Microbial Diseases of the Nervous System – Key Vocabulary

Structure and Function of the Nervous System

• Central Nervous System (CNS)
  • Consists of brain and spinal cord
  • Responsible for integration and processing of information
• Peripheral Nervous System (PNS)
  • Nerves that branch from the CNS and innervate tissues
  • Relay sensory input to CNS and motor commands to effectors
• Meninges
  • Three protective membranes around brain & spinal cord: dura mater, arachnoid mater, pia mater
  • Subarachnoid space contains cerebrospinal fluid (CSF)
  • CSF cushions, provides nutrients, removes wastes
• Blood–Brain Barrier (BBB)
  • Tight endothelial junctions + selective transport
  • Limits pathogen, toxin, and drug penetration into CNS
  • Therapeutic challenge: many antibiotics/antibodies poorly cross BBB

Key Inflammatory Definitions

• Meningitis: inflammation of meninges
• Encephalitis: inflammation of brain parenchyma
• Meningoencephalitis: concurrent inflammation of meninges & brain
  • All can be bacterial, viral, protozoal, or prion-related

Bacterial Meningitis – General Clinical Course

• Early (hours): high fever, intense headache, stiff neck (nuchal rigidity)
• Intermediate: nausea, vomiting, photophobia
• Late/severe: convulsions, altered mental status, coma
• Mortality often due to shock + cytokine storm triggered by bacterial endotoxin / cell-wall fragments
• Viral meningitis is more common but generally self-limited and milder

Haemophilus influenzae Type b (Hib) Meningitis

• Characteristics
  • Gram-negative, aerobic coccobacillus; normal throat flora in many adults
  • Capsule antigen type b is main virulence factor (polyribitol phosphate)
• Epidemiology
  • Primarily 6 mo – 4 yr children (waning maternal antibody, immature adaptive immunity)
  • Accounts for ≈ 45 % of bacterial meningitis, ≈ 6 % mortality with treatment
• Prevention: conjugate Hib vaccine induces capsule-specific antibodies; part of routine childhood series
• Pathogenesis: colonization → bloodstream invasion → BBB penetration → meningeal infection

Neisseria meningitidis (Meningococcal) Meningitis

• Morphology: aerobic, gram-negative diplococcus with polysaccharide capsule
• Carriage: ~40 % healthy nasopharyngeal carriers (asymptomatic reservoir)
• Clinical course
  • Starts as sore throat ± upper‐respiratory infection
  • Rapid bacteremia → petechial rash & DIC; Waterhouse-Friderichsen crisis possible
• Outbreaks: common in crowded living (dorms, military barracks); droplet spread
• Vaccines: quadrivalent (A, C, W, Y) & separate B polysaccharide-protein conjugates; recommended for teens, military, travelers

Diagnosis & Empiric Therapy of Acute Bacterial Meningitis

• CSF sampling via lumbar puncture/spinal tap
  • Immediate gram stain, culture; organisms fragile at room-temp
  • Typical findings: turbid CSF, ↑ opening pressure, neutrophilia, ↓ glucose, ↑ protein
• Prompt empiric IV third-generation cephalosporins (e.g., ceftriaxone) ± vancomycin until organism identified
• Adjunct corticosteroids (dexamethasone) sometimes used to dampen inflammation

Listeriosis (Listeria monocytogenes)

• Gram-positive, facultative intracellular rod; motile (“tumbling”) @ room temp
• Transmission: usually food-borne (unpasteurized dairy, deli meats, soft cheeses, raw veggies); grows at refrigeration temps (psychrotroph)
• Clinical manifestations
  • Healthy adults: mild flu-like or subclinical
  • Immunocompromised/pregnant: septicemia, meningitis, fetal infection → stillbirth
• Pathogenesis
  • Phagocytosed → escapes phagosome via listeriolysin O → replicates cytosolically
  • Utilizes host actin polymerization to form “actin rockets” for cell-to-cell spread (immune evasion)
• Treatment: ampicillin ± gentamicin; prevention via food safety & pasteurization

Intracellular Movement of Listeria (Stepwise)

1. Entry by induced phagocytosis
2. Phagosome lysis & escape
3. Cytoplasmic replication
4. ActA protein triggers actin tail formation
5. Actin propels bacterium to host membrane protrusion
6. Adjacent cell engulfs protrusion, bacterium enters new cell
7. Cycle repeats without extracellular exposure

Botulism (Clostridium botulinum)

• Gram-positive, endospore-forming obligate anaerobe; spores abundant in soil & sediments
• Disease is primarily an intoxication: ingestion of preformed botulinum neurotoxin (BoNT)
• Neurotoxin specifics
  • Zinc endopeptidase composed of heavy & light chains
  • Binds cholinergic nerve terminals → endocytosis → light chain cleaves SNARE proteins (syntaxin, SNAP-25, synaptobrevin)
  • Blocks acetylcholine release: flaccid paralysis → respiratory/cardiac failure

Forms, Prevention & Treatment of Botulism

• Food-borne: improperly canned, anaerobic, low-acid foods
• Infant botulism
  • Ingested spores germinate in immature gut microbiota
  • Classically linked to honey; manifests as “floppy baby” syndrome
• Wound botulism: spore contamination in anaerobic wound (IV drug use)
• Management
  • Immediate trivalent or heptavalent antitoxin (equine) to neutralize circulating toxin
  • Intensive respiratory support (mechanical ventilation)
• Prevention: proper heat-pressure canning; \text{NO_2^-} preservatives in cured meats inhibit C. botulinum

Tetanus (Clostridium tetani)

