N' meningitidis Meningitis N' gonorrheae Gonorrhea

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N. meningitidis - MeningitisN. gonorrheae -
Gonorrhea

• Non-motile, Gram negative
• Usually diplococci
• Aerobic to microaerophilic, fastidious
• Fragile

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Neisseria gonorrheae

• History
• Known since 100 AD
• Known to be venereal since 1200
• First cultivated in 1882
• Introduction of sulfa, penicillin successful, but
  followed by development of resistance
• Antibiotic therapy has not decreased incidence

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Neisseria gonorrheae

• Gonorrhea may be the most prevalent human
  bacterial disease
• Leading cause of STD in US
• gt400,000 cases reported yearly
• May be over 1 million
• Why is it called the clap?

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Gonorrhea

• Infection of cervix (women) or urethra (men,
  inflammatory response gt purulent discharge)

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Gonorrhea

• Urethral infections ...may cause pain during
  urination.... (pipe-benders disease)
• Male infection may extend to prostate and
  epididymis, causing sterility

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Gonorrhea

• Cervical colonization can ascend to uterus and
  fallopian tubes, causes salpingitis or pelvic
  inflammatory disease
• May have persistent pain in abdominal area, but
  many asymptomatic
• Scarring of fallopian tubes infertility, ectopic
  pregancy

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Gonorrhea

• Systemic disease arthritis, endocarditis,
  meningitis
• Gonorrhea neonatorum (ophthalmia neonatorum)
• eye infection during passage through birth canal
• can lead to blindness

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Virulence Factors and Pathogenesis

• Limited survival outside host
• Transmitted by direct contact
• Attaches by pili to columnar epithelium
• cervix, urethra, throat, rectum
• postpubescent women genital infection restricted
  to cervix
• vaginal mucosa squamous not columnar epithelium,
  cannot colonize squamous
• Phagocytic uptake follows attachment
• Adherence, invasion by process affecting actin
  rearrangements

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Virulence Factors and Pathogenesis

• Enter subepithelial space, causing purulent
  urethral/cervical discharge
• iron aquisition from transferrrin, lactoferrin
• acute inflammatory response, many PMNs
• some internalized bacteria remain intact
• vigorous antibody response includes sIgA against
  bacterial surface proteins
• repeated infection common due to variable surface
  antigens

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Virulence Factors and Pathogenesis

• Genetic variabliltiy in pili, other surface
  antigens occur in fraction of population
• gt 1 million possible pilus antigens
• arise from genetic rearrangements, pressure of
  immune response
• become dominant form in population
• original sIgA response rapidly becomes obsolete
• sIgA protease formed gt putative virulence
  attribute, not proven

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Virulence Factors and Pathogenesis

• Serum resistance
• especially important in systemic disease
• some covalently attach sialic acid to galactose
  residues on LOS
• sialic acid is an ubiquitous molecule, complement
  is not activated
• MAC does not form productively around altered LOS

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Treatment and Prevention

• Repeated attacks are common
• Adhesions
• Antibiotic-resistance some now resistant to
  beta-lactam, tetracycline
• Vaccine development in progress
• Difficult due to antigenic variation

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Neisseria meningitidis

• Causes meningitis, septicemia
• Only natural reservoir human nasopharyngeal
  mucosa
• 10 average nasal carrier rate
• many isolates may be from clones not associated
  with invasive meningococcal disease
• rate may be as high as 90 in some populations
• Transferred via direct contact or droplets

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Grouping of N. meningitidis

• Polysaccharide capsule 13 serogroups
• 20 serotypes, 10 subtypes (OMP antigens), 13
  immunotypes lipooligosaccharide (LOS)
• Group A epidemics ( 10-25/100,000 usually young
  adults)
• Groups B,C, Y endemic disease ( 2/105 usually
  children lt 5 years)
• Groups A, ltlt C important in 3rd world countries

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Colonization and Invasion

• Damage to ciliated epithelium increases risk of
  carriage and invasive disease (smoke, stress,
  viral infections)
• Adherence
• mediated by pili, OMPs (opacity proteins)
• engulfment by epithelial cells gt transcellular
  traversal (invasion)
• Most important virulence factor polysaccharide
  capsule
• protects against C, impedes phagocytosis

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Clinical Disease

• Subclinical/minimal disease
• transient meningococcemia, short febrile flu-like
  episode, cleared spontaneously
• Overt disease
• Fulminant meningeal sepsis (FMS)
• massive and rapid proliferation in bloodstream
• blood culture positive, usually also involves
  meningitis
• rapid clinical deterioration
• Meningitis
• lt bacterial proliferation in the bloodstream
• bacterial invasion of meninges, rapid
  proliferation in CSF
• endotoxin-mediated release of inflammatory
  mediators (permeability of BBB)
• influx of PMNs by upregulation of adherence
  molecules
• release of PMN products contributes to
  development of meningitis
• cerebral edema gt increased intracranial
  pressure, decreased perfusion
• brain stem herniation, intractable, rapidly fatal

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Pathogenesis of Septicemic DiseaseShock and
disseminated intravascular coagulation (DIC)

• Shock
• endotoxin causes capillary leakage, poor vascular
  tone, intravascular microthrombi, myocardial
  dysfunction
• C3a, C5a, inflammatory mediators cause
  vasodilatation, capillary leakage
• hypoperfusion gt shock
• DIC
• endothelial damage gt hemorrhages, microthrombi
• endotoxin, cytokines cause vasculitis
• upregulation of adhesion molecules on endothelium
  
• degranulation of activated neutrophils

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Diagnosis

• Early diagnosis of FMS or meningitis difficult,
  but crucial
• Later stages
• FMS skin lesions appear after 6 - 12 h, easier
  to recognize disease
• Meningitis skin lesions 12 - 18 h after onset,
  no lesions in 20 of patients
• Bacteriologic diagnosis
• FMS Gram stain of skin lesion biopsy specimen,
  buffy coat, CSF
• meningitis only CSF positive
• prior antibiotic therapy can cause false negative
  blood, CSF culture, skin biopsy specimens
  unaffected

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Therapy

• Survival little improved during last few decades
• Most important therapeutic principles
• therapy should never be delayed by diagnostic
  procedures
• antibiotics are the most important part of
  treatment
• Penicillin, cephalosporins
• Bacteria can remain viable in the nonperfused
  center of ischemic lesions for many hours

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Prevention

• Primary defense in naïve host is complement
  system
• Most important virulence factor polysaccharide
  capsule
• protects against C, impedes phagocytosis
• Specific immune response
• highest incidence at 6 - 24 months (loss of
  maternal antibodies)
• Polysaccharide vaccines based on group-specific
  antigens (A, C)
• major drawback absence of activity against group
  B
• vaccination should not influence upper
  respiratory colonization selection pressure may
  increase immunogenic variability
• Prevent disease in contacts by eradication of
  carrier state
• close contacts have 1,000X-higher incidence than
  general population
• prophylaxis for kissing contacts with rifampin

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Outcome - Mortality and Sequelae

• Meningitis
• lt 1 with treatment
• 85 without treatment
• neurological sequelae in 8 - 20 of survivors
  (deafness, mental retardation, concentration
  disturbances)
• Septicemia
• rapidly progressive antibiotic therapy often too
  late
• high mortality even with treatment