1
Q
What is the shape of Neisseria?
A
Diplococci
2
Q
Are Neisseria gram negative or gram positive?
A
Gram negative
3
Q
What percentage similarity do N. gonorrhoeae and N. meningitidis have?
A
80-90%
4
Q
Where does N. meningitidis colonise?
A
The human upper respiratory tract
5
Q
Where does N. gonorrhoeae infect?
A
Primarily infects the urogenital epithelia but can also cause pharyngitis and conjunctivitis
6
Q
What can N. gonorrhoea lead to?
A
- Epididymitis
- Cervicitis
- Endometriosis
- PID
- In rare cases can have disseminated gonococcal infection (DGI), arthritis and endocarditis
7
Q
What percentage of men have asymptomatic N. gonorrhoeae infections?
A
10-15%
8
Q
What Neisseria has a capsule?
A
N. meningitidis
9
Q
What is the key virulence factor of N. meningitidis?
A
Endotoxin
10
Q
What is meningitis?
A
Inflammation of the meninges
11
Q
What are the signs and symptoms of meningococcal meningitis?
A
- Vomiting
- Excruciating intense headache due to escalated CSF pressure
- Confusion
- Drowsiness
- Fever
- Sensitivity to light
- May get a skin rash
- Eventually the neck stiffens as nerves along the spine become increasingly irritated
- Convulsions
12
Q
What can meningococcemia progress towards?
A
- Septic shock
- Purpura fulminans
- Acute systemic inflammatory response
- Intravascular coagulation
- Tissue necrosis
13
Q
What is the mortality of meningococcal sepsis?
A
40%
14
Q
What percentage of patients with meningococcal sepsis will have severe sequelae?
A
20%
15
Q
Describe the infection pathway of Neisseria meningitidis
A
- Inhalation of respiratory droplets
- Nasopharyngeal colonisation
- Epithelial cell invasion
- Survival in blood
- Bacteraemia leading to septicaemia or meningitis
16
Q
What is the natural habitat of N. meningitidis?
A
Human nasopharynx
17
Q
How is N. meningitidis transmitted?
A
From person to person by aerosol droplets or direct contact with contaminated fluids
18
Q
Describe the carriage of N. meningitidis
A
- 10-35% carriage -> some university students up to 55%
- The human nasopharynx is the sole ecological niche and carrier isolates show extensive genetic diversity as compared with hyper-invasive lineages
- Horizontal gene exchange and recombinant events during residence in the human nasopharynx result in antigenic diversity
- Carriage offers some immunity
19
Q
Describe the molecular interactions between N. meningitidis and its human host
A
- The mucus in the nasopharynx is poorly nutritive but rich in microbiota -> competitive niche
- Meningococci survive by expressing capsule, lipooligosaccharide, the MtrCDE efflux pump and factors that capture nutrients
- N. meningitidis also express 2 families of polymorphic toxins -> MafB and CdiA
- For an unknown reason, meningococci cross the epithelial layer and enter the bloodstream
- In the bloodstream bacteria adhere to the vascular wall and form microcolonies
- Adhesive bacteria proliferate and induce an active signalling that leads to better adhesion and opening of the vascular barrier, vessel leakage and massive thrombrosis
20
Q
How do we protect against meningitis?
A
Antibody directed towards capsule play a major role in protection against meningitis and form the basis of the vaccination and typing strategy
21
Q
What serogroup of N. meningitidis isn’t antigenic?
A
Serogroup B -> molecular mimicry
22
Q
What serogroups of N. meningitidis cause life threatening disease?
A
- A
- B
- CW-135
- X
- Y
- Z
23
Q
Can capsular switching occur in N. meningitidis?
A
Yes
24
Q
What are serogroups based on?
A
The composition of the capsular polysaccharide
25
What is LOS?
- LPS but without the O antigen
- Endotoxin
- Major antigenic and immunogenic component of pathogenic Neisseria
26
What does LOS cause?
- Induces and immune cascade
- Produces a lot of cytokines
- Can lead to endotoxic shock
27
What is the main adhesion protein of Neisseria?
Pili
28
What do pili target?
- Epithelial cells
- Endothelial cells
- RBCs
29
Describe the adhesion of Neisseria
- Pili enable the organisms to 'twitch'
- Pili traverse the capsule and act as adhesins
- The integral outer membrane adhesins (OM), Opa and Opc, also mediate interactions with specific host-cell receptors
- LOS may interfere with the adhesion functions of OM proteins, but can also contribute to cellular interactions by interacting with various cellular receptors
30
How do meningococci survive in serum?
