Molecular Mechanisms of Microbial Pathogenesis¶
Chapter 125 | Part 5: Infectious Diseases
KEY CLINICAL POINTS¶
- Microbial pathogenesis involves adhesion, secretion systems, immune evasion, and tissue damage mechanisms.
- Bacterial adhesion is mediated by adhesins like pili, flagella, and autotransporters, which target host receptors.
- Secretion systems (Type III, IV, V, VI) enable intracellular survival, immune evasion, and toxin delivery.
- Pathogens evade innate immunity through complement inhibition, antimicrobial peptide resistance, and oxidative stress.
- Inflammasomes and autophagy are critical for host defense against bacterial infections.
1. DEFINITION & OVERVIEW¶
Microbial pathogenesis involves complex interactions between pathogens and host defenses. Pathogens must overcome host barriers, evade immune responses, and establish infection through molecular mechanisms such as adhesion, secretion, and immune evasion.
Table 124-5: Initial Empirical Antibiotic Therapy for Skin Infections¶
| Clinical Syndrome | Common Etiologies | Antibiotic(S) | Comments |
|---|---|---|---|
| Skin and soft tissue infection | S. aureus, Streptococcus pyogenes | Dicloxacillin, Cephalexin, Clindamycin, Nafcillin/oxacillin | MRSA consideration: vancomycin, linezolid, TMP-SMX |
| Skin and soft tissue infection | S. aureus, Streptococcus pyogenes | Clindamycin | Use with caution for MRSA |
| Skin and soft tissue infection | S. aureus, Streptococcus pyogenes | TMP-SMX | Limited efficacy for skin infections |
1.1 Entry into the Human Host¶
Pathogens enter via respiratory, gastrointestinal, or genitourinary routes. Respiratory pathogens spread via droplets, gastrointestinal pathogens via contaminated food/water, and genitourinary pathogens via sexual contact or instrumentation.
1.2 Adhesion and Niche Establishment¶
Adhesion to host tissues is mediated by adhesins (pili, flagella, autotransporters) and host receptors. Pathogens establish niches by modifying host cell signaling and avoiding immune clearance.
2. ADHESION AND NICHES¶
Adhesins mediate bacterial attachment to host tissues. Pili, flagella, and autotransporters are key adhesion structures. Pathogens exploit host receptors to establish niches and avoid clearance.
Table 125-1: Bacterial Pathogens, Diseases, and Niches¶
| Most Common Tropism | Bacterium | Disease |
|---|---|---|
| Skin, respiratory tract, small intestine | Bacillus anthracis | Anthrax |
| Respiratory tract | Bordetella pertussis | Pertussis |
| Systemic | Borrelia burgdorferi | Lyme disease |
| Colon | Clostridioides difficile | Colitis |
| Pharynx | Corynebacterium diphtheriae | Diphtheria |
Table 125-2: Classes of Bacterial Adhesion Proteins and Their Host Receptors¶
| Adhesin | Example | Receptor |
|---|---|---|
| Type I pili | Fim protein, uropathogenic E. coli | Terminal mannose of uroplakin N-glycan |
| Type IV pili | Tfp protein, Neisseria gonorrhoeae | CD64, CR3, integrins |
| Autotransporter | Invasin, Yersinia pseudotuberculosis | b1-Integrins |
| Flagellum | FliC protein, Pseudomonas aeruginosa | Asialo-GM1 ganglioside |
2.1 Adhesins and Host Receptors¶
Pili (Type I, P, IV) bind to host glycoproteins (e.g., uroplakin, CD64). Flagella mediate motility and adhesion. Autotransporters (e.g., invasin, intimin) facilitate bacterial internalization.
2.2 Biofilm Formation¶
Pathogens like S. aureus and P. aeruginosa form biofilms to resist phagocytosis and antibiotics. Biofilms consist of extracellular polysaccharides and DNA.
3. SECRETION SYSTEMS¶
Bacterial secretion systems (Type III, IV, V, VI) deliver effector proteins to modulate host cell processes. These systems are critical for intracellular survival and immune evasion.
