Day 8: Sepsis, bloodstream infections, infective endocarditis and innate defence Flashcards
HC 20, 21
In sepsis, the immune system is..
Strongly deranged
Levels of severity in bloodstream infection
- Bacteremia/viremia/fungemia: in blood
- Systemic Inflammatory Response Syndrome (SIRS)
> temperature deregulated
> Heart rate increased
> Breathing frequency increased
> High leukocyte concentration - Sepsis: SIRS due to infection
- Severe sepsis: with organ failure, low blood pressure, hypoxia, oliguria, or bahavioural changes and reduced consciousness
- Septic shock: severe sepsis with permanent low blood pressure despite blood pressure supporting medication
- Multiple organ failure (MOF): loss of function of multiple organs with no recovery without medical intervention
Mortality MOF
Around 20% but dependent of level of organ failure
Most frequent causes bloodstream infections
- Airways
- Abdomen
- Urinary tract
- Skin or soft tissues
- Central venous catheters
- Deep infections such as endocarditis/meningitis
A lot of bacteria in the blood and immune system
Activate pathogen related patterns > inflammation reaction to control pathogens
> also complement activation, production anaphylatoxins which attract immune cels and activate phagocytosis by attaching to pathogen
» stronger immune activations
Neuro-endocrine regulation of immune repression when bloodstream infection
Immunosuppression
> acetylcholine through nervus vagus > inhibition pro-inflammatory cytokine production (transcription)
Immune suppression when bacteremia
Less functioning immune cells
Neuro-endocrine regulation
Inhibition of pro-inflammatory transcription
Bloodstream infective bacteria”: common names
52% grampositive
> Staphylococcus aureus
> Streptococcus pneumoniae
38% gramnegative
> Escherichia coli
> Klebsiella
> Pseudomonas aeruginosa
How do Human Antimicrobial peptides in blood (AMPs) (from endothelial cells, leukocytes and platelets) selectively interact with microbial cell membranes
AMPs bind electrostatically and with hydrophobic interaction with more negative head groups in outer leaflet bacterial membrane
> in human cells, cholesterol with neutral head in outer leaflet, less attraction to it
Resistance AMPs by Salmonella
Inducible aminoarabinose addition to LPS > repulsion of cationic AMP
AMP resistance in Proteus
Proteus can swim very well: urinary infections
> Constitutive aminoarabinose on LPS: repulsion cationic AMP
AMP resistance of S. aureus
expression dlt operon
> D-alanine (cationic) decorates the lipoteichoic acid (LTA) > repulsion cationic AMP
- Also, ATP dependent exporters
Evasion neutrophils by bloodstream bacteria
- Neutrophils respond to chemotactic stimuli: bacteria can block chemotaxis: S. aureus CHIPS, bind to C5a (complement factor with chemotactic character for neurophils): Chemotaxis Inhibiting Protein.
- Toxins attracting and killing neutrophils: S. aureus Panton-Valentine leucocidin, phenol-soluble modulins PSMs and various other toxins
- Biofilm formation: out of reach of phagocytes (also in fungi)
Blood platelets functions
- Blood clotting and immune responses
- MHC-1 and Fc receptors for IgA and IgE, activate complement
- Secreting cationic thrombocidins: platelet microbicidal proteins from alpha granules > secreted first when thrombine secreted in coagulation
Macrophages and monocytes
- Express receptors for sugar residues on surface microorganisms
- Express TLRs for lipopolysaccharides (LPS), peptidoglycan and lipoteichoic acid (LTA), flagellin
- Bind opsonizes microorganisms using Fc receptors and complement receptors CR1/3
- Produce antimicrobial proteins, ROS, NO and peroxidase
Phagocytosis evasion (8)
- Toxins inhibit chemotaxis
- Prevent attachment
- Inhibition phago-lysosome fusion
> by molecules made by bacterium - Catalase against H2O2 in S. aureus, prevent oxidative burst
- Highly resistant outer wall
- Block response to IFN gamma
> IFN gamma receptor bound, higher concentration oxidative radicals made in cell against pathogen - Block antigen presentation: no efficient T-cell activation
- Multiply in cytoplasm: use actin cytoskeleton to travel through cells and transfer to other cells: actin rocket
Complement functions
- Control inflammation
- Alternative pathway: innate
- Classical pathway: antibody-mediated: adaptive
- Bind to surface pathogen: opsonization or lysis
- Effects
> Opsonization: induce phagocytosis
> Chemotaxis: C5a
> Lysis of microorganisms - Direct killing: lysis of only gram negatives
Complement evasion strategies
- Capsule prevents complement activation
- Steric hindrance by eg LPS to prevent C3b complement receptor contact > LPS sticks out and prevents binding
- LPS directs binding of C3 and MAC away from cell membrane
- Surface molecules binding Factor H, causing degradation of C3b
Factor H original function
Sometimes C3b binds human cell > Factor H made to prevent own cell death
» mechanism used by pathogens
Antibody types
- IgG: major in human serum
- IgM: pentameric structure, early appearing
- IgA: predominant in mucosal secretions: saliva, mils, tears
- IgD/IgE: less than 1% of serum, role in immunity against worms and associated with allergic diseases
Fc region antibody
Contant region, the tail, heavy chains
Pathogens are … by immune complexes
Immobilized
> also
> pathogens opsonized for activation complement
> antibody opsonized pathogens phagocytosed through Fc receptor binding
Evasion antibodies
> Phase variation: different protein expression: antibodies are less bound
antigenic variation: point mutations
> for example 8 silent gene copies of pilE, called pilS in Nm: recombination: pillus made which cannot be bound by antibody
uptake external DNA and intracellular recombination
Decoy: capture/block antibody
Ig-proteases
Fc receptors on bacterial surface: bind antibody wrong way around and hide from immune system (Staphylococcus aureus and Streptococcus pyogenes): Protein A and Protein G
HC21: Endocarditis
Microbial infection of endocardial surfaces: heart valves
Route to endocarditis
- Bacteremia
- Fever
- Heart valve vegetations: attach to heart valves
- Valve destruction (S. aureus)
- Heart failure
- Emboli can release from the vegetation as well.
