MMI 301: Lecture 24: Neisseria

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  1. Neisseria species
    • Pathogenic:
    • N. gonorrhoeae
    • N. meningitidis
    • Symbiotic:
    • N.cinerea
    • N.flavescens
    • N.lactamica
    • N.mucosa
    • N.sicca
    • N.subflava
  2. Neisseria Morphology
    Gram - diplococci
  3. Neisseria motility
    • No flagella, non-motile in liquids
    • Motile on solid surface via twitching (type IV pili)
  4. Neisseria endotoxin
    • Differs structurally from common LPS
    • There is not a repeating O-antigen polysacc.
    •      -Has lipoolligosaccharide (LOS not LPS)
    • LOS cannot protect from membrane attack complex
  5. Neisseria meningitis
    • Pathogensis/disease: Colonizes nasopharynx in 5-15% of people, usually symbiont
    • Can spread to deeper tissue blood (meningococcemia) and meninges (meningitis)
    • Polysaccharide capsule inhibits phagocytosis/needed for virulence
    • Disease causes vascular damage
    •       -Damage from immune response to LOS shed as outer membrane blebs (vesicles)
  6. Meningococcal disease
    • Very dangerous
    • Can occur without meningitis (fulminant disease with high mortality)
    • Protection from disease mediated by serum bactericidal, anticapsular antibodies (Vaccine from 4 of six major disease causing capsule types- A, C, Y & W)
    • Type B strains, do not make protective antibodies. Type B capsule composed of polysialic acid, a host antigen. Type B causes 45% of disease in US
  7. Most common victims of meningitis
    Babies and Young adults (increased in tight quarters)
  8. Where is the meningitis belt
    Sub-saharan africa
  9. Meningococcal capsule structures used in conjugate vaccines
    • MenA, MenC, MenW, MenY
    • Recommended for infants/young adults (19-21)
  10. Serogroup B capsule made of what?
    Polysialic acid, a host antigen
  11. What Serogroups effect who?
    • B: Constantly effective (Spikes at baby/young adult)
    • C: Young adult-middle age
    • Y: Mostly the elderly
    • Other:  Mostly babies
  12. Components of Bexsero vaccine
    • Heparin-binding antigen--GNA1030
    • Factor H binding protein (fHBP)--GNA2091
    • Neisseria adhesion A (NadA)
    • Alum hydroxide
    • Outer membrane vesicles from serogroup B strain NZ98/254
  13. Infection by parasitic Neisseria
    Serum resistance allows pili to enable invasion of epithelial cells, followed by transcytosis and intracellular survival.
  14. Neisseria gonorrhoeae infections
    • Men: Urethritis--->Epididymitis-->Sterility
    • Women: Cervicitis-->Pelvic Inflammatory Disease--->Sterility
    • Child:
    • From women (birth): Ophthalmia-->Disseminated Gonococcal Infection-->Arthritis/Meningitis/Endocarditis
    • From man: same as women but starts at DGI
  15. Gonococcal Diseases:
    • Urethritis/Cervicitis: Most common, purulent exudate (pus)/dysuria(pain while piss),often asymptomatic in women
    • Proctitis: Rectal infection, oftern asymptomatic, common in women with cervicitis and gays
    • Pharyngeal infection: Almost always asymptomatic
    • Ophthalmia: Conjunctival infection, occurring often in babies born to infected women, prevented by erythromycin at birth
    • Pelvic Inflammatory Disease: Endometritis, salpingitis, tubal or ovarian abscess
    • Disseminated gonococcal infection: Spread of Gc to bloodstream and distant sites->arthritis, skin lesions, meningitis, endocarditis
  16. Problems with gonorrhea treatment:
    • Asymptomatic in women (50-80%)
    • Infected women can develop PID, can fuck with reproduction
    • Very few men experience mild symptoms
  17. Pelvic Inflammatory Disease (PID)
    • Caused by Neisseria gonorrhoeae or Chlamydia trachomatis
    • Host inflammatory response damages cells
    •      -tubal scarring/occlusion, adnexal                  adhesions, sometimes abscess
    • Ofter asymptomatic at first
    •      -Develops into chronic pain
    • Large source of infertility
    • Huge cost to healthcare system
  18. Neisseria gonorrhoeae adherence mechanisms
    • Pili:
    • -type IV pilus
    •     -Bind I-domain of CR3 on host cells
    •     -Bind Gc to Gc
    •     -Retractable, allow twitching
    •     -needed for DNA uptake for transformation
    • Opacity proteins:
    • -Family of 11 OM proteins
    •      -one binds heparin sulfate proteoglycans
    •      -some bind CD66
    •      -bind Gc to Gc
    • LOS
    • -6 possible forms (1 expressed at a time) bind to cell surface molecules
  19. Activities of Type IV pili
    • Adherence to host cells
    • Adherence to other gonococci
    • Twitching motility
    • Uptake of DNA for transform
  20. Variable components of gonococcal cell surface
    LOS, Pili, Porin, Opacity
  21. Antigenic variation
    Alteration of primary sequence of a protein or the chemical composition of a carbohydrate molecule that results in antigenic differences recognized by the host
  22. Phase Variation:
    Presence or absence (on/off) of one or more multiple virulence/antigenic determinants
  23. Mechanics of Pilin antigenic variation
    • Genome arrangement of pilin includes silent copies (pilS1, pilS2, pilS3, ect. S=silent)
    • Single active pilin (pilE E=expressed)
    • Homologous recombination puts pilS into pilE locus via transformation/gene conversion
    • Results in transcription of new pilE, new pilus on surface
  24. How many silent pili in gonorrhoeae
  25. What causes the higher rate of recombination in gonorrhoeae
    • Unusual DNA structure, G-quartet upstream of pilE.
    • If this fomration is not repaired often bacteria die
    • Formation is cut often to force constant recombination
  26. What causes phase variation of opa in gonorrhoeae
    • Slipped-strand mispairing
    • Multiple copies of CTCTT in leader region
    • Loss of a repeat results in failed protein
  27. Virulence factors for gonorrhoeae
    • Invasion: Opa, Porin
    • Intracellular survival: IgA1 protease, Porin
    • Iron acquisition: Tbp (transferrin binding), Lbp (lactoferrin binding), Type IV secretion system
    • Serum Resistance: LOS, Porin (1A+others)
    • Toxins: LOS, Peptidoglycan
  28. Gonorrhoeae releases what peptidoglycan monomers
    • Nod1 agonist: causes death/sloughing of ciliated cells, induces arthritis, induce inflammatory cytokines (IL-1, IL-6, TNF)
    • Tracheal cytotoxin (TCT)
  29. Why need new treatments for gonorrhoeae
    • No long lasting immunity due to antigenic variation
    • Vaccine trials failed: Pilin vaccine only gets one strain, Porin vaccine made patients more likely  to become infected
    • Antibiotic resistance rampant
  30. Imminent threat of untreatable gonococcal infection
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MMI 301: Lecture 24: Neisseria
MMI 301
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