Molecular Mechanisms of Microbial Pathogenesis¶
Chapter 125 | Part 5: Infectious Diseases · Part 5 – Infectious Diseases: Bacterial · Chapter 125
Key Clinical Points¶
- Infectious diseases occur when a live pathogen enters or a toxic pathogen product is ingested by the host.
- The infection process involves a multi-step progression: microbial entry (colonization), attachment in favored niches, immune evasion, replication, and transmission.
- Bacterial attachment to host tissues relies on receptor–ligard interactions mediated by pili (Type I, IV), flagella, and autotransporter proteins.
- The Type III Secretion System (T3SS) functions as a 'needle-and-syringe' mechanism to deliver effector proteins into eukaryotic cells (e.g., Salmonella, Shigella).
- Bacteria utilize diverse strategies for nutrient acquisition in nutrient-poor infection sites.
- The complement system is a critical innate defense; pathogens often evolve mechanisms to target and evade specific points of the cascade, including opsonization and Membrane Attack Complex (MAC) formation.
- Biofilms provide protection against immune clearance and significantly hinder antibiotic penetration.
- Host factors such as CFTR mutations or FUT2 deficiency significantly influence susceptibility to specific infections.
- Pathogen tropism determines the clinical site of infection (e.g., S. aureus in soft tissue, M. tuberculosis in the respiratory tract).
1. DEFINITION & OVERVIEW¶
• Core Concept: The study of infectious diseases focuses on host–microbial interactions, reflecting an evolutionary arms race between pathogens and the immune system. • Infection Process: - Microbial entry (colonization) - Attachment in favored niches - Immune evasion - Deployment of virulence factors causing tissue damage - Transmission to new hosts - Modulation by host microbiota
2. EPIDEMIOLOGY¶
• Global Impact: Infectious diseases account for approximately 1/6 of global deaths. • Emerging Threats: Includes SARS-CoV-2, mpox, and viral hemorrhagic fevers. • Biosecurity: Microbial bioterrorism remains a significant threat. • Host Genetics: Cystic fibrosis (CF) prevalence (>2.5% in Caucasians) is linked to increased resistance against Salmonella Typhi due to CFTR receptor interactions.
3. ETIOLOGY & PATHOPHYSIOLOGY¶
• Entry Routes: Skin/mucosal barriers, respiratory droplets, gastrointestinal ingestion, genitourinary colonization. • Pathogen Types: - Preformed toxins (e.g., S. aureus enterotoxins, botulinum toxin) - Live pathogens with tissue-specific tropism (e.g., Group A streptococci cause pharyngitis but not pneumonia). • Table 125-1: Lists bacterial pathogens, associated diseases, and tissue tropism.
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 | |
| Systemic | Borrelia burgdorferi | Lyme disease |
| Systemic | Brucella abortus | |
| Systemic | Burkholderia pseudomallei | Melioidosis |
| Eyes, venereal | Chlamydia trachomatis | Various chlamydioses |
| Colon | Clostridioides difficile | Colitis |
| Colon | Corynebacterium diphtheriae | Diphtheria |
| Systemic | Coxiella burnetii | Q fever |
| Colon | Enterohemorrhagic Escherichia coli | |
| Stomach | Helicobacter pylori | Gastritis, gastric ulcers |
| Respiratory tract | Legionella pneumophila | Legionnaires’ disease |
| Systemic, central nervous system | Listeria monocytogenes | Listeriosis |
| Respiratory tract | Mycobacterium tuberculosis | Tuberculosis |
| Urogenital tract | Neisseria gonorrhoeae | Gonorrhea |
| Respiratory tract | Pseudomonas aeruginosa | Pneumonia |
| Systemic | Salmonella enterica serovar Typhi | Typhoid fever |
| Systemic | Salmonella enterica serovar Typhimurium | Typhoid fever |
| Colon, rectum | Shigella spp. | Dysentery, shigellosis |
| Soft tissue | Staphylococcus aureus | Skin infection |
| Soft tissue | Group A Streptococcus | Soft tissue infection |
| Small intestine | Vibrio cholerae | Cholera |
| Systemic | Yersinia pestis | Plague |
Table 125-2 Classes of Bacterial Adhesion Proteins and Their Host Receptors
| ADHESIN | EXAMPLE | RECEPTOR |
|---|---|---|
| Type I pili | Fim protein, uropathogenic Escherichia coli | Terminal mannose of uroplakin N-glycan in urinary epithelial cells |
| Type P pili | Pap protein, uropathogenic E. coli | |
| Type IV pili | Tfp protein, Neisseria gonorrhoeae | CD64, CR3, I domain–containing integrins |
| Opa | Opa protein, Neisseria meningitidis | CEACAMsa |
| MSCRAMM | SdrC protein, Staphylococcus aureus | β-Neurexin |
| Flagellum | FliC protein, Pseudomonas aeruginosa | Asialo-GM1 ganglioside |
| Autotransporter | Invasin, Yersinia pseudotuberculosis | β1-Integrins |
| Autotransporter | Ag85, Mycobacterium tuberculosis | Fibronectin |
3.1 Attachment Mechanisms¶
• Receptor–Ligand Interaction: Critical for niche establishment. • Adhesin Types: - Pili: Type I (e.g., E. coli to uroplakin N-glycan) and Type IV (e.g., N. gonorrhoeae to CD64, CR3, or integrins). - Flagella: Facilitate chemotaxis and adhesion (e.g., P. aeruginosa to Asialo-GM1). - Autotransporters: Mediate intimate interactions (e.g., Invasin in Y. pseudotuberculosis to β1-Integrins; Ag85 in M. tuberculosis to Fibronectin). • Table 125-2: Details specific adhesin classes and their corresponding host receptors (e.g., Opa protein binding to CEACAMsa).
