WEEK 2: MECHANISMS OF BACTERIAL PATHOGENESIS I & II Flashcards
What % of bacteria are pathogenic?
Less than 5%
Can some types of bacteria have both pathogenic and non pathogenic strains?
- YES
- e.g. E.coli and EPEC (enteropathogenic E.coli)
What is an opportunistic infection defined as and examples of when this can occur?
- When there is a breakdown of the normal microbiota
- e.g. Antibiotic use, chemotherapy, burn trauma–> pseudomonas aeruginosa)
What are HAIs and some examples?
- When the normal microbiota is transferred to (b/w) health COMPROMISED people
- e.g. Surgical wound infection–> MRSA S.aureus (Mecithillin Resistant)
- Bacterial pneumonia
What are 3 things that determine the nature and extent of damage between a pathogen and the host?
- Particular pathogen –> vibrio cholerae only infecting humans
- Particular Host –> Salmonella enterica (Typhoid in humans but nothing in mice)
- Host microbiota –> C. dificille
Why do pathogens cause disease in the context of commensal bacteria?
- They express VIRULENCE DETERMINANTS not expressed by commensal organisms
What are 5 things that virulence factors mediate?
- colonisation of de novo niches in body
- Adhesion (ligands for host cell expressed proteins)
- Invasion
- Immune evasion mechanisms (capsules on bacteria)
- tissue damage (toxins)
How do commensal bacteria become pathogens?
- Bacterial virulence genes present on mobile genetic elements and ACQUIRED through horizontal gene transfer
What are the 3 main mechanisms that horizontal gene transfer occurs via to acquire mobile gene elements?
- Plasmids (Conjugation)
- Bacteriophages (Transduction)
- Transposons (transformation)
What are pathogenicity islands a combination of?
- Plasmids, bacteriophages, and transposons
What are 5 properties of virulence plasmids?
- Circular, extrachromosomal
- Self replicating
- Found in Gram -ve and +ve bacteria
- transmitted between bacteria by CONGUGATION
- Encode VIRULENCE genes for invasion, toxins, drug resistance
What are 3 properties of bacteriohpages?
- Bacterial viruses
- Carry genes encoding toxins
- Lysogenic (or can be lytic)
What are 3 examples of toxins that bacteriophages are involved with?
- Diptheria
- Cholera toxin A-5B
- Shiga Toxin (Shigella)
What are transposons?
- DNA segments capable of random integration
- Transferred on plasmids or bacteriophages
What are pathogenicity islands and some features?
- Large areas of bacterial chromosome that are dedicated to virulence
- Have a different G-C content to the host DNA (usually lower)
- Discrete genetic units with defined boundaries (gained and lost ‘as a package’)
Are different PAIs present in different pathogens?
- YES!
- These allow it to release different toxins
What do PAIs have systems for?
- Allowing the bacteria to inject protein into host cell
When are virulence genes expressed?
- WHEN BACTERIA SENSE A SPECIFIC NICHE (Temperature, O2, lack of nutrients etc)
- IN RESPONSE TO POPULATION DENSITY
- Quorum sensing (signalling through small organic molecules)
What is quorum sensing?
- Tells the individual bacteria whether to turn genes on or off
- Communication system that bacteria use
Which application is quorum sensing important in?
- Biofilms
What were Koch’s postulates designed to establish?
- Establish a causative relationship between microorganism and disease
What is Koch’s postulate 1? `
- “The microbe must be present in every case of the disease (and absent from healthy hosts) “
What is Koch’s postulate 2?
- “The microbe must be isolated from the diseased host and grown in pure culture”
What is Koch’s postulate 3?
- ” The disease must (SHOULD ) be reproduced when the culture is introduced into the healthy (susceptible) host”
What is Koch’s postulate 4?
- “The microbe must be recoverable from an experimentally infected host”
What is Koch’s 5th postulate that was developed later?
