Principles of pathogenesis: bacterial infection Flashcards
What are the several overlapping ways in which disease can come about?
1) some bacteria entirely adapted to the pathogenic way of life in humans - never part of normal flora but can cause subclinical infection
2) some are part of normal flora and can acquire extra virulence factors making them pathogenic
3) some are from normal flora and can cause disease when they gain access to deep tissues by trauma, surgery. lines, especially if associated with a foreign body
4) immunocompromised patients many free living bacteria and components of the normal flora can cause disease especially if introduced into deep tissues
What are koch’s postulates?
- pathogen must be present in every case of the disease
- pathogen must be isolated from the disease host and grown in pure culture
- specific disease must be reproduced when a pure culture of the pathogen is inoculated into a healthy susceptible host
- pathogen must be recoverable from the experimentally infected host
= knowing whether a given pathogen causes a specific disease
What is the iceberg concept of infectious disease?
spectrum of virulence
part of the iceberg under the water = asymptomatic infection
the bottom bit above the water = less severe disease and the top bit = classical clinical disease
How do we know that a given pathogen causes a specific disease?
diagnosis and effective treatment of infection depends not just on isolating an organism but in establishing a plausible link between the laboratory findings, recognised syndromes and the patients clinical condition
What evidence suggests a potential pathogen might be of clinical significance?
isolated in abundance isolated in pure culture isolated on more than one occasion isolated from deep tissues evidence of local inflammation evidence of immune response to pathogen fits with clinical picture
Why can our normal flora be a problem?
it can contaminate specimens and it can also cause disease
Why is our normal flora beneficial?
can protect against infection by preventing pathogens colonising epithelial surfaces (colonisation resistance)
removal of the normal flora with antibodies can cause superinfection usually with resistant microbes
What are exotoxins?
bacterial proteins - can elicit the features of a bacterial infection when injected as pure proteins
What did toxoid vaccinations lead to?
vaccination with inactivated toxins led to a spectacular decline in the incidence of many bacterial infections
What is bacterial virulence?
needed to colonise and/or damage tissues
- molecular koch’s postulates = delete genes, show loss of virulence in model system, add gene back, show restoration of virulence
- biochemical evidence of damaging potential
distinguishes pathogen from commensal
What are the steps in successful infection?
sex comes before disease = acquire virulence genes swim to site of infection stick to site of infection scavenge nutrients - especially iron survive stress stealth - avoid immune system strike back - damage host tissues spread- through cells and organs
How can bacteria acquire virulence genes?
3 ways of exchanging DNA:
- transformation - cells take up naked DNA
- transduction - phages carry DNA
- conjugation - cells mate through specialised appendages
What are some mobile genetic elements in bacterial sex?
transposons = st enterotoxin genes
virulence plasmids
phage encoded virulence
What is meant by pathogenicity islands?
concept originated from study of uropathogenic E.coli strains
- defining feature:
=> carriage of (many) virulence genes
=> presence in pathogenci vs non-pathogenic strains
=> occupy large chromosomal regions (10-100)
=> often encode secretion systems
=> can also encode adhesins, siderophores, toxins
How are bacterial pathogens motile?
motility is crucial for virulence in some cases
usual organelle of motility is flagellum
variants:
- twitching motility
- swarming
How to bacteria stick to avoid physical and immunological removal?
adhere to cell surfaces and extracellular matrix = resp, GIT
solid surfaces = teeth, heart valves
direct interaction
molecular bridging via fibronectin
adherence often combined with manipulation of host cell signalling and cytoskeleton - invasion and intimate adherence
What is meant by scavenge nutrients? eg. iron
free iron levels very low in body fluids
- acute phase response causes further drop
- iron overload increases susceptibility to infection
many different bacterial systems scavenge for iron
- siderophores chelate available iron and transport it into bacteria
- iron can be scavenged direct from host iron binding proteins
- some pathogens avoid the problem by cutting out need for iron e.g. treponema
What is iron used to do?
regulate aggressive virulence factors
- diphtheria toxins, shiga like toxin and pseudomonas aeruginosa exotoxin A
What stresses do pathogens face?
acid stress within stomach
heat shock during fever
oxidative shock within phagocytes
How do pathogens cope with stress?
stress response proteins such as chaperonins feature as immunodominant antigens
detoxification proteins play a role in virulence
infectious dose for enteric pathogen much lower in achlorhydria (no need to overcome acid stress)
What is meant by pathogens need stealth?
avoid the immune system
- IgA proteases = metalloproteases active against IgA
- immunoglobulin-binding proteins = protein A of S aureus
- resist complement, opsonisation = capsule, lipopolysaccharide, surface proteins and OMPs
- antigenic mimicry = sialic acid capsule of group B meningococcus
How can a pathogen strike back?
endotoxin (e.g. LPS)
- pyrogneicity, leucopenia the leucocytosis, hypotension (life threatening complication of septicaemia)
most of the effects of endotoxins are mediated by tnf
exotoxins
- toxins acting on cell membranes
- toxins active inside cells
- superantigens
What is involved in membrane damaging exotoxins ?
bacterial toxins form pores in eukaryotic cell membranes producing oligomeric rings
e.g. streptolysis O of streptococcus, listeriolysis of listeria, alpha toxin of s aureus
other toxins such as phospholipases, degrade components of the membrane e.g. clostridium perfringens alpha toxins
How can toxins act inside the cells?
toxins often consist of translocation and binding B subunit that delivers the active A subunit into the host cell cytoplasm
e.g. AB toxin= diphtheria toxin
What are the spreading factors?
degradative enzymes that allow bacteria to spread through tissues
- streptococcus pyogenes secretes = hyaluronidase (destroys connective tissue), DNase thins viscous pus (DNS thickens pus), streptokinase (Activates plasminogen producing plasmin which destroys fibrin clots)
