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Medical Microbiology > Day 6: Invasive meningicoccal disease, Vaccines for N. meningitidis and Biofilms, antimicrobials resistance > Flashcards

Day 6: Invasive meningicoccal disease, Vaccines for N. meningitidis and Biