Damage caused by bacteria Flashcards
a) ways that bacterial can cause damage
b) overview of direct damage by toxins
a) Can result directly from bacterial action, or indirectly as a consecquence of the host immune response to the pathogen. Most pathogen cause both
b) many pathogenic bacteria secrete protein toxins (exotoxins). These can be denatured (toxoided) by factors like heat, and sometimes this is used to produce non-toxic immunogenic forms for vaccination
Two broad categories of exotoxin: cytolysins and intracellular enzymatic toxins
Direct damage by exotoxins: cytolysins
Target host cell membranes
Can cause enzymatic degradation of membrane phospholipidssecreted by phospholipases (like Clostridium perfringens α-toxin
Can cause pore formation in membranes (like Streptococcus pneumoniae pneumolysin, Streptococcus pyogenes streptolysin O, E. coli haemolysin, Helicobacter VacA
Lead to target cell lysis, but at lower concentrations they subvert host cell signal transduction, causing release of leukkotrienes, histamine, and apoptosis.
They disable the immune cells and assist tissue damage and bacterial spread
Direct damage by exotoxins: enzymatic intracellular toxins (+ different types)
Poison host cells by specific catalytic activity
Called A-B toxins, as their function depends on receptor-binding (B) and intracellularly active (A) components. Can be single polypeptides cleaved to active fragments (like in diptheria, tetanus and botulinum toxins), or multimeric (anthrax, pertussis and cholera toxins)
These intracellular-acting toxins get inton host cells by receptor-mediated endocytosis and/or retrograde transport
Types: i) ADP-ribosylating enzymes ii) adenylate cyclases iii) glycosidases iv) glycosylating toxins v) genotoxins vi) deamidases vii) neurotoxins
Enzymatic intracellular toxins - ADP-ribosylating enzymes
a) overview of ADP-ribosylating enzymes
b) Cholera toxin and Vibrio cholerae
a) Cholera toxin, E. coli enterotoxin (labile toxin, LT) and pertussis toxin ADP-ribosylate regulators of host adenylate cyclase. Leads to disturbance of cAMP levels, signalling and ion balance. Diptheria toxin ADP-ribosylates translation elongation factor 2, so blocks protein synthesis
b) Vibrio cholerae causes the severe diarrhoeal disease cholera, spread by fecal-oral route from contaminated water in developing countries. Is an acute infection, and if untreated, 50% mortality, although electrolyte replacement reduces this to 1%
V. cholerae colonises small intestine mucose by fimbrial adhesin, and principal disease symptoms are caused by the secreted cholera toxin (CTX). CTX genes carried on a bacteriophage intergrated into bacterial chromosome and are co-regulated with adhesin and other genes by a HAP signal transduction system
Toxin structure is AB₅, B binds to host receptor GM₁-gangliosude, uptake by receptor-mediated endocytosis and retrograde transport to ER. Active A subunit translocates into the host cell cytosol
CTX short-circuits control of adenyl cyclase activity by ADP-ribosylating stimulatory Gs (GTP-hydrolysing), fixing it in the ‘on’ state, resulting in uncontrolled high levels of cAMP. Increased intracellular cAMP disrupts activity of CFTR and Na+ membrane pumps. Ion imbalance leads to water and electrolyte loss into gut lumen
Copious water diarrhoae (rice water), shock, collapse, potentially cardiac failure as a result
Enzymatic intracellular toxins - ADP-ribosylating enzymes
Diptheria toxin (overview and action)
Diptheria is caused by Gram-positive rod Cornebacterium diptheriae (extracellular toxigenic bacterium) causes severe respiratory infection, re-emerging where vaccination uptake is inadequate. Produces diptheria toxin (DTX), the gene for which is carried on a bacteriophage integrated into the bacterial chromosome. DTX gene is controlled by a bacterial transcription factor DtxR, which represses gene expression when bound by iron (transcription switched on in the host where the concentration of free iron is low. After colonisation of nasopharyngeal epithelium, bacteria secrete A-B toxin, resulting in intense local inflammation and damage to mucosal cells, growth of bacteria in inflammatory exudate and formation of a pseudomembrane, which occludes airway. Toxin can lead to irregular heartbeat, coma and death.
Action: single (A-B) polypeptide binds to receptor HB-EGF via the B domain. A-B polypeptide is nicked by host protease (furin), but A and B domains remain covalently connected by disulphide bridge. Toxin taken up by endocytosis. Acidification of endosome (by V-ATPase proton pump) triggers B-dependent translocation of A across vesicle membrane into cytosol. In host cytosol, disulphide bridge is reduced, A is released and blocks protein synthesis by ADP-ribosylating translation elongation factor-2 (EF-2)
Enzymatic intracellular toxins
a) Adenylate cyclases
b) Glycosidases
c) Glycosylating toxins
a) Bordetella pertussis and Bacillus anthracis produce toxins that are adenylate cyclases, mimicking mammalian enzymes. Though toxin action is mechanistically different, the effects on host cells are similar to cholera toxin (but not in intestinal cells!)
