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Bacterial Meningitis: Neisseria, Listeria, Haemophilus
ID Week 2**
30
Medical
Graduate
04/15/2010

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Cards

Term
What is chocolate agar?
Definition

Essentially, enriched blood agar. Blood agar has been slowly heated to lyse some cells, releasing growth factors including heme and NAD.

 

Note: Thayer-Martin VCN media is chocolate agar with competing antibiotics to kill off everything but Neisseria.

Term
What is the oxidase test?
Definition

Paper pH test that looks for cytochrome c oxidases, indicating oxidative phosphorylation for energy production. Positive test turns blue/black when bacterial colony is spread on paper.

Note: Useful for distinguishing Neisseria from other Gram- organisms; Neisseria is oxidase+.

Term
What does H. influenzae look like under the microscope? In culture?
Definition

Gram- coccobacilli.

Requires chocolate agar, grows gray smooth colonies. 


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Term
What are virulence factors of H. influenzae?
Definition

Adherence:

-- Pili


Immune Evasion:

-- Capsule (on virulent serotypes): made of polyribitol phosphate (PRP)

Note: Non-encapsulated ("non-typeable") isolates responsible for >90% of localized disease (e.g. otitis media, sinusitis, bronchitis), but capsulated species cause >90% of invasive disease (e.g. meningitis). Of those, 9 serotypes account for 80% of invasive disease worldwide.

-- IgA protease: cleaves IgA on respiratory mucosa

Note: Convergent evolution with Pneumococcus, Meningococcus, which also cleave IgA


Damaging:

-- Endotoxin (LPS): stimulates innate immune response (cytokine storm)

Term
How does the vaccine against H. influenzae type b (Hib) work?
Definition

Targets capsular antigens (particularly polyribitol phosphate, PRP). PRP conjugate vaccine available, successful.


Note: While capsule initially helps bacteria evade host immune response, capsular polysaccharides are prime target for antibodies once humoral immunity kicks in.


Note: Capsules are typed a, b, c, d, e, f. Hib is most virulent.


Term
How do we type H. influenzae?
Definition

Based on their capsule, so only capsulated isolates are typeable. 6 types are names a, b, c, d, e, f.

 

Note: Type b is the most virulent, hence the Hib vaccine.


Note: Noncapsulated (non-typeable) isolates cause >90% of local, non-invasive infections such as otitis media or bronchial infection. COPD patients get recurrent non-typeable H. influenzae infections. Capsulated isolates are responsible for invasive disease, e.g. meningitis.

Term
H. influenzae meningitis is most prevalent in young children (<4), but not newborns. Why?
Definition

Young children haven't yet developed mechanism T-cell independent antibody response to polysaccharides. Newborns have conferred immunity from mother's antibodies.

Term
What could cause failure of the Hib vaccine, which is generally highly effective?
Definition

An elevated number of copies of gene coding for capsule is associated with decreased efficacy of vaccine. 

Note: Just emphasizes importance of capsule!

Term
What does Neisseria look like under the microscope? In culture?
Definition

Gram-, kidney bean-shaped pilated diplococci. Grows on Thayer-Martin VCN media (chocolate agar + selective antibiotics to eliminate competition) in small, bluish-gray colonies.


Note: Lots of Gram- rods cause infection, but Neisseria is the main disease-causing Gram- coccus.

 

[image]


[image]

Term
What laboratory tests are useful for distinguishing Neisseria from other Gram- bacteria?
Definition

Grows on Thayer-Martin VCN media, ferments maltose and glucose and is oxidase positive. (So are other Gram- bacteria like P. aeruginosa, so I'm not sure why Swanson made a point of this.)

Term
What are virulence factors of meningococcus (N. meningitidis)?
Definition

Adherence:

-- Pili: can have phosphorylcholine on surface; mimics phosphatidylcholine, allows stealth adhesion to respiratory mucosa.

Note: C-reactive protein targets phosphorylcholine in bloodstream; inborn error-prone polyG mechanism allows phase-variation of expression, survival a subset of organisms in blood.


--Opc, Opa: outer membrane proteins important for adherence and invasion

Note: Phase-variation of surface proteins important to virulence


Immune Evasion:

-- Capsule

-- IgA1 protease


Damage:

-- Endotoxin (LPS): N. meningitis exhibits copious blebbing/shedding of cell wall, releasing endotoxin which induces cytokines TNFa, IL-1.

Note: Can causes blood vessel damage/hemorrhage, which presents as petichiae. 

-- Hemolysin

Term
What is phase variation?
Definition

Immune evasion technique that involves stochastic switching of antigenic phenotype, e.g. LPS phenotype. This confers heterogeneity to a bacterial population, and increases the chance that at least some will survive under varying circumstances


Note: E.g. Expression of phosphoryl choline on N. meningococcus is beneficial during adherence to respiratory mucosa, but is a target of C-reactive protein in the blood. If some organisms switch of phosphoryl choline expression after invasion, they will survive in blood.

