → Acute (symptomatic) → Decline → Convalescence (or death).

Canonical Stages of Pathogenesis

Entry via portal (skin, mucosa, parenteral).
Attachment/adhesion to host tissue.
Infection/colonisation + growth (local or systemic).
Host damage → clinical symptoms.
Exit by corresponding portal (facilitates transmission).

Portals of Entry & Key Microbial Tricks

Skin breaches: arthropod vectors, wounds, follicles (C. tetani, Y. pestis).
Respiratory mucosa: inhalation of 400–900 microbes \text{m}^{-3}; mucociliary escalator; ciliary paralyzers (B. pertussis, P. aeruginosa).
GI tract: acid/bile resistance (H. pylori, V. cholerae mucinase, Salmonella spp. bile-tolerant); rapid doubling (one E. coli \rightarrow 10^{8} in 18 h).
Urogenital: normally sterile urine; pathogens include E. coli,\; N.\; gonorrhoeae,\; Chlamydia,\; HIV.
Conjunctiva: lysozyme, tears; Chlamydia trachomatis binds heparan-sulfate.
Placental (vertical) & Parenteral (needles, surgery, insect vectors).

Exit Portals

Often mirror entry: respiratory droplets, feces, urine, blood, semen, milk, skin flakes.
Controlling exits (isolation, safe disposal) interrupts transmission.

Adhesion & Biofilm Formation

Adhesins (lectins) on fimbriae/pili bind host sugars (E. coli, Neisseria pili).
Non-fimbrial adhesins: Yersinia, B. pertussis, Mycoplasma.
Streptococcus pyogenes uses lipoteichoic acid + F-protein.
Biofilms: polysaccharide matrix on teeth (≈300–400 species), catheters, valves.

Passive vs Active Defence Mechanisms (from Pathogen POV)

Passive

Capsule – anti-phagocytic (≤10 encapsulated S. pneumoniae lethal in mice).
Cell-wall lipids (mycolic acid in Mycobacterium) block phagolysosome fusion & drug entry.

Active (Extracellular Proteins / Enzymes)

Hyaluronidase – digests “cement” (Strep, Staph, Clostridia).
Collagenase – degrades collagen (C. perfringens α-toxin).
Streptokinase – dissolves clots, aids spread.
Coagulase – opposite effect, walls-off S. aureus.
DNase, lipase, protease – nutrient liberation + immune evasion.

Toxin Taxonomy

EXOTOXINS (secreted proteins)

Cytolytic (hemolysins): phospholipases, streptolysin O.
A-B toxins: separate Binding & Active subunits (diphtheria, botulinum, tetanus).
Superantigens: non-specific T-cell activation → cytokine storm (TSST-1).
ENTEROTOXINS: act on small intestine (V. cholerae, S. aureus food poisoning) → fluid loss.

ENDOTOXINS (LPS lipid A)

Integral to Gram(−) outer membrane; released on lysis.
Bind macrophage/B-cell receptors → IL-1, TNF-α, IL-6, complement C3a/C5a → fever, hypotension, DIC, shock.

Showcase Diseases & Molecular Mechanisms

Botulism (Clostridium botulinum)

A-B neurotoxin \approx 150\,\text{kDa}: heavy chain (binding/protection), light chain (Zn-endopeptidase).
Cleaves SNARE proteins → blocks \text{ACH} release ⇒ flaccid paralysis.
One gram could kill 10^7 humans.
Forms: food-borne, infant (honey spores; low gut flora, pH), wound.
Diagnosis: mouse bioassay or Endopeptidase-MS; therapy: horse antitoxin, debridement, ventilation.

Diphtheria (Corynebacterium diphtheriae)

A-B toxin inactivates EF-2 by ADP-ribosylation → protein-synthesis arrest (one molecule kills a cell).
Iron regulates tox gene (high Fe ↓ toxin).
Pseudomembrane throat lesion; systemic cardiomyopathy & neuropathy.
Treat with antitoxin + penicillin; toxoid vaccine (Schick test for immunity).

Staphylococcus aureus Syndromes

Enterotoxins (≥20; A, B, C1-3, D, E) = superantigens ⇒ vomiting/diarrhea.
Toxic Shock Syndrome: TSST-1 (enterotoxin F) absorbed via tampons → fever, rash, hypotension.
Scalded-Skin Syndrome (exfoliatin) – epidermal splitting in neonates (Ritter’s disease).
Panton-Valentine leukocidin: bi-component S/F proteins form pores in leukocytes.
Multiple hemolysins, carotenoids (anti-ROS), coagulase (+) pathogenesis of abscesses, carbuncles, impetigo, septicemia, gangrene.

Endotoxin-Related Pathologies

Neisseria meningitidis: virulence requires capsule, fimbriae & LPS.
Brucella & Francisella tularensis: LPS drives chronic symptoms; infectious dose <10 cells (inhalational) for F. tularensis.

Quantitative Nuggets

Exponential growth: 20-min doubling for 24 h ⇒ 2^{72} \approx 4.7 \times 10^{21} cells (theoretical upper bound).
Air exposure: inhalation ≈\frac{400\text{–}900\,\text{CFU}}{\text{m}^3} \times 8\,\text{L min}^{-1} \Rightarrow 10^4 microbes/day.
Capsule experiment: <10 encapsulated pneumococci lethal vs 10^4 decapsulated.

Host Factors in Pathogenesis

Age

Neonates & elderly show heightened susceptibility.

Stress

Over-exercise, malnutrition, dehydration, climatic shifts ↓ immunity ⇒ lower infectious dose threshold.

Innate Barriers

Skin: acid mantle pH\approx5 from sebaceous fatty + lactic acids.
Mucociliary escalator; ciliated epithelium clears particles.
Gastric acid pH\approx2; lysozyme in tears/kidneys; blood β-lysins disrupt bacterial membranes.
Normal intestinal flora (≈10^{10}\,\text{CFU g}^{-1}) competitively exclude pathogens.

Compromised Host & Nosocomial Risk

Immunosuppression, surgery, catheters, antibiotics foster opportunists & biofilm infections.

Environmental Modifiers

Temperature extremes, UV exposure, organic/inorganic pollutants influence pathogen survival & host resistance.

Ethical & Practical Implications

Vaccine production relies on controlled attenuation (safety vs immunogenicity balance).
Misuse of potent toxins (e.g., botulinum) = bioterror threat → drives development of rapid diagnostics (Endopeptidase-MS) & antitoxins.
Hospital infection-control: limit portal entry/exit, sterilise parenteral instruments, manage vector populations.
Emerging recognition of archaea & microbiome shifts calls for nuanced therapeutic approaches (target harmful syntrophic networks rather than single agents).

Key Formulae & Statistical References (LaTeX)

Theoretical exponential growth: N = N_0 \times 2^{t/g} where g = generation time.
Infectious dose metrics: ID_{50} = dose infecting 50\% of hosts.
Lethal dose metrics: LD_{50} for toxins/organisms.

Exam-Style Prompt (Mock)

Describe specific virulence factors—capsules, pili, exotoxins, endotoxins, invasins—detailing molecular biology, functional role, and contribution to pathogenesis. [45 marks]