Lecture 24

• current global burden of tuberculosis

  1/3 of world population infected

  about 2 billion people

  2-3 mil deaths per year

  leading killer of HIV positive people
• tuberculosis (TB)

  Mycobacterium tuberculosis

  inhaled, lung phagocytosed by macrophages, survives intracellularly

  infectious dose <10 cells (very low)

  cell wall mycolic acids - preparation
• tuberculosis host response

  forms tubercles, bacteria can become latent

  25% of worlds population have latent TB (13 million in US)

  people with laten TB not infectious, cant spread bacteria

  tubercles can liquify, bacteria can spread to blood, organs, become transmissible

  
• TB skin test

  mantoux tuberculin skin test (TST)

  standard method of determining whether person has had TB or been exposed to M. tuberculosis
• mantoux tuberculin skin test (TST)

  bacterial proteins injected in forearm

  immune response (induration) measured in mm (48-72 hrs)

  reaction: delayed hypersensitivity

  antigen presenting macrophages attract and activate sensitized memory T cells

  Koch tried to develop vaccine out of tuberculin
• TB vaccine

  Bacille Calmette-Guerin

  live avirulent M. bovis

  not generally recommended in US
• TB diagnosis

  bloody sputum, chest x ray, acid fast staining, culture
• TB antimicrobial therapy

  rifampin and isoniazid (inhibits mycolic acid synthesis)

  daily, 6-9 months

  antibiotic resistance emerging (MDR, XDR)
• streptococcal diseases

  Streptococcus pyogens (group A beta hemolytic) or S. pneumoniae

  impetigo (skin), throat, lung, pneumoniae, ear (otitis media)

  treatment: penicillins, erythromycin
• streptococcal diseases diagnosis/ prevention

  diagnosis: culture and strep test, uses labeled antibody to detect cell wall carbohydrates

  prevention: pneumococcal vaccine (prevnar), polysaccharide based
• streptococcal virulence factors

  capsule and M protein

  promote adherence

  antibody to M can cross react with heat tissue, causing Rheumatic fever (autoimmune disease)
• Group a streptococci can also cause invasive infections

  some strains make tissue destroying protease

  necrotizing fascitis

  flesh eating bacteria
• streptococcus mutans

  part of dental plaque (biofilm)

  fermentation -> acid -> enamel (decay)
• whooping cough (pertussis)

  Bordetella pertussis (gram negative)

  colonizes ciliated cells of respiratory tract

  stage 1: cold like symptoms

  stage 2: prolonged cough (with inspiratory gasp or whoop)
• virulence factors of pertussis

  pili: adherence

  siderophores: acquire iron

  pertussis toxin: AB exotoxin, some MOA as cholera toxin
• pertussis vaccination and treatment

  subunit vaccine DTP (1940)

  DT: toxoids

  P: killed bacteria

  DTaP currently

  • DT
  • aP: acellular, toxoid and other protein antigens

  Tdap booster

  antibiotics: tetracycline and erythromycin
• meningitis

  inflammation brain, spinal cord meninges (membranes)

  bacteria, viruses, fungi

  bacteria

  • Haemophilus influenzae
  • Streptococcus pneumoniae
  • Neisseria meningitidis
• Neisseria meningitidis

  gram negative

  leading cause meningococcal disease in children, young adults

  person to person, respiratory or throat secretions

  can cross mucosal barrier into blood
• serogroups - neisseria meningitidis

  groups of strains with common surface antigens (A, B, C, Y, W)

  based on capsular polysaccharides
• virulence factors - neisseria meningitidis

  pili

  capsules

  endotoxin
• neisseria meningitidis - meningitis

  initial sore throat, vomiting, confusion, stiffness in neck, rash

  prevention: vaccines

  MCV4: based on capsular polysaccharide

  protects against A, C, Y and W (not B)

  bexsero: based on group B outer membrane protein
• neisseria meningitidis - meningitis diagnosis and treatment

  diagnosis: gram stain spinal fluid, culture bacterium

  treatment: antibiotics (cell wall, translation inhibitors)
• black death or plague spread throughout europe during the middle ages, claiming millions of victims
• the plague

  Yersinia pestis (gram negative)

  2 forms:

  • bubonic: flea
  • pneumonic: person to person - flu like (fatal if not treated early), category A bioweapons agent

  Yersinia injects toxic protein into human cells using type 3 secretion system
• type 3 secretion system - plague

  used by many gram negative pathogens

  injectisome

  injects protein (sops, yops)

  effector targets (cytoskeleton, signaling NFkappaB)

  A) pore

  B) needle

  C) basal body

  
• yersinia injects effectors into human cells including macrophages

  what effect do effectors have?

  blocking cytoskeleton rearrangements
• An average of only seven human plague cases are reported in the U.S. each year. Almost all bubonic.

  Most cases are in the west, where many types of animals can be infected, including rock squirrels, wood rats, ground squirrels, prairie dogs, chipmunks, mice and rabbits.
• lyme disease

  most commonly reported tick borne disease in US

  caused by spirochete Borrelia burgdorferi

  vector: blacklegged deer tick - Ixodes

  clinical: varies with stage of disease
• reported cases of Lyme disease

  30,000 confirmed cases reported to CDC annually
• stages of lyme disease - localized

  7-10 days

  bullseye rash (erythema migrans), flu like symptoms

  most treatable

  doxycycline (tetracycline, penicillins)
• stages of lyme disease - disseminated

  weeks or months

  muscle pain, arthritis (autoimmunity?)

  antibody to borrelia proteins, many cross react with human MHC molecules

  late (years): nervous system
• direct contact diseases

  anthrax (also airborne and zoonotic routes of transmission)

  staphylococcal diseases
• anthrax

  Bacillus anthracis

  virulence factors: capsule

  toxin: AB but 3 parts, targets macrophages, cell death

  toxin and capsule genes encoded on separate plasmids
• forms of anthrax

  cutaneous: cut, abrasion

  pulmonary: spores inhaled, enter macrophages in lung, germinate and produce toxin - kills macrophages and other cells

  active bacteria spread, fatal if bacteria reach bloodstream

  early treatment critical (ciprofloxacin)

  spores used for an act of bioterrorism in 2001 causing 17 cases of pulmonary anthrax (5 deaths)
• Staphycoccal diseases

  two major species

  S. aureus: invasive, virulent (coagulase positive)

  S. epidermidis: less invasive, less virulent (coagulase negative)

  clinically, the coagulase test can be used to differentiate

  diseases: boils, carbuncles, toxic shock syndrome, food poisoning
• S. aureus has an arsenal of virulence factors

  superantigens (TSST-1)

  enterotoxins (food poisoning)

  capsules

  IgA protease

  coagulase

  virulence genes often controlled by quorum sensing and 2 component systems