Term
How does N. meningococcus use phosphorylcholine as a virulence factor?
Definition

It mimics phosphatidylcholine, commonly found on mucosal host cells, so it helps menigococcus evade immune response and adhere

Note: After invasion into the bloodstream, phosphorylcholine becomes a liability (target of CRP); phase-variation allows differential expression so some bacteria survive.

Term
What is C-reactive protein (CRP)? How does it interact with N. meningococcus?
Definition

A protein (non-antibody B globulin, restricted to serum) that is upregulated during acute-phase inflammation that opsonizes cells expressing phosphatidylcholine and activates complement. The idea is that it binds components of microbes and damaged tissues (that shouldn't be in blood compartment).

 

When meningococcus invades the bloodstream, organisms decorated with phosphorylcholine (which mimics host phosphatidylcholine) are targeted.

Term
Dynamic antigenic variation is key to the virulence of N. meningococcus'. By what mechanisms does it vary expression of surface proteins?
Definition

Slipped strand mispairing generates variants at high frequency.

 

Note: Phosphorylcholine expression depends on number of polyG repeats; if 8 or 11, expressed (note - one codon difference; frameshift negligible); 9 or 10 not expressed. Same idea with Opa, but repeats are CTCTT.


Term
Who is most susceptible to meningococcal disease? Why?
Definition

Young children (don't have T cell-independent response to capsule), but not newborns (who have mother's residual antibodies).

 

Army recruits, college students, others who come from different geographical locales (immunity to local variants, but maybe not others) and live in close quarters.

Term
How does the meningococcal vaccine work?
Definition

Includes capsular antigens from various serotypes (A, C, W135, Y), which induce T cell-independent antibody response. 

-- Does not protect young children; we have no conjugated vaccine for meningococcus

-- Does not contain type B antigen, which is a polymer of sialic acid, and mimics host cell structures. Thus, B antigen does not elicit immune response.


Term
Why don't young children receive the meningococcal vaccine? Who does receive the vaccine?
Definition

We have no conjugated vaccine, so it will not be useful in young children. Military recruits and college students receive meningococcal vaccine.

Term
What is the reservoir for H. influenzae? How is it transmitted?
Definition

Nasopharynx. Part of normal flora. Transmitted by respiratory droplets.

Term
What is the reservoir for N. meningitidis?
Definition

Upper respiratory tract; 5-10% of people are carriers.

Transmitted by respiratory droplets.

Term
Of the 9 N. meningococcus serotypes, B is a major one. Why is the B-type antigen NOT included in the vaccine?
Definition

Its primary capsular antigen is a homopolymer of sialic acid, which is present on host cells and thus a poor immunogen.

Term
What does Listeria look like in culture?
Definition
Term
What does Listeria look like under the microscope?
Definition
Term
What is the reservoir for Listeria?
Definition

Soil, water, GI tracts of animals. NOT part of human flora.

Note: Very hardy; can survive pasteurization and grow at 4oC (refrigerator); found in meats, cheeses

Term
How do humans get infected with Listeria?
Definition

Eating meats, cheeses, other dairy products housing the bacteria.

Note: Really only affects immunocompromised.

Term
Why is the antibody response ineffective against Listeria?
Definition

Once infected, the entire life cycle of Listeria is intracellular (even transmission to other cells is through protective host-membrane sheath); bacteria are protected from serum, so antibodies don't have access.

Term
Describe the life cycle of L. monocytogenes, including virulence factors.
Definition

1. Internalin induces entry into host cells

2. Hemolysin, aka Listeriolysin O (LLO): pore-forming toxin for escape from phagolysosome.

3. ActA: Recruits host actin for motility (ActA induced actin nucleation behind bacteria)

4. Forms protrusion, which is surrounded and phagocytozed by neighboring cell (protrusion covered by PM, so Listeria never exposed to serum/ immune system)

5. LLO and phospholipase C allow escape from phagolysozome in new host cell.

Note: Once inside a cell, Listeria is an intracellular pathogen and will not see the outside again.

Term
Videos of Listeria show it swimming frantically in host cell cytoplasm. What confers its motility?
Definition

Actin-based motily; host actin is recruiting. "Comet-tail" is not moving; rather, Brownian motion causes slight movements, and ActA induces polymerization behind bacteria so it can't slip back, propelling it forward.

Note: Remember, the advantage is evasion of innate immune system; Listeria requires full T-cell function. 

Term
Who is most at risk for Listeriosis?
Definition

Those lacking a full T-cell response (immunocompromised, pregnant, neonates). Cell-mediated immunity is required to activate macrophages to destroy Listeria (before it becomes intracellular?)

Term
Strep B...
Definition
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