WEEK 2 - The Pathogenesis of Invasive Meningococcal Disease Flashcards
What is meningitis
Acute inflammation of meninges (surrounding layer of brain) due to an infective agent
- inflammation causes intracranial pressure
- its a notifiable disease (= reported to gov.)
Meningitis can be:
- bacterial (most severe)
- e.g. e.coli, neisseria meningitis, strep. pneumonia
- fungal (rare)
- viral (more common + less severe)
- aseptic (no known microbiological cause)
What is the most common causative agent of meningitis
Neisseria Meningitidis a.k.a. Nm / N.meningitidis
(bacterial agent)
Neisseria Meningitidis (Nm) Info
- Is gram -ive diplococci organism
- Has type 4 pilil (T4P) which aids attachment and colonisation of Nm
- Being a carrier of Nm depends on: age, behaviour and population
- Found in nasopharynx (in URT)
- BUT doesn’t colonise area permanantley, may last few days to months
- Nm colonisation is usually asymptomatic - Transmitted via aerosol droplets
Colonisation of nasopharynx by Nm challenges:
- commensal microbiota already in nose (competing with Nm)
- mucocillary pathway (traps pathogens in mucus and clears it)
- antimicrobial defences (IgA antibody is found in nose)
- Categorised according to their capsular group (have 12 capsule types)
- type A, B, C cause 90% of disease
- diff. vaccines have included diff. type e.g. MenC vaccine = lead to selection pressure and B capusle dominated
- MenB is vaccine used now as B is the most causative agent in young children
List the 5 steps involved in the pathogenesis of meningitis
- Bacteria-host interaction
- Invasion into blood stream (invasive infection)
- Proliferation in bloodstream
- Movement across BBB
- Proliferation in the CNS
Explain the “bacteria-host interaction”
Pathogenesis
- Nm bacteria attaches to surface of non-cilliated epithelial cells using type 4 pili
- Nm then has to cross the nasopharynx cells on surface of URT
- Once crossed Nm will invade bloodstream causing invasive disease (next step)
Explain the “invasion into blood stream (invasive infection)”
Pathogenesis
- Nm binds to receptors (on epithelial cell surface) called opacity proteins (Opa and Opc)
- binding causes Nm to be endocytsoed into epithelia
- Nm has to invade blood stream AND survive via
- Immune invasion
- capsule expression provides resistance to phagocytes + innate immune system
- capsules are -ively charged = neutrophils stopped from binding
- Nm B capsule mimics host NCAM = immune system recognises Nm as a host cell = doesnt attack
- factor H biding protein is coated around Nm = downregulates immune system
- recruiting host immunomodulatory proteins e.g. factor H biding protein - Nm wants to bind but can’t due to blood being under sheer force / movement of blood
- Nm attach via T4P + proliferate in capillaries = aggregation
- Immune invasion
Risk factors influencing Nm invasion:
- genetic + environmental
- smoking = physical damage to epithelia = easier for Nm to get through
- e.g. viral infection, deficiency
NOTE: invasion of bloodstream is required to get invasive meningococcal disease
Explain the “proliferation in bloodstream”
Pathogenesis
Uncontrolled Nm growth in blood can lead to 2 things:
- Meningococcal Septicaemia
- blood poisoning - Meningococcal Meningitis
- crossing BBB + entering CNS
- infection + inflammation of the meninges
Explain the “movement across the BBB”
Pathogenesis
2 Routes Nm moves across BBB
1. Paracellular
- Nm adheres to surface receptor on brain endothelial cells (CD147) using T4P (PilE and PilV)
- Nm remodels host cell causing formation of microvilli structure
- Nm eventually damages tight junctioncs between endothelial cells
- Nm can acces meninges via movement between cells
- Transcytosis
- Nm binds to opacity protein (Opa / Opc) = endocytosed
NOTE:
- Nm has to cross BBB to cause meningitis (if not septicaemia is caused)
- BBB has tight junctions, regulates ions and molecules moving in / out of brain
Explain the “proliferation in the CNS”
Pathogenesis
- Nm replicates releasing pro-inflammatory compounds = accumulation
- WBC + immune factors move across BBB into CNS = inflammation
- these should NEVER be in brain
3.
What is Meningococcal Septicaemia
Blood poisoning
- Nm does blebbing ~ release of very potent endotoxin LOS
- Nm makes too much cell wall, wall contains LOS which is released into environemnt
- LOS presences causes huge immune response (TNF, IL-1, IL-6, IL-8, cytokines, chemokines and nitric oxide)
- Nm outer layer is called LOS (Lipooligosaccharides
Inflammation causes:
- microvasculature to become leaky = ↓ electrolyes and fluid
- ↑ vascular permeability (not good)
- vasoconstriction, intravascular thrombosis, impaired myocardial function, cardiac function
Explain the 3 virulence factors of Nm
- Capsule Expression
- help organism evade immune system clearance
- occurs once in blood, early expression would prevent bacteria attaching to host cell
- Type 4 Pili (T4P)
- extensions from the bacteria membrane
- key attachment factors
- targets specific receptor allowing initmate contact with host cell surface
- allows Nm to attach to non-cilliated nasopharynx cell
- IgA Protease Production
- Nm prodcues IgA protease which cleaves (destroys) IgA = humoral response inhibited
Explain the role of virulence factor … in disease process
What are the symptoms of meningitis
- Non blanching rash:
- Petechial rash (1-2mm)
- this rash develops into purpural rash
- Purpural rash (bigger)
- occurs due to blood vessel damage
- bacteria is in capillaries, reproducing, damaging capillaires + releasing endotoxins
- Petechial rash (1-2mm)
- Stiff neck
- Altered mental status
- confusion, delirium, impaired consciousness - Photophobia
- Bulging fontanelle (<2 year old)
NICE GUIDELINES: Meningitis treatment
- Prompt antibiotic treatment
3mth+ = IV Ceftriaxone (7 to 14 days)
<3mth = Cefotaxamine AND Amoxicillin or Ampicillin
