Bacterial Pathogens And Disease 1 Flashcards
Define pathogen
A microorganism capable of causing disease.
Define pathogenicity
The ability of a infectious agent to cause disease
Define virulence
The quantities ability of a agent to cause disease
Define toxigenicity
The ability of a microorganism to produce a toxin that contributes to the development of disease
What are the 4 virulence mechanisms?
Adherence factors
Biofilms
Invasion of host cells and tissues
Toxins- endotoxins and exotoxins
What are exotoxins?
Heterogeneous group of proteins produced and secreted by living bacterial cells
Produced by both gram negative and gram positive bacteria
Cause disease symptoms in host during disease
Act via a variety of diverse mechanisms
What is the advantage of bacteria having exotoxins?
- Evade immune response
- Enable biofilm formation
- Enable attachment to host cells
- Escape from phagosomes
All allowing for colonisation, niche establishment and carriage - evolutionary advantage
Do toxins cause disease?
No, but may help transmission
How does the case of straphylococcus aureus express the important of exotoxins?
Haemolytic toxins cause cells to lyse by forming pores and have a Importance in symptoms of S aureus
Phenol soluble Modular’s PSM - aggregate the lipid bilayer of host cells (lysis)
Describe the function of the different toxins associated with the movement of staphylococcus aureus?
Alpha toxin - initial attachment
Beta toxin - accumulation
E DNA - secondary structure formation
PSMs - detachment
How are exotoxins classified?
Classification can be by the toxins activity
- membrane acting toxins - type 1
- membrane damaging toxins - type 2
- intracellular toxins - type 3
Where are toxins expressed in the bacterial genome?
By extrachronsomal genes
- Plasmids
- Lysogenic bacteriophage
What is the problem with classifying exotoxins?
Many toxins may have more than one type of activity
As mechanisms better understood this classification tends to break down
How to membrane acting toxins TYPE 1 work?
Act:
- act from without the cell.
Interfere:
- interfere with host cell signalling by inappropriate activation of host cell receptors
Target:
- target receptors include:
. guanylyl cyclase (increase intracellular cGMP)
. adenyl cyclase, (increase intracellular cAMP)
. Rho proteins
. Ras proteins
Give a example of membrane acting toxin?
E coli table heat toxin
How do membrane damaging toxins TYPE 2 work?
Interact with the receptor and form a pore
- Insert channels into host cell membrane (beta sheet toxins and alpha helix toxins)
- Enzymatical damage
Can be receptor mediated or receptor independent
How do intracellular toxins work?
Have 2 components (A and B)
Component B has the capacity to interact with a specific receptor - gets internalised by receptor mediated endocytosis
Component A is a toxigenic (enzymatic) that interfere with cellular processes
AB5 is heat sensitive while the rest are heat resistant
Give examples of component A of intracellular toxins
ADP - ribosyl transferase
Glucosyltransferase
Deamidase
Protease
Adenylcyclase
What are the 2 mechanisms by which exotoxins can induce a inflammatory response?
- Superatigen
- via activation of the different inflammasome leading to release IL1 and IL18
How can exotoxin’s cause inflammation by superantigen?
Non specific bridging of the MHC class 2 and class T cell receptor leading to cytokine production.
How can toxins be inn-activated?
inactivated using formaldehyde or glutaraldehyde → toxoids
What are toxoids?
Toxoids are inactive proteins but still highly immunogenic – form the basis for vaccines.
How are toxin mediated diseases treated?
Affected by administering preformed antibodies to the toxin
Eg.
. Diphtheria antitoxin – horse antibodies.
• Tetanus – pooled human immunoglobulin.
What is clostridium difficile?
• gram-positive bacillus.
• anaerobic.
• spore-forming.
• toxin-producing.
• can be carried asymptomatically in the gut. • 3 toxins.
What is the epidemiology of C. difficile?
. Common hospital acquired infection worldwide.
• Spread by ingestion of spores
Risk factors
- antibiotic use,
- age,
- antacids
- prolonged hospital stay.
How can antibiotics contribute to the spread of C. difficile?
. Thought to act by disrupting the microbial ecosystem within the gut.
