21 Neisseria - immune system Flashcards
what is neisseria like
large genus of Gram-negative bacteria
where is neisseria found
Natural inhabitants of the mucous membranes of mammals
Several human commensals inhabiting the mucus membranes
human pathogens - neisseria
N. meningitidis
N. gonorrhoea
what causes meningococcal diseases
Neisseria meningitidis,
what meningococcal diseases can occur
meningococcal sepsis
meningitis
what are meningococcal diseases like
while normally a harmless commensal, can cause devastating diseases
what is meningococcal sepsis caused by
inappropriate immune response
what causes the characteristic of meningococcal diseases - glass cup
capillary networks break down and blood not in circulatory system – why glass test occurs
Glass test – rash doesn’t disappear
carriage of meningococcal diseases
normally inhabits the nasopharynx
Colonises up to 50% of individuals within a population
transmission of meningococcal diseases
Associated with close contact – transmission
Can be coughing, sneezing, kissing
Meningococcal sepsis symptoms
High fever
Rash
Arthritis (achy joints)
Coagulopathy (evident as skin lesions but occurs throughout the body)
coagulopathy effect - meningococcal sepsis
bacteria will eventually affect the adrenal glands and adrenal insufficiency quickly leads to death
Meningococcal meningitis symptoms
Severe headaches Photophobia High fever Pain and stiffness of the neck, back, and shoulders nausea Rash
post infectious sequelae - meningococcal infection
Loss of extremities
Liver or kidney failure
Memory loss
what is a gonococcal infection like
may be asymptomatic but ultimately this organism is always a pathogen
symptoms of gonococcal disease
urethritis (purulent discharge)
where does gonococcal infections infect
mucous membranes of the urogenital tract and nasopharynx
what is the major problems with gonococcal diseases
antibiotic resistance
More serious for women – can lead to infertility
how is gonococcal diseases spread
usually always sexually transmitted disease – but usually is - Infants can get during birth from infected mother
what gonococcal disease can infant get
opthalmia neonatorum
Meningococcal pathogenesis
Start in oral pharynx and nasopharynx
Associates with mucosal membrane can get between these cells and get into bloodstream
Cross the blood brain barrier - manipulates endothelial cells that make up blood brain barrier
Organisms can get into cerebrospinal fluid
neisseria meningitidis groups
Different serogroups if Neisseria meningitidis – depends on which capsule it makes
Serogroup A
Serogroup B, C, W & Y
what is the capsule controlled by
Phase-variable antigen (can be turned on/off)
where are Acapsulate isolates of N. meningitidis often found in
nasopharynx
when are capsulate isolates found
found in cases of invasive meningococcal disease
Exceptions include individuals with complement deficiencies
what is the problem with serogroup B
Serogroup B capsular polysaccharide is identical to molecules found on some neuronal cells
Seen as a self-antigen and is thus hypoimmunogenic
how does type IV pilus grow
pilE form structure of the pilus – added in the periplasm as added the pilus gets pushed out
how does type IV pilus disassemble
pilT protein removes subunits – depolymersises pili and pulls it back in
what does pilT require
PilT-dependent twitching motility
PilT is required for pilus retraction and therefore necessary for motility
what is TspB
T cell stimulating protein B - potent stimulant of T cells
where is TspB
outer membrane protein
what encodes TspB
prophage found in most hyperinvasive isolates
TspB function
Binds immunoglobulin
Inhibits IgM-mediated activation of the classical complement pathway as binds to Fc not FAB part
what does TspB do
Promotes survival in normal human serum
what is the matrix composed of that envelopes bacteria aggregates
A matrix composed of TspB, IgG and DNA envelopes aggregates of bacteria
what makes fHbp
Produced by most strains of N. meningitidis (not all strains)
what is fHbp
OM protein
what does fHbp do
binds Factor H onto own surface ‘pretend to be host’ so downregulates complement activity
what does factor H do
regulates the Alternative pathway of the complement system
what is fHbp important for
survival in human blood, serum and in the presence of antimicrobial peptides
Mechanisms that contribute to the resistance ofNeisseria meningitidisagainst complement-mediated killing
- Polysaccharide capsule prevent insertion of MAC
- Expression of full length LPS is necessary for complement resistance
- C4BP to PorA - significantly increase the survival of the bacteria in the presence of an active complement system
- type IV pilus
what makes IgA protease
Produced by a number of mucosal pathogens
what does IgA protease do
Cleave IgA1, prominent on mucosal surfaces cuts FAB part from Fc part = ineffective
what are the Neisserial IgA proteases virulence-related functions
Cleavage of LAMP1 promotes intracellular survival
Acts as a superantigen - massive cytokine release
what is IgA protease
Gram-negatives belongs to a class of secreted proteins called autotransporters
Antigenic variation
Expression of antigenically distinct functionally conserved moieties within a clonal population
Phase variation
Reversible switching between all-or-none (on/off) expressing phase, resulting in variation in the level of expression of one or more molecules between individual cells of a clonal population
phase variation examples
Streisinger model of slipped strand mispairing
Phase variation mediated by transposons
Streisinger model of slipped strand mispairing
DNA replication when strands come back together the growing strand can result in addition or removal of one or more repeat units from the daughter duplexes
Simple repeats, typically mono-, di- or tetranucleotides, are liable to slipped strand mispairing
Streisinger model of slipped strand mispairing - repeats occur in promoter region
can affect the spacing or turn of elements of the promoter (e.g. -10 and -35 regions) and thus the efficiency of the promoter
Streisinger model of slipped strand mispairing - repeats occur in ORF
changes in repeat number (where the repeat unit does not contain a whole number of codons) can result in placing the region of the gene downstream of the repeat region in or out of frame
Phase variation mediated by transposons
Transposons are DNA elements encoding their own excision and insertion at specific sequences within DNA molecules. Insertion within a gene can disrupt it
In most cases transposons do not excise themselves precisely and can not mediate phase variation
what can switch off capsule expression
Capsule expression can be switched off by transposition
how does transposition switch off capsule expression
Insertion sequences responsible for loss of capsule expression in carriage isolates by insertion into siaA and siaD genes (which are necessary for capule production)
Gene conversion in Neisseria meningitidis
Gene conversion responsible for antigenic variation particularly of the pilus
pilE – pilus Expressed locus
Many pilS loci in genome – S =silent (not expressed) can recombine with pilE = new variants
Type IV pilus can take up DNA and can then recombine it
how is meningococcal immune evasion is triggered
high temperature
what are the 3 independent RNA thermosensors in 5’ region of genes involved in immune evasion
Capsule biosynthesis
Factor H-binding protein
LOS sialylation
what does gonococcal infection elicit
TGF-β-mediated suppression of Th1 and Th2 responses (cell-mediated responses and antibody reponses)
what do gonococcal lack
No capsular polysaccharide or fHb – don’t normally see disseminated gonococcal disease is rare
