Bacterial Meningitis

Pathogenic agents causing meningitis in persons >60 y.o. in the USA
1. 49% - Streptococcus pneumomiae
2. 14% - Listeria monocytogenes
3. 4% - Neisseria meningitidis
4. 3% - Group B Streptococcus
5. 4% - Haemophilus influenzae
6. 26% - Others
Streptococcus pneumoniae
1. Gram +ve bacteria
2. More than 90 known serotypes
3. Major virulence factor - polysaccharide capsule
4. Cheap and easy to do epidemiological tests
5. Capsular type-specific antibody is protective
6. Fastidious - grows best in 5% carbon dioxide
  1. Nearly 20% of fresh clinical isolates require fully anaerobic conditions
  2. Growth requires catalase (e.g. blood) to neutralise the hydrogen peroxide produced by the bacteria
  3. Has a doubling time of 20-30 minutes in complex blood media at 37'C
7. Culture
  1. Grown on blood agar
  2. Alpha haemolytic
  3. Zone of inhibition around optochin disk
  4. 1mm glistening colonies
  5. Phase Variation
    1. Two serotypes - types 3 and 37 are mucoid
      1. Serotyping
        The Quellung reaction (swelling reaction) is used
        Bacterial capsule swells with binding of a homologous antibody
        Mix a loopful of colony with equal quantity of specific antiserum and examine under a microscope at x1000
        Cross-reactivity has been observed between capsular types 2 and 5/3and 8/7 and 18/13 and 30
        Cross-reactivity has also be observed with E. coli, Klebsiella, H. influenza type b and some viridans Streptococci
        viridans = alpha haemolytic
    2. Spontaneously undergo a genetically determined phase variation
      1. Colonies change from opaque to transparent at a rate of 1 in 10^5
        Transparent colony type is adapted to colonization of nasopharynx
        Opaque colony type is adapted to survival in the blood
      2. Significant difference in surface protein expression between two serotypes
8. Nasopharangeal carriage may occur in 60% of healthy pre-school children and 30% of healthy children and adults
S. pneumoniae Cell Wall
1. 6 layers thick
  1. Comprised of peptidoglycan with teichioic acids attached to every 3rd N-acetylmuramic acid
    1. Leipoteichioic acids and Teichioic acids
      1. Lipoteichioic acid is chemically identical to teichioic acid but binds to a lipid moiety
        Teichioic acid and lipoteichioic acid contain phosphorylcholine - 2 choline residues can covalently bind to each carboyhrate repeat
        Choline binds to choline-binding receptors found on almost all human cells
        Linked via a C-terminal fatty acyl group
      2. Carbohydrate phosphate polymers, rich in choline
    2. Linked via a phosphodiester linkage
2. Pili
  1. Hair-like structures which extend from the surface
  2. Contribute to colonization of upper respiratory tract
  3. Increase the formation of large amounts of TNF during invasive infection
3. Surface Proteins
  1. More than 500
  2. Some are membrane-associated lipoproteins, some are physically associated with the cell wall
    1. Cell-wall proteins include 5 penicillin binding proteins (PBPs), 2 neuraminidases, 1 IgA protease and Choline-binding proteins (CBPs)
  3. Pneumococcal surface antigen (PsaA)
    1. Located underneath the peptidoglycan layer
      1. Attached to cell membrane via an LXXC motif
  4. Penicillin binding proteins (PBPs)
    1. Located in the periplasmic space
    2. Interact with the peptidoglycan
    3. Display a single, N-terminal transmembrane helix
  5. Hyaluronate lyase (Hyl)
    1. Tethered to the peptidoglycan via an LPXTG motif
  6. Choline binding proteins (CBPs)
    1. 12 CBPs non-covalently bind to the choline moiety and 'snap' different functional elements onto the bacterial surface
    2. All share a common C-terminal CB domain with different N-terminals
    3. Include PspA (protective antigen), Lyt A/B/C (autolysins) and CbpA (adhesin)
Colonization
1. ECM Interaction
  1. 1st mechanical barrier
  2. Colonization is facilitated by cleavage of bound IgA1 by the IgA1 protease and removal of terminal sialic acids by NanA
  3. Glycolytic enzymes enolase and GAPDH bind human plasminogen (PLG)
    1. Converted to the protease plasmin (PA) and promotes ECM compound degredation
  4. ZmpC activates MMP-9 which has collagenase activity - degrades the ECM
  5. Non-classical surface-associated protein PavA binds to immobilized fibronectin (Fn) and modulates pneumococcal adherence
2. Cellular Receptors
  1. ECM degradation could be a prerequisite for pneumococci-receptor interactions
  2. Major adhesion of pneumococci is PspC
    1. Interacts with the ectodomain of the human polymeric immunoglobulin receptor (plgR)
  3. PCho mediates pneumococcal adherence to stimulated cells via interaction with upregulated PAFr
  4. The lipoprotein PsaA may act as an adhesin
Pathogenesis
1. Disease usually caused by spread from the site of colonization
2. Middle ear = otitis media (non-invasive)
3. Alveoli = pneumonia (non-invasive)
4. Blood = bacteraemia (invasive)
  1. Most common in children under 2
5. Mucocillary escalator - mucus is coughed up and swallowed
6. CSF = meningitis (invasive)
  1. Most common cause of bacterial meningitis in US - mostly <2 y.o.
Risk Factors
1. Sickle cell anaemia
2. HIV intection
3. Race/Ethnicity
4. Out-of-home group care
5. Functional/Anatomic asplenia
Investigation
1. Surveillance
  1. Measure the burden of invasive pneumococcal disease among all ages
  2. Track emerging antibiotic resistance
  3. Study the impact of pneumococcal vaccines
2. Reporting
  1. Isolates causing invasive pneumococcal disease (IPD) in children <5 y.o. and are drug resistant are reported as DRSP
  2. Isolates susceptible to antibiotics (or unknown susceptibility) are reported as IPD (not drug resistant)
3. Critical Data
  1. Demographic
  2. Clinical
  3. Risk Factors
  4. Vaccination History
  5. Compare state rates to other states
  6. Compare among populations within state
  7. Epidemiologic investigation if rates of invasive disease are elevated
4. Serotyping no longer routinely available
Vaccine
1. Must contain antigens from multiple serotypes - large amount of diversity
  1. Serotypes are grouped according to antigenic similarities in Danish numbering classification system
  2. Cross-reactivity within serotypes increases vaccine serotypic coverage by 80%
  3. ~90% of penicillin-resistant isolates and in serotypes found in 23-valent vaccine (in 1990)
2. Immune response
  1. Poor correlation between immunological response and protection
    1. Antigens change
  2. 23-valent vaccine doesn't elicit a satisfactory immune response in children <2 y.o.
  3. In HIV-positive patients, immune response is decreased in those with a CD4+ count <500 cells/ul
3. Given to elderly people
4. 79% clinical effectiveness against pneumonia/bacteremia
M Protein Gene Typing
1. emm gene (Streptococcus pyogenes gene)
2. Amplified with primers 1 and 2
3. Encodes the cell surface M virulence protein
  1. Responsible for at least 100 known M serospecificities of S. pyogenes
htrA
1. S. pneumonia gene
2. Regulated by the CiaRH 2-component system
3. Involved in nasopharangeal colonization

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Bacterial Meningitis

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	Created by maisie_oj about 11 years ago