1
Q
Meninges
A
- the membranes that envelop the CNS (brain and spinal cord)
- includes pia mater, arachnoid mater, and dura mater
- CSF is between the arachnoid and pia maters
2
Q
What is meningitis?
A
- viral or bacterial infection of the meninges
3
Q
Is viral or bacterial meningitis more sever?
A
- viral is less severe and usually resolves without specific treatment
- bacterial meningitis can be rapid and life-threatening
4
Q
What is the Blood Brain Barrier?
A
- a protective cellular structure that restricts passage of chemicals, toxins, and microorganisms from the blood to the CNS
- also protects your CNS from the peripheral immune system
5
Q
What creates the BBB?
A
endothelial cells stitched together by structures called “tight junctions” to prevent things from diffusing across
6
Q
What is the role of astrocytes and pericytes in the BBB?
A
- provide support for other cells of the CNS, including the BBB
7
Q
What is the role of microglia cells in the BBB?
A
- they are the tissue macrophages of the CNS but not really designed to fight microorganisms - more fore eating up cellular debris
8
Q
are WBCs present in the CNS?
A
- no they are normally not present in the CNS, therefore there are no b cells or antibodies.
- inflammation is not very good here
9
Q
Bacterial Meningitis Process (10 steps)
A
- nasopharyngeal colonization
- invasion into blood
- multiplication in blood
- crossing of the blood brain barrier (BBB)
- invasion of the meninges
- production of proinflammatory cytokines/chemokines
- recruitment of leukocytes into CNS
- Edema, increased cranial pressure
- inflammation
- neuronal damage
10
Q
How do microorganisms transverse the BBB?
A
- method is not well understood
- three ways: transcellular, paracellular, trojan-horse
11
Q
Transcellular Transversal
A
- Invade into endothelial cells and go out through other side
- Essentially eating through the cell
- Most meningitis pathogens probably use this pathway
12
Q
Paracellular Transversal
A
- Bacteria drive themselves through tight junctions
- e.g. Lyme disease
13
Q
Trojan-horse Mechanism
A
- Bacteria gain access to macrophage that is living within a phagocyte and phagocyte crosses through
- Tuberculosis
14
Q
The Disease: Bacterial Meningitis
A
- a rare but very dangerous disease – can kill in days
- early signs may be non-specific
- in an outbreak, the first people to develop disease are most at risk (because they delay treatment)
- mortality rate has remained high (10-25%)
- survivors may have irreversible damage
brain damage, blindness, hearing loss, learning disabilities
15
Q
Clinical symptoms of Meningitis in children and adults
A
- high fever
- severe headache
- stiff neck
- confusion
- vomiting or nausea
- seizures
- sleepiness or difficulty waking up
- photophobia - sensitivity to light
- skin rash in cases of meningococcal meningitis
16
Q
Clinical symptoms of Meningitis in infants
A
can be subtle, variable and non-specific:
- fever
- constant crying
- excessive sleepiness or irritability
- poor feeding
- inability to maintain eye contact
- a bulge in the soft spot on top of a baby’s head (fontanel)
- stiffness in the baby’s body and neck
- skin rash in cases of meningococcal meningitis
17
Q
Risk factors for bacterial meningitis
A
- lack of vaccination
young age (infants) - living in a community setting (university students living in dormitories, military personnel, boarding schools, child care facilities, prisons)
- immunocompromised individuals due to disease or chemotherapy
- cranial surgery
18
Q
Bacterial Meningitis Diagnosis
A
- history and symptoms
- blood tests for inflammatory markers, culture
- CT imaging
Lumbar puncture (spinal tap): spinal needle inserted between 3rd and 4th lumbar vertebrae
- cloudy CSF
- Gram stain and culture
- presence of white cells (neutrophils)
- low glucose
19
Q
Physical Signs of Bacterial Meningitis
A
Nucal Rigidity, Brudzinksi’s sign, Kernig’s sign
- if there were no signs, it is inconclusive (you may or may not have the disease) BUT if the signs are present, you have meningitis
20
Q
Nucal rigidity
A
inability to flex the head forward
21
Q
Brudzinski’s sign
A
severe neck stiffness causes a patient’s knees to flex when the neck is flexed
22
Q
Kernig’s sign
A
severe stiffness of the hamstrings causes and inability to straighten the leg when the hip is flexed to 90 degrees
23
Q
Treatment of bacterial meningitis
A
- must be sought immediately
- intravenous antibiotics (prior to culture analysis)
- corticosteroids (dexamethasone) to reduce swelling in the meninges
- supportive therapies (monitoring, oxygen, fluids etc)
24
Q
What are the major causes of meningitis?
A
Almost all known bacterial pathogens have the potential to cause meningitis, but relatively few account for most cases. Major causes of bacterial meningitis:
- Neisseria meningitidis
- Streptococcus pneumoniae
- (Haemophilus influenzae)
- Listeria monocytogenes
In infants:
- streptococcus agalactiae (Group b streptococcus)
25
Which virulence factor is mainly produced by meningitis causing bacteria?
capsules (except by listeria)
26
What is a capsule?
- a loose, relatively unstructured network of polymers that cover the surface of some bacteria
- most are composed of polysaccharides
27
What is a capsule's main role in meningitis?