• Gram-positive, spore‐forming obligate anaerobe; spores ubiquitous in soil/dust
• Entry via deep puncture wounds, burns, intravenous drug sites
• Toxin: tetanospasmin (potent A-B exotoxin)
  • Block synaptic release of inhibitory neurotransmitters (glycine & GABA) at spinal interneurons
  • Mechanism: light chain cleaves synaptobrevin → unchecked acetylcholine release at NMJ → spastic paralysis (rigid muscles, “lockjaw,” opisthotonos)
  • Death via respiratory muscle spasms & autonomic instability

Prevention & Therapy of Tetanus

• Vaccine: toxoid component of DTaP (childhood) & Tdap (adult) induces neutralizing antibodies; booster every 10 yrs
• Incidence: < 10 U.S. cases/yr; 25–50 % mortality without intensive care
• Post-exposure prophylaxis: wound cleaning + tetanus immune globulin (TIG) ± booster; debridement removes anaerobic niche

Leprosy (Hansen’s Disease)

• Agent: Mycobacterium leprae
  • Acid-fast, obligate intracellular, prefers cooler (30 °C) peripheral tissues
  • Very slow generation time (≈ 12 days)
  • Invades Schwann cells → demyelination & sensory loss
• Transmission: prolonged skin contact or inhalation of nasal droplets; low contagiousness (95 % naturally immune)
• Clinical spectra
  • Tuberculoid (paucibacillary): localized plaques, peripheral nerve damage, hypoesthesia
  • Lepromatous (multibacillary): disseminated nodules, leonine facies, mucosal involvement; high bacillary load
• Diagnosis: acid-fast bacilli in skin smear/biopsy, serology (PGL-1 antibody)
• Treatment regimen (6–24 mo)
  • \text{Dapsone} + \text{Rifampin} (± Clofazimine for multibacillary)
• Ethical/social note: historical stigma & isolation colonies; WHO MDT programs have reduced prevalence dramatically

African Trypanosomiasis (Sleeping Sickness)

• Agent: Trypanosoma brucei gambiense (chronic), T. b. rhodesiense (acute)
• Vector: tsetse fly (Glossina spp.); human reservoir vs. zoonotic variants
• Geography: west & central Africa (gambiense); east Africa (rhodesiense)
• Stages
  1. Hemolymphatic: fever, lymphadenopathy (Winterbottom’s sign), arthralgia
  2. Meningoencephalitic: CNS invasion → daytime somnolence, nighttime insomnia, personality change, coma
• Immune evasion: antigenic variation of variant surface glycoprotein (VSG) coat; hampers vaccine development
• Control: vector eradication (insecticide traps), screen/treat reservoirs

Amebic Meningoencephalitis (Naegleria fowleri)

• Free-living thermophilic protozoan (amoeba)
• Entry: water forced up nasal cavity during swimming/diving; crosses cribriform plate → brain
• Disease: Primary Amebic Meningoencephalitis (PAM)
  • Rapidly progressive (days), hemorrhagic necrosis; almost 100 % fatal
• Prevention: avoid warm freshwater nasal exposure, use nose clips, chlorine maintenance in pools

Rabies

• Virus: Lyssavirus, enveloped, bullet-shaped, \text{ssRNA(−)}; high mutation rate
• Transmission: bite from infected mammal; saliva inoculation; rarer via aerosols (bat caves) or organ transplant
• U.S. reservoir: silver-haired bats major, also raccoons, skunks, foxes
• Pathogenesis
  1. Viral replication at bite myocytes
  2. Retrograde axonal transport via PNS to CNS (incubation 30–50 days; depends on bite site distance)
  3. Encephalitis, Negri body inclusions in neurons
  4. Centrifugal spread to salivary glands, cornea, kidneys
• Clinical forms
  • Furious (classic): agitation, hydrophobia, hypersalivation, aerophobia
  • Paralytic (dumb): flaccid paralysis, minimal agitation
• Post-exposure prophylaxis (PEP)
  • Immediate wound cleansing, rabies immune globulin (RIG) infiltration, 4-dose inactivated vaccine series (days 0, 3, 7, 14)

Prion-Associated Neurodegenerative Diseases

• Prion = misfolded protein (PrP^{\text{Sc}}) that catalyzes conformational change of normal cellular PrP^{\text{C}}
• Mechanism (see step diagram)
  1. Cells synthesize & surface-display PrP^{\text{C}}
  2. PrP^{\text{Sc}} (acquired or mutated) binds PrP^{\text{C}}
  3. Interaction induces refolding into β-sheet-rich PrP^{\text{Sc}}
  4. Misfolded proteins aggregate → endocytosed → accumulate in endosomes/lysosomes
  5. Neuronal vacuolation (spongiform change) → apoptosis → brain atrophy
• Transmissible Spongiform Encephalopathies (TSEs)
  • Sheep scrapie
  • Bovine spongiform encephalopathy (BSE, “mad cow”)
  • Creutzfeldt–Jakob disease (CJD) & variant CJD in humans
• No treatment; prevention via feed bans, surgical instrument sterilization (NaOH + autoclave)

Integrated Themes & Exam Tips

• Capsule barriers (Hib, meningococcus) vs. intracellular lifestyle (Listeria) illustrate distinct immune evasion strategies
• Clostridial neurotoxins are prototypes of A-B exotoxins; memorize opposing paralysis patterns:
  • BoNT → flaccid (↓ ACh release)
  • Tetanospasmin → spastic (↓ GABA/Gly release)
• Blood–brain barrier limits drug entry; choose antibiotics with good CNS penetration (3rd-gen cephs, meropenem)
• Antigenic variation (trypanosomes) vs. mutation (rabies) vs. conformational templating (prions): compare mechanisms impairing vaccine design
• Public health relevance: vaccination (DTaP, Hib, meningococcal, rabies), food safety (botulism, listeria), vector control (tsetse)
• Ethical implications: leprosy stigma, prion surveillance, antibiotic stewardship to prevent resistance