Causative microorganisms endocariditis
- Viridans streptococcus, half
- S. aureus, quarter
Mortality infective endocarditis
High, especially in eldery
Pathogenesis infective endocarditis by S. aureus
Acute and fulminant
> in 30-40% no pre-existing heart vegetation
> can also bind endothelium and make colony and toxins
> make own coagulate
Pathogenesis viridans streptococcal endocarditis
Subacute
> pre-existing heart vegetation
To survive in bloodstream, a .. is essential
Polysaccharide capsule
S. aureus endocarditis
Interaction with undamaged endothelium
1. binding
2. internalization
3. cellular damage, coagulation, infected vergatation
V. streptococcal endocarditis
Normal valves
> rheumatic fever: congenital defects
or
> Mitral valve relapse: degenerative valvular disease
Scarring
> platelets, fibrin
Non-bacterial thrombotic endocarditis
> bacteremia
Bacterial endocarditis
Viridans streptococci hiding
Within platelet-fibrin clots > shielded from phagocytes
Bacterial clusters v. streptococci
Sometimes bits release into bloodstream
> thrombus
> activate inflammation
Virulence factors viridans streptococci
- Exopolysaccharides: glucans, fructans, dectran: adherence
- MSCRAMM: microbial surface components recognizing adhesive matrix molecules
- Platelet aggregation-associated protein (PAAP) > bind platelets > matrix made > aggregation and sort of encapsidation
Virulence factors S. aureus
o Capsule, anti-phagocytic > survive in the bloodstream
o Adhesins
> Fibronectin-binding protein (FnBP)
> Clumping facro (CflA), fibrinogen binding
> Protein A and collagen adhesin, collagen binding
> Adhesins for endothelial cells
o Toxins
> Enterotoxins A- E
> Exotoxins alpha – delta
> Toxic shock syndrome toxin-1 (TSST-1)
> Leucocidin
> Epidermolytic toxins
o Exoenxymes
Incidence native valve IE (infective endocariditis) is ….
Low
> daily low level transient bacteriemia due to eating and toothbrushing
> bacteria adhering to / embedded in vegetations are shielded from phagocytes: expected to cause IE!
> but, even when at risk, not infection per se > vegetation in heart valves alredy and which brush teeth etc. > bacteria can enter blood a bit
> protective mechanism: Thrombocidins / PMP
> Adherence is not enough, initial clearance
Human platelet Thrombocidins, cationic AMPs
> Thrombin causes release of thrombocidins type 1 and 2 from platelets
Thrombin activation of platelets
Thrombocidins are derived from CXC-chemokines
> dual role in host defense
CXC-chemokines
> CXCL7: PMN attraction and activation
> CTAP-III: connective tissue activation
From the CXC-chemokines which are bactericidal, after C-terminal truncations, what can be made; What do they do
TCs: thrombocidins > sterilization of damaged tissue
When rabbits treated with TC-specific antibodies, higher IE incidence, so …
Neuralization of thrombocidin bactericidal activity increases susceptibility for experimental IE
> neutralized rabbit platelet bactericidal acitiy of sera rabbits vaccinated with human platelet sonicates
> TCs likely protect against infective endocarditis
Biomaterial implants for in situ tissue engineering of heart valves: in situ regeneration process
- Bioresorbable scaffold
- Inflammatory phase
- monocytes bind and proliferate to a tissue which comes close to final tissue
- self-assembling polymers: tissue regenerative and antimicrobial material
Infection risk of self-assembling polymers: use microbicidal 15-mer peptides
> Microbicidal 15-mer peptides derived from TC-1 primary sequence
peptides L3 and R4 in N-terminal region most potent peptides
L3-inspired optimized peptide: TC19
TC19 is a derived antimicrobial peptide
Viridans step. and S. aureus from IE patients are … to TCs
less susceptible
Viridans streptococci require …
Platelet-fibrin vegetation
S. aureus can invade epithelium and is thus … than viridans strep.
more virulent