- to protect bacteria from the complement system
- complement: innate immune system serum proteins (e.g. C3b)
- encapsulated bacteria are less likely to be opsonized by through the complement system
28
Capsules as vaccines
- an effective host response against capsules is the generation of antibodies from B cells that can recognize the capsule
- antibodies that recognize the capsule promote opsonization and phagocytosis
- capsules can therefore be used as vaccines
29
What is a problem associated with using capsules as vaccines?
- polysaccharide vaccines do not provide long-term memory because they are T cell-independent
- T cells provide "help" to B cells
- long-term memory
BUT, T cells respond to proteins/peptides, not sugars
30
Conjugate Vaccines
- polysaccharide conjugated to protein carrier
- this vaccine will be T cell-dependent
- you are essentially tricking the immune system
31
Neisseria Meningitidis
- "meningococcus"
- Gram-negative, diplococcus
- a human specific pathogen
- colonizes the nose and throat – asymptomatic carriage is common
- produces a polysaccharide capsule
- antigenic variants (i.e. serotypes)
- A, B, C, W135 and Y
- a leading cause of bacterial meningitis and also meningococcemia - termed invasive meningococcal disease
- this infection is highly contagious and may cause local epidemics in college dormitories, boarding schools and on military bases
32
How are Neisseria meningitidis antigenically different?
- all strains of not make the same capsule (antigenically different)
33
Meningococcal disease
- meningitis occurs after bacteria enter the bloodstream and cross the BBB
- endotoxin (LPS) can lead to septic shock
- disseminated intravascular coagulation
- widespread blood clotting
- ischemia
- purpuric rash
34
What is a purpuric rash?
- basically a rsh underneath the skin
| - clotting factors are used up which leads to small skin bleeds
35
How do you test if rash is a purpuric rash?
rash does not fade under pressure ("glass test”)
36
Vaccines for Neisseria meningitidis
- Menactra (Sanofi Pasteur)/Menveo (GSK) – quadrivalent conjugate capsule vaccine from 4 serotypes of meningococcus (serogroup A, C, Y, W-135)
- Serogroup B most common for invasive disease in Canada but the capsule is poorly immunogenic
- Bexsero (GSK) – contains 4 recombinant protein antigens – now licensed (as of 2014) for use in Canada --> now used to go after serogroup B strains
37
The African Meningitis Belt
- the highest burden of the disease in the world
- up to ~500/100,000
- mostly caused by serogroup A
38
The pathogen: Streptococcus pneumoniae
- "pneumococcus"
- Gram-positive cocci, grows in chains
commonly resides asymptomatically in the nasopharynx
39
What symptoms does streptococcus pneumoniae cause?
- causes pneumonia, ear infections, sinusitis and many other diseases
- the leading cause of bacterial meningitis in children > 2 years and adults
40
How many people die by Streptococcus pneumoniae globally per year?
> 700 000
41
How Streptococcus pneumoniae work?
produces a polysaccharide capsule (may different serotypes exist)
42
Vaccine for Streptococcus pneumoniae
- A pneumococcal vaccine has been licensed for use in Canada
- Previously a 7 serotype vaccine (PCV7)
- now Prevnar 13 (PCV13)
- use of the vaccine is associated with decreasing rates of invasive pneumococcal disease in Canada and elsewhere
- 23-valent polysaccharide vaccine for high-risk adults, but poorly immunogenic in children (T cell-independent)
43
What is prevnar 13 (PCV13)
- a conjugate capsule vaccine from the 13 most prevalent serotypes of pneumococcus
44
What is a trend seen with the vaccines for Streptococcus pneumoniae?
- people are vaccinated for only the most prevalent serotypes
- as those strains are vaccinated against, others that were less common (and not present in the vaccine), are becoming more prevalent
45
Haemophilus influenzae type B
- "Hib"
- Gram negative, coccobacillus, produces a polysaccharide capsule
primarily causes meningitis in children under 5
- when it occurs, it tends to follow an upper respiratory infection, ear infection or sinusitis
46
Hib Vaccine Effectiveness
- Hib conjugate vaccine available as part of the routine childhood immunization schedules has reduced 99% of invasive Hib disease to low levels (<1 per 100,000)
- Before the 1990s, H. influenzae type b was the leading cause of bacterial meningitis
47
Listeria monocytogenes
- Gram-positive rod
- not your 'typical' meningitis pathogen
a food-borne pathogen
- "listeriosis" can range from gastroenteritis --> bacteremia --> meningitis
- high rates of mortality in immunocompromised individuals including neonates and the fetus
- can grow at 4°C (a psychrotroph) – important for a food-borne pathogen (soft cheeses often implicated)
- Listeria causes <5% of meningitis cases
48
How does listeria escape your immune system?
- Escapes into cytoplasm (intracellular bacteria)
- There is a protein on its surface that polymerizes actin that drives the bacteria along (NOT FLAGELLA)
- Can push itself into an adjacent cell
- Listeria invades intestinal epithelial cells and replicates within the cytosol (actin-based motility and cell-to-cell spread)
49
Streptococcus agalactiae
- Group B Streptococcus" (GBS)
- Gram positive cocci, grows in chains
- produces a capsule
many women carry S. agalactiae in the urogenital tract as a commensal
- GBS can be passed from the mother to infant during labour
- women are usually tested for GBS at ~36 weeks
- women who are positive may be treated with antibiotics during labour to prevent infection of the newborn
Microimm 2500
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