3.2 Mechanisms of Microbial Entry¶
• Trigger Mechanism: - Pathogens: Shigella, Salmonella spp. - Pathway: T3SS → delivery of effector proteins → cytoskeleton manipulation → formation of membrane ruffles → endocytosis. • Zipper Mechanism: - Pathogens: Yersinia, Listeria spp. - Pathway: Bacterial surface proteins → host receptor clustering → 'zipping' of the membrane → uptake in a tightly opposed vacuole. • Intracellular Movement: Actin-based motility enables cell-to-cell spread (e.g., L. monocytogenes, Rickettsia).
3.3 Survival in the Vacuole¶
• Endosomal Subversion: Bacterial effector proteins prevent maturation (e.g., L. pneumophila phospholipase VipD). - T4SS systems deliver proteins to alter vacuolar environments. • Escape Strategies: - L. monocytogenes: Uses listeriolysin O. - Shigella: Utilizes T3SS for escape. • Innate Immune Recognition: - Autophagy (Xenophagy): Detection of invasion or nutrient depletion → phagophore formation → autophagosome → fusion with lysosome → degradation. - Inflammasome Activation: Sensing of PAMPs/DAMPs → Inflammasome assembly → Caspase-1 activation → [Pro-inflammatory gene expression (IL-1β, IL-18)] and [Gasdermin D pore formation → K⁺ efflux → pyroptotic cell death]. • Table 125-3: Lists Pattern Recognition Receptors (PRRs) and their ligands (e.g., TLR2/Lipoproteins, TLR5/Flagellin, STING/Cyclic dinucleotides).
4. CLINICAL FEATURES¶
• Tissue Tropism: Manifestations are determined by the specific site of infection (e.g., systemic vs. localized). • Toxin-Mediated Disease: Examples include botulism and cholera. • Chronic Carriage: Driven by successful immune evasion strategies.
5. DIFFERENTIAL DIAGNOSIS¶
• Etiology Distinction: Differentiate bacterial vs. viral infections based on clinical presentation. • Mechanism Differentiation: Distinguish between toxin-mediated vs. invasive disease mechanisms. • Host Factor Influence: Consider host factors (e.g., CFTR mutations, FUT2 deficiency) that affect susceptibility.
6. INVESTIGATIONS & DIAGNOSIS¶
- Clinical Assessment: Evaluate symptoms based on tissue-specific manifestations.
- Microbiological Culture: Primary method for identifying pathogens and serotyping.
- Molecular Testing: Used for rapid identification and detection of specific virulence factors.
- Imaging: Utilized for abscess localization or assessing systemic involvement.
- Complement Assays: Used in research/clinical settings to study immune evasion.
7. MANAGEMENT & TREATMENT¶
- Antibiotic Therapy: Target specific virulence mechanisms (e.g., inhibiting T3SS or biofilm formation).
- Adjunctive Therapies: Use immunoglobulins for conditions like C. difficile.
- Biofilm Disruption: Strategies to overcome antibiotic resistance in chronic infections.
- Vaccination: Targeted at pathogens utilizing specific adhesins.
8. PROGNOSIS & COMPLICATIONS¶
• Prognostic Factors: Determined by pathogen virulence, host immunity, and timing of treatment. • Common Complications: Sepsis, abscess formation, and chronic carriage. • Long-term Sequelae: e.g., postbotulism neuropathy in toxin-mediated cases.
9. SPECIAL CONSIDERATIONS¶
• Cystic Fibrosis: Altered CFTR function → increased S. Typhi adherence. • Glycan Deficiency: FUT2 nonfunctional alleles → altered susceptibility to infection. • Microbiome Influence: Host microbiota modulates all stages of infection.