- Effective therapeutic or preventive measure(s) should eliminate disease
Are Koch’s factors in use a lot now?-
NO!
- Not common use anymore because too many limitation
What is a demonstration of Koch’s postulates?
- Helicobacter pylori isolation from Australians
What are the 5 limitations of Koch’s postulates?
- No host factors taken into account (carrier states or opportunistic infections)
- Emphasis on ability to culture the organism
- Organisms can lose virulence/pathogenicity during lab culture e.g. mycobacterium TB may lose lipids (i.e. virulence) in culture
- Disease may not require the organism to infect the host (e.g. toxins) BUT IS RARE–> botulinum -poorly processed food
- requires a suitable/susceptible animal model (e.g. Vibrio cholera only infects humans, not other animals)
What are Koch’s UPDATED molecular postulates (1988)?(4)
- The ‘virulence’ gene is ALWAYS found in strains with a particular virulence phenotype
- The gene should be expressed in the host
- Mutation (inactivation) of that particular gene ABOLISHES (reduces) the virulence phenotype
- Reintroduction of the gene reconstitutes the virulence phenotype
What are the 6 general steps that a pathogen must take to cause disease?
- Enter body
- Colonise the host
- Invade
- Evade HOST DEFENSES
- Multiply and disseminate
- Cause DAMAGE TO HOST
Does colonisation = infection?
- NOOOO!!!
What is virulence determined by?
- Adhesion
- Penetration into cells
- Antiphagocytic activity
- Production of toxins
- Interaction with the immune system
What are genetic changes in bacteria due to?
- Gain or loss of integrins
- Pathogenicity islands
- Transposons
- Plasmids
What is a virulence factor that H.pylori produces?
- Urease
What are three things that adhesion is mediated by?
- Pili and fimbriae
- Afimbrial adhesions
- Capsules
What type of surface is the bacterial cell membrane in terms of adhesion mediated by capsules and why?
- Sticky
- To allow adhesion to each other like in biofilms
- To allow adhesion to surfaces like teeth (plaque)
Where can obligate intracellular pathogens multiply?
- Inside the CELL
What is bacterial invasion?
-Where bacteria invade cells that are not phagocytic
What are the two forms of bacterial invasion?
- Into cells (INVASION) –> enteropathic E.coli
2. Through cells (TRANSCYTOSIS)
What is bacterial invasion mediated by?
- Bacterial INVASINS (virulence factors)
What are the two TRIGGERS for bacterial invasion?
- TRIGGER MECHANISM (bacterial trigger)
- ZIPPER MECHANISM ( cell surface receptor/ligand interactions)
Which two things do both the zipper mechanism and the trigger mechanism result in from bacterial invasion?
- Actin polymerisation and depolymerisation
- Pseudopod and membrane ruffle formation
Which form of the bacterial triggers works from the outside in?
- The zipper mechanism
What is the example for the zipper mechanism for bacterial trigger to invasion?
- Listeria Integrin A binds to + activates host cell E-cadherin
- Yersinia OM invasin interacts with host cell Beta 1 integrins
- Causes actin rearrangement in host cytoskeleton and internalisation
Which form of the bacterial tirggers works from the inside out?
- Trigger mechanism
What is an example of the trigger mechanism for bacterial invasion?
- SALMONELLA spp and SHIGELLA sp
T3SS–> Type 3 Secretion System –> changes Actin dynamics
- Causes induction of membrane ruffling and closure after entry 1 - EPEC (enteropathic E.coli)
What is the process of EPEC (enteropathic E.coli) using the trigger mechanism for invasion?
- T3SS used for E.coli to ADHERE to + damage intestinal epithelial cells
- T3SS INJECTS Tir
What does Tir that T3SS injects in EPEC do bind and what does this cause?
- Binds bacterial intimin
- Causes actin polymerisation and induction of pedestals
How does having a capsule present allow a pathogen to avoid complement fixation?