Table 125-3: Pattern Recognition Receptors and Ligands¶
| Pattern Recognition Receptor | Ligand or Mode of Activation |
|---|---|
| TLR2 (with TLR1 or TLR6) | Lipoproteins |
| TLR4 | LPS |
| TLR5 | Flagellin |
| TLR9 | CpG DNA |
| NOD1 | Peptidoglycan |
| NOD2 | Peptidoglycan |
3.1 Type III Secretion System (T3SS)¶
Delivers effector proteins into host cells to manipulate cytoskeleton and inhibit immune responses. Used by Shigella, Salmonella, and Chlamydia.
3.2 Type IV Secretion System (T4SS)¶
Transfers DNA and proteins into host cells. Involved in horizontal gene transfer and virulence factor delivery.
4. AVOIDANCE OF INNATE IMMUNE RESPONSES¶
Pathogens evade innate immunity through complement inhibition, antimicrobial peptide resistance, and oxidative stress. They also subvert signaling pathways like NF- κ B and MAPK.
4.1 Complement Evasion¶
Pathogens inhibit complement activation via capsules, surface proteins (e.g., M proteins), or enzymatic degradation of complement components.
4.2 Antimicrobial Peptide Resistance¶
Gram-negative bacteria modify LPS to reduce binding of defensins. Gram-positive bacteria use thick peptidoglycan layers for resistance.
5. INFLAMMASOMES AND INFLAMMATORY RESPONSES¶
Inflammasomes (NLRP3, pyrin, AIM2) drive inflammatory responses by activating caspase-1 and releasing IL-1 β and IL-18. Pathogens inhibit inflammasome activation to avoid immune clearance.
5.1 NLRP3 Inflammasome¶
Activated by ion flux, mitochondrial damage, or crystalline structures. Inhibited by bacterial toxins like YopH and MARTX.
5.2 Caspase-1 Activation¶
Caspase-1 cleaves GSDMD to form pores, leading to pyroptosis and cytokine release. Pathogens block this via effector proteins.
6. AUTOPHAGY AND EPGENETIC CONTROL¶
Autophagy degrades intracellular pathogens via lysosomes. Pathogens inhibit autophagy by blocking LC3 activation or lysosome fusion. Epigenetic modifications regulate immune gene expression.
7. BACTERIAL CYTOTOXINS¶
AB toxins (e.g., Shiga toxin, diphtheria toxin) disrupt host cell function. Pore-forming toxins (e.g., listeriolysin O) lyse host membranes and resist phagocytosis.
7.1 AB Toxins¶
A subunit (enzymatic activity) and B subunit (receptor binding). Examples: Shiga toxin, diphtheria toxin, cholera toxin.
7.2 Pore-Forming Toxins¶
Induce membrane permeabilization. Examples: Listeriolysin O, hemolysins, leukocidins.
8. TISSUE DAMAGE AND PATHOGEN DISSEMINATION¶
Pathogens disrupt tight junctions and epithelial barriers to invade deeper tissues. This facilitates dissemination to lymphatics and bloodstream, enabling systemic infection.
8.1 Disruption of Tight Junctions¶
Toxins like RTX-A and SPATEs degrade junctional proteins, compromising epithelial integrity.
8.2 Organ Tropism¶
Pathogens like V. cholerae target intestinal epithelium, while L. monocytogenes spreads via actin-based motility.
9. TRANSMISSION TO NEW HOSTS¶
Pathogens spread via respiratory droplets, fecal-oral routes, or vector-borne transmission. Bacteriophages influence V. cholerae's aquatic lifecycle and disease transmission.
9.1 Respiratory Transmission¶
Coughing aerosolizes pathogens, enabling inhalation by new hosts. Examples: TB, influenza.
9.2 Fecal-Oral Transmission¶
Contaminated food/water spreads pathogens like S. typhi and E. coli. Hand hygiene reduces transmission.
10. BACTERIOPHAGES AND PATHOGEN LIFESTYLE¶
Bacteriophages influence pathogen survival in aquatic environments. V. cholerae's lifecycle is regulated by phage infection, affecting disease outbreaks.
10.1 Phage-Lyse Cycle¶
Phages lyse V. cholerae, releasing viral particles into water. This influences bacterial population dynamics and disease transmission.
10.2 Environmental Reservoirs¶
Pathogens like V. cholerae persist in aquatic environments, awaiting host entry for replication.