- Neisseria uptake nutrients and iron from extracellular environment
- Pathogenic N. meningitidis are capsulated which is anti-phagocytic and the sialic acid on group B capsules inhibits complement deposition
- Several mechanisms to resist intracellular oxidative killing -> e.g. catalase and superoxide dismutase
- Meningococci avoid complement killing by antigenic variation and complement resistance
31
How do meningococci evade the immune system?
- A signature property of the pathogenic Neisseria is their ability to modulate their surface antigen very fast
- Pilin antigenic variation is mediated by gene conversion
- The PilE protein contains a highly conserved N-terminal domain and a variable C-terminal domain (antigenicity)
- The variable region is the result of non-reciprocal transfer of DNA from 1 of many silent partial pilS loci to the single pilE expression
- Extensive surface variation also poses a substantial problem in developing effective vaccines
32
How does antigenic variation occur in Neisseria?
Free exchange between genes (gene conversion) both within and between the genomes of Neisseria sp.
33
Why is Neisserial DNA in the environment?
Arises by autolysis and by an identified type IV secretion system that actively transports DNA out of the cell
34
Describe the epidemiology of meningitis
- Meningococcal disease mainly affects children
- Most disease in Europe and USA is caused by serogroup B and C whereas group A is responsible for most cases worldwide
- The highest incidence of disease occurs in the tropics in the meningitis belt
- Peaks occur in winter months in industrially developed countries
35
What are the symptoms of Neisseria gonorrhoeae?
- Discharge from the genitals
| - Burning when peeing
36
What can disseminated gonococcal disease lead to?
- Endocarditis
- Arthritis
- Pelvic inflammatory disease
37
What occurs in pelvic inflammatory disease?
- Abnormal vaginal discharge
- Bleeding between your periods, or having heavier periods than normal
- Pain in lower part of your abdomen
- Uncomfortable or painful sex
- Pain or difficulty wen urinating
- Fever
- Can cause abscesses, scarring and damage to your reproductive organs
- Can cause pelvic pain, infertility and ectopic pregnancies
38
Give an overview of the Neisseria gonorrhoeae infection
- Adherence to urogenital epithelium
- Competition with resident microbiota, nutrient acquisition and microcolony formation
- Colonisation and invasion of epithelium
- Release of peptidoglycans, LOS and outer membrane vesicles
- Cytokine, chemokine and inflammatory TF activation
- Peptidoglycans, LOS and OMVs cause NOD and TLR activation on epithelial cells, macrophages and dendritic cells
- HBP causes activation of TIFA-dependent innate immunity in epithelial cells and macrophages
- Influx of neutrophils -> adherence and phagocytosis of N. gonorrhoeae
- A neutrophil-rich purulent exudate facilitates transmission
39
How does N. gonorrhoeae modulate the immune system?
- Prevents deposition of complement
- Prevents opsonisation
- Modulates activity of macrophages, dendritic cells and neutrophils -> modulates apoptosis
- Immunosuppressive
- Modulates T cell function
40
Describe the epidemiology of N. gonorrhoeae
- Gonorrhoea mainly affects people in their 20s
- Increasing incidence in the UK
- Increase transmission of HIV
41
How is meningococcal disease diagnosed?
- Often diagnosed on the signs and symptoms
- CSF and blood samples
- Gram stains and microscopy to look for gram negative diplococci
- Culture takes too long
- PCR
- Detection of soluble bacterial polysaccharides in CSF by latex agglutination
42
How is gonococcal disease diagnosed?
- Direct examination of exudates in genitourinary medical (GUM) clinics
- Endocervical, cervical, anal and eye swabs
- Urines
- Gram stain and microscopy
- Nucleic amplification tests
- QRT PCR
- Old fashioned culture methods
43
How is meningococcal disease treated?
- IV antibiotics -> benzyl penicillin or amoxicillin, third generation cephalosporins
- Maintenance therapy for shock
- Vasoactive treatments -> e.g. IV adrenaline
- Steroids
- Experimental therapies, such as anti-cytokine and anti-endotoxin have been investigated
44
How is gonococcal disease treated?
- First line treatments now extended spectrum
| - Duel treatments are now recommended
45
What is the biggest issue for the meningococcal vaccine?
Surface variation poses a big problem in vaccine development
46
How was the Bexsero B vaccine developed?
Reverse vaccinology
47
What is the future of treating gonorrhoea?
- LpxC inhibitors
- Molecules mimicking host defensins
- Host defense proteins
- NanoCapc