- It does not allow C3b to stick to surface (bind) because capsule is in way
e. g. Haemophillus influenzae, Strep.phneuimoniae
What are the three ways that a pathogen can avoid complement fixation?
- Having a capsule to prevent C3b from binding
- Secrete complement DEGRADING molecules which cleave complement –> S.puogenes –> C5a peptidase
- Bind Ig via Fc receptor –> NO ACTIVATION OF MAC –> Staphylococcal protein A
What are the three broad ways that bacteria can evade phegocytes?
- Avoid being recognised or or inhibit internalisation
- Kill phagocyte/induce apoptosis (anti-phagocyte toxins)
- Inhibition of phagolysosome (i.e. survive phagocytosis)
What are 3 ways of avoiding being recognised or internalisation?
- Avoid Opsonisation (prevent C3b opsonisation or prevent Ig opsonisation)
- Form capsules to hide PAMPs (K.pnemoniae to hide LPS)
- Form biofilms
What are the 4 ways that there can be inhibition of the lysosome?
- Blocking fusion to lysosomes (Salmonella typhimurium. Mycobacterium)
- Lyse phagosomal membrane –> escape into cytoplasm –> Shigella
- block/be resistant to ACIDFICATION (Mycobacterium–> lives happily in phagosome)
- Block assembly of NADPH oxidase
Which part of the IgA molecule does the IgA protease cleave?
- Hinge region
What are the 5 ways bacteria can avoid eliciting or detection by Igs?
- Remain inside host cells
- Host mimicary
- Coat with host proteins
- Colonise sites with POOR access for Igs (or not accessed by APCs)
- Keep ahead of the immune system-antigenic variation
What is the growth limiting micronutrient for bacteria?
- IRON
What is the main iron cheltor that pathogens use to obtain iron?
- Siderophores
What are 4 ways in which pathogens obtain iron despite being in a low iron environment?
- Secreting HIGH AFFINITY iron-chelators and having siderophore receptors to capture them
- Expressing high affintiy iron binding membrane proteins
- Expressing receptors for iron capture proteins like transferrin
- Expressing toxins like haemolysins to release host Fe
In which two ways can INVASIVE bacteria cause damage to the host?
- Extracellular enzymes that DAMAGE tissue
- Modulation of host immune responses
What type of bacteria (invasive or non invasive) are bacterial toxins made?
- NON INVASIVE
What does DIRECT effect of bacterial toxins mean?
- Secreted or cell associated bacterial toxins with a DIRECT cellular pathogenic consequence (action at the site of infection)
What does INDIRECT effect of bacterial toxins mean?
- Damage to the host caused by an EXAGGERATED IMMUNE RESPONSE - at a site or sites REMOTE to the toxin
What is an example of a situation where the toxin is sufficient to produce the disease?-
- Clostridium botulinum–> poorly preserved food
Are exotoxins produced by BOTH gram positive and gram negative bacteria?
- YES!
In which 3 ways are Exotoxins characterised by?
- They type of cell it damages (neurotoxin, cytotoxin)
- The bacteria that produce them
- Its pathogenic activity (enterotoxin–> enteric symptoms)
What are the 3 types of protein exotoxins?
- Membrane disrupting toxins (haemolysins)
- A-B toxins
- Super antigens (S.aureus toxic shock toxin)
What are the two types of non protein heat stable exotoxins?
- Glycopeptides
- Polyketides –> mycolactones –> cytotoxic and immunosuppressive
What are the two types of membrane disrupting toxins>
- Phospholipases
- Pore forming toxins
What do subunit A and B do respectively inA-B exo toxins?
- A has catalytic activity (potency) and B recognises membrane receptors and thus determines the cell specificity`
What are the 4 types of A-B toxins?
- Diptheria
- Botulinum
- Cholera toxin
- Tetanus
What do endo toxins do/what effect in general do they have on the body?-
- Induce EXAGGERATED immune response –> LPS (Lipid A)