10. KEY PEARLS & CLINICAL TRAPS¶
• T3SS Importance: Essential for bacterial intracellular survival and host cell manipulation. - Trigger mechanism (Salmonella/Shigella) vs. Zipper mechanism (Listeria/Yersinia). • Biofilms: Primary cause of antibiotic resistance in chronic infections. • Complement Evasion: A critical virulence mechanism; pathogens may inhibit specific points in the cascade to avoid opsonization or MAC formation.
TABLES¶
Table 125-3: Pattern Recognition Receptors of the Innate Immune System and Their Ligands | PATTERN RECOGNITION RECEPTOR | LIGAND OR MODE OF ACTIVATION | | --- | -- | | TLR2 (with TLR1 or TLR6) | Lipoproteins | | TLR5 | Flagellin | | NLRP1 | Enzymatic cleavage | | NLRP6 | Lipoteichoic acid, RNA | | STING | Cyclic dinucleotides | | NOD1 and NOD2 | |
Reference Tables¶
TABLE 124-5 Initial Empirical Antibiotic Therapy for Common Infectious Disease Presentations a¶
Harrison's 22e, p.964
| CLINICAL SYNDROME | COMMON ETIOLOGIES | ANTIBIOTIC(S) | COMMENTS | SEE CHAPTER(S) |
|---|---|---|---|---|
| Skin and soft tissue infection |
S. aureus, Streptococcus pyogenes |
Dicloxacillin, 250–500 mg PO qid or Cephalexin, 250–500 mg PO qid or Clindamycin, 300–450 mg PO tid or Nafcillin/oxacillin, 1–2 g q4h |
If MRSA is a consideration, clindamycin, vancomycin (15 mg/kg q12hb), linezolid (600 mg IV/PO q12h), or TMP-SMX (1–2 double-strength tablets PO bidg) can be used. |
134 and pathogen- specific chapters |
| 125 | Molecular Mechanisms of Microbial Pathogenesis Jordan B. Jastrab, Marcia B. Goldberg |
TABLE 125-1 Bacterial Pathogens, Diseases, and Niches¶
Harrison's 22e, p.965
| MOST COMMON TROPISM |
BACTERIUM | DISEASE |
|---|---|---|
| Skin, respiratory tract, small intestine |
Bacillus anthracis | Anthrax |
| Bordetella pertussis | ||
| Systemic | Borrelia burgdorferi | Lyme disease |
| Brucella abortus | ||
| Systemic | Burkholderia pseudomallei | Melioidosis |
| Chlamydia trachomatis | ||
| Colon | Clostridioides difficile | Colitis |
| Corynebacterium diphtheriae |
||
| Systemic | Coxiella burnetii | Q fever |
| Enterohemorrhagic Escherichia coli |
||
| Stomach | Helicobacter pylori | Gastritis, gastric ulcers |
| Legionella pneumophila | ||
| Systemic, central nervous system |
Listeria monocytogenes | Listeriosis |
| Mycobacterium tuberculosis | ||
| Urogenital tract | Neisseria gonorrhoeae | Gonorrhea |
| Pseudomonas aeruginosa | ||
| Systemic | Salmonella enterica serovar Typhi |
Typhoid fever |
| Salmonella enterica serovar Typhimurium |
||
| Colon, rectum | Shigella spp. | Dysentery, shigellosis |
| Staphylococcus aureus | ||
| Soft tissue | Group A Streptococcus | |
| Vibrio cholerae | ||
| Systemic | Yersinia pestis | Plague |
TABLE 125-2 Classes of Bacterial Adhesion Proteins and Their Host Receptors ADHESIN Type I pili¶
Harrison's 22e, p.966
| ADHESIN | EXAMPLE | RECEPTOR |
|---|---|---|
| Type I pili | Fim protein, uropathogenic Escherichia coli |
Terminal mannose of uroplakin N-glycan in urinary epithelial cells |
| Pap protein, uropathogenic E. coli | ||
| Type IV pili | Tfp protein, Neisseria gonorrhoeae |
CD64, CR3, I domain– containing integrins |
| SdrC protein, Staphylococcus aureus |
||
| Opa | Opa protein, Neisseria meningitidis |
CEACAMsa |
| FliC protein, Pseudomonas aeruginosa |
||
| Autotransporter | Invasin, Yersinia pseudotuberculosis |
β1-Integrins |
| Ag85, Mycobacterium tuberculosis |
TABLE 125-3 Pattern Recognition Receptors of the Innate Immune System and Their Ligands¶
Harrison's 22e, p.971
| PATTERN RECOGNITION RECEPTOR | LIGAND OR MODE OF ACTIVATION |
|---|---|
| TLR2 (with TLR1 or TLR6) | Lipoproteins |
| TLR5 | Flagellin |
| NLRP1 | Enzymatic cleavage |
| NLRP6 | Lipoteichoic acid, RNA |
| STING | Cyclic dinucleotides |