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Medical Microbiology > Day 8: Sepsis, bloodstream infections, infective endocarditis and innate defence > Flashcards

Day 8: Sepsis, bloodstream infections, infective endocarditis and innate defence Flashcards

HC 20, 21

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1
Q

In sepsis, the immune system is..

A

Strongly deranged

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2
Q

Levels of severity in bloodstream infection

A
  • 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
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3
Q

Mortality MOF

A

Around 20% but dependent of level of organ failure

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4
Q

Most frequent causes bloodstream infections

A
  • Airways
  • Abdomen
  • Urinary tract
  • Skin or soft tissues
  • Central venous catheters
  • Deep infections such as endocarditis/meningitis
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5
Q

A lot of bacteria in the blood and immune system

A

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

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6
Q

Neuro-endocrine regulation of immune repression when bloodstream infection

A

Immunosuppression
> acetylcholine through nervus vagus > inhibition pro-inflammatory cytokine production (transcription)

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7
Q

Immune suppression when bacteremia

A

Less functioning immune cells
Neuro-endocrine regulation
Inhibition of pro-inflammatory transcription

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8
Q

Bloodstream infective bacteria”: common names

A

52% grampositive
> Staphylococcus aureus
> Streptococcus pneumoniae
38% gramnegative
> Escherichia coli
> Klebsiella
> Pseudomonas aeruginosa

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9
Q

How do Human Antimicrobial peptides in blood (AMPs) (from endothelial cells, leukocytes and platelets) selectively interact with microbial cell membranes

A

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

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10
Q

Resistance AMPs by Salmonella

A

Inducible aminoarabinose addition to LPS > repulsion of cationic AMP

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11
Q

AMP resistance in Proteus

A

Proteus can swim very well: urinary infections
> Constitutive aminoarabinose on LPS: repulsion cationic AMP

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12
Q

AMP resistance of S. aureus

A

expression dlt operon
> D-alanine (cationic) decorates the lipoteichoic acid (LTA) > repulsion cationic AMP
- Also, ATP dependent exporters

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13
Q

Evasion neutrophils by bloodstream bacteria

A
  • 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)
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14
Q

Blood platelets functions

A
  • 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
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15
Q

Macrophages and monocytes

A
  • 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
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16
Q

Phagocytosis evasion (8)

A
  • 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
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17
Q

Complement functions

A
  • 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
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18
Q

Complement evasion strategies

A
  • 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
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19
Q

Factor H original function

A

Sometimes C3b binds human cell > Factor H made to prevent own cell death
» mechanism used by pathogens

20
Q

Antibody types

A
  • 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
21
Q

Fc region antibody

A

Contant region, the tail, heavy chains

22
Q

Pathogens are … by immune complexes

A

Immobilized
> also
> pathogens opsonized for activation complement
> antibody opsonized pathogens phagocytosed through Fc receptor binding

23
Q

Evasion antibodies

A

> 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

24
Q

HC21: Endocarditis

A

Microbial infection of endocardial surfaces: heart valves

25
Q

Route to endocarditis

A
  • Bacteremia
  • Fever
  • Heart valve vegetations: attach to heart valves
  • Valve destruction (S. aureus)
  • Heart failure
  • Emboli can release from the vegetation as well.
26
Q

Causative microorganisms endocariditis

A
  • Viridans streptococcus, half
  • S. aureus, quarter
27
Q

Mortality infective endocarditis

A

High, especially in eldery

28
Q

Pathogenesis infective endocarditis by S. aureus

A

Acute and fulminant
> in 30-40% no pre-existing heart vegetation
> can also bind endothelium and make colony and toxins
> make own coagulate

29
Q

Pathogenesis viridans streptococcal endocarditis

A

Subacute
> pre-existing heart vegetation

30
Q

To survive in bloodstream, a .. is essential

A

Polysaccharide capsule

31
Q

S. aureus endocarditis

A

Interaction with undamaged endothelium
1. binding
2. internalization
3. cellular damage, coagulation, infected vergatation

32
Q

V. streptococcal endocarditis

A

Normal valves
> rheumatic fever: congenital defects
or
> Mitral valve relapse: degenerative valvular disease
Scarring
> platelets, fibrin
Non-bacterial thrombotic endocarditis
> bacteremia
Bacterial endocarditis

33
Q

Viridans streptococci hiding

A

Within platelet-fibrin clots > shielded from phagocytes

34
Q

Bacterial clusters v. streptococci

A

Sometimes bits release into bloodstream
> thrombus
> activate inflammation

35
Q

Virulence factors viridans streptococci

A
  • 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
36
Q

Virulence factors S. aureus

A

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

37
Q

Incidence native valve IE (infective endocariditis) is ….

A

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

38
Q

Human platelet Thrombocidins, cationic AMPs

A

> Thrombin causes release of thrombocidins type 1 and 2 from platelets
Thrombin activation of platelets

39
Q

Thrombocidins are derived from CXC-chemokines
> dual role in host defense

A

CXC-chemokines
> CXCL7: PMN attraction and activation
> CTAP-III: connective tissue activation

40
Q

From the CXC-chemokines which are bactericidal, after C-terminal truncations, what can be made; What do they do

A

TCs: thrombocidins > sterilization of damaged tissue

41
Q

When rabbits treated with TC-specific antibodies, higher IE incidence, so …

A

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

42
Q

Biomaterial implants for in situ tissue engineering of heart valves: in situ regeneration process

A
  • 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
43
Q

Infection risk of self-assembling polymers: use microbicidal 15-mer peptides

A

> 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

44
Q

Viridans step. and S. aureus from IE patients are … to TCs

A

less susceptible

45
Q

Viridans streptococci require …

A

Platelet-fibrin vegetation

46
Q

S. aureus can invade epithelium and is thus … than viridans strep.

A

more virulent

Medical Microbiology (11 decks)

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