• Antibiotics provide a competitive advantage to spore forming anaerobes over non spore forming anaerobes.
• Allows C. difficile colonisation and growth.
• All antibiotics have potential for causing disease.
What are the cytotoxins of C. difficile?
Cytotoxin A - TcdaA coded by TcdaA gene
Cytotosin B - TcdB coded by TbdaB gene
Binary toxin C - minor role in disease
Describe the process by which TedA/TedB cause down stream effects within the host cell.
- Toxins binding to specific host cell receptors
- Toxins internalisation
- ENDO some acidification
- Pore formation in the endosome
- GTD release from the endosome to the host cell cytoplasm
- Rho GTPase inactivation by
- Downstream effects within the host cell.
What is the symptoms of C. difficile?
Asymptomatic
Watery dihoreah
Dysentery
Pseudomembranous Colitis
Toxic Megacolon and Peritonitis
How is C. difficile diagnosed in patients?
• Clinical signs and symptoms
• Raised white cell count in blood.
• Detection of organisms and toxins in stool
• Detection of tcdA and tcdb genes – PCR
• Colonoscopy – pseudomembranous colitis
How is C. difficile detected with its toxin using the 2 stage test?
- Glutamate dehydrogenase – detects if C. difficile organism present.
- Toxin enzyme linked immunosorbent assay (ELISA) for TcdA and TcdB toxins.
How is C. difficile treated?
Dependent on severity and presence of surgical complications
• Ideally removal of offending antibiotic – not always possible
• Antibiotics fidaxomicin or metronidazole or vancomycin
• Surgery – partial, total colectomy
• Recurrent – faecal transplant.
What is VTEC disease?
Also known as Shiga-toxin (Stx) producing E. coli (STEC) can cause disease mild to life threatening disease.
• Identified usually by growth on sorbitol MacConkey agar (SMac) – does not ferment sorbitol and hence is clear.
What is the epidemiology of VTEC disease?
naturally colonizes the gastrointestinal tracts of cattle who are generally asymptomatic.
Transmission
• Predominantly via consumption of contaminated food and water
• Person to person, particularly in child day-care facilities, and from
• Animal to person. E.g. in petting zoos, dairy farms, or camp grounds.
What is the pathogenesis of the toxin causing VTEC?
Toxin – Shiga like toxin (SLT) = shigatoxin (Stx) = verocytotoxin (VTEC)
. Type III exotoxin – AB5
• Enzymatic component A = N-Glycosidase
• Bound to 5 B subunits
What is the mechanism by which Stx toxin effects cells?
• Bind to receptor globotriaosylceramide Gb3 or globotetraosylceramide (Gb4) on host cell
membrane
• Bound toxin internalised by receptor mediated endocytosis.
• Carried by retrograde trafficking via the Golgi apparatus to the endoplasmic reticulum.
• The A subunit is cleaved off by membrane bound proteases
• Once in the cytoplasm A1 and A2 disassociate
• A1 binds to 28S RNA subunit – blocks protein synthesis.
Describe the pathogenesis of STEC
• STEC closely adheres to the epithelial cells of the gut mucosa.
• The route by which Stx is transported from the intestine to the kidney and other tissues is debated, possibly polymorphonuclear neutrophils (PMNs)
• Bind to glomerular endothelial cells of kidney, cardiovascular and central nervous system.
• Very high levels of Gb3 in kidney so kidneys most affected.
• Thought that Stx favours inflammation resulting in microvascular thrombosis and inhibition of fibrinolysis.
What is STEC disease?
Children under 5 years are at greater risk
Can be severe and life threatening
Abdominal cramps, watery or bloody diarrhoea - may not be present
How is STEC diagnosed?
•Clinical signs and symptoms
•Haematological and biochemical evidence.
•Stool culture – Growth on SMac
•PCR for Stx genes
How is STEC treated?
•Supportive including renal dialysis and blood product transfusion
•Antibiotics have little to no role
What are the symptoms of STEC disease?
• Haemolytic uraemic syndrome
• Anaemia
• Renal Failure
• Thrombocytopaenia
• Less common are neurological symptoms
• lethargy,
• severe headache,
• convulsions,
• encephalopathy.