b) Shigella (causes dysentery) produces shiga toxin, and enterohaemorrhagic E. coli (EHEC) produces shiga-like toxin. Both depurinate 28S rRNA to block translation (protein synthesis)
c) Clostridium difficile toxins glycosylate small GTPases involved in signal transduction - disrupt actin cytoskeleton and tight junctions
d) Salmonella typhi, E. coli and Campylobacter produce Cytolethal Distending Toxins (CDTs) which are genotoxins that cleave DNA
e) Uropathogenic E. coli (UPEC) and meningitis-causing E. coli produce Cytotoxic Necrotising Factors, deamidases that target host cell GTPases disrupting signal transduction to reorganise the actin cytoskeleton
Enzymatic intracellular toxins
Neurotoxins
Tetanus neurotoxin (TeNT) is made during anaerobic growth of the pathogen in a wound. TeNT B chain bindd to a receptor on peripheral nerve membranes. The A chain is internalised and undergoes retrograde transport to the CNS. The A-chain cleaves synaptobrevin, blocking the release of inhibitory neurotransmitters. This results in uncontrollable muscle contraction, spastic paralysis and death from spasms of the respiratory muscles
Botulinum neurotoxin (BoNT) has the same proteolytic action but acts on peripheral nerves, preventing the release of stimulatory neurotransmitters, resulting in flaccid paralysis
a) advanage of enzymatic intracellular toxins
b) Superantigens as toxins (+ disease caused by them, and advantage)
a) aid colonisation (kill ciliated cells in whooping cough), aid transmission (cough droplets for diptheria, faecal-oral route for cholera and dysentry)
b) In conventional antigen presentation, antigen is engulfed by APCs and degraded to peptides. These are bound by MHC class II molecules and presents on APC surface, where it is recognised by T cell receptor, generating protective T cells.
Superantigen (SAg) bridges the weakly interacting MHCII and TCR by binding outside the normal antigen-binding pocket, hence activating various useless T cells by promoting tighter binding and stronger signalling in the T cells, causing a cytokine storm
Toxic shock syndrome (TSS) is caused by the superantigen (TSST) produced by Staph. aureus growing in highly absorbent tampons. Strep. pyogenes produces a similar toxin and causes toxic shock-like syndrome (TSLS) - symptoms of shock and multi-organ failure, similar to those caused by the LPS endotoxin.
Staphylococcal toxins involved in food poisoning are also superantigens
They may deflect the immune response, hence useful
Indirect damage by host response
a) outline acute inflammation and why a good host alarm signal
b) what happens when acute inflammation occurs in the wrong place (example)
a) triggered by lipid A component of Gram-negative bacterial LPS, which is released from dead bacteria, then bound by LPS-binding protein and delivered to macrophage receptors CD14 and TLR4, triggering signalling pathways that activate cytokine genes. Lipid A is unique to bacteria, making it a good host alarm signal, triggering a strong innate immune response, which underlies some of the common uncomfortable symptoms of bacterial infections like pyelonephritis, gastroenteritis and cystitis. Lipid A overload (large numbers of bacteria die) can be dangerous eg in septicaemia causing septic shock. Acute inflammation is also triggered by other bacterial components, like peptidoglycan and flagellin (PAMPs)
b) Meningitis - caused by several pathogens (some of which colonise the nasopharynx asymptomatically). Neisseria meningitidis,Haemophilus influenzae type B (Hib), Streptococcis pneumoniae, E. coli (neonatal meningitis). Bacteria cross epithelium into blood (bacteraemia). Endithelial cell damage occurs, and bacteria cross the blood brain barrier. Inflammation in meninges caused primarily by LPS lipid A.
E. coli K1 and some N. meningitidis strains have sialic acid capsules, an example of host mimicry as sialic acid is common in host tissues. Polysaccharides are weakly immunogenic, but anti-capsular antibodies can protect against specific serotypes
Indirect damage by host response
a) effect of chronic inflammation
b) other examples of immunopathology
a) Relatively uncommon in bacterial disease, but long-term inflammation caused by Chlamydia can lead to pelvic inflammatory disease and infertility, and by Helicobacter pylori can lead to gastric ulcers and cancer. A particular danger is granulomatous inflammation resulting from the host response to persisting Mycobacterium tuberculosis in the disease TB. Mycobacteria can be successfully cleared bt CD4+T cell-activated macrophages, bu the pathogen commonly persosts and the resulting infiltration of further large numbers of activated macrophages leads to a granulomatous lesion surrounding the pathogen, characterised by ongoing inflammation, tissue destruction and repair (fibrosis)
Other chronic bacterial infections are leprosy, caused by Mycobacterium leprae (also involves granuloma formation) and syphilis, caused by Treponema pallidium
b) Streptococcal glomerulonephritis (type III hypersensitivity reaction) follows lodging of immune complexes in the kidney
Lyme disease caused by Borrelia burgdorferi involves not only LPS-induced inflammation, but also type III hypersensitivity. Deposition of immune complexes in the joints induces inflammation and possibly arthritis, if depositied in the vasculature and meninges can lead to neurologic symptoms
Also possible examples of bacterial antigen contributing to autoimmune disease and rheumatoid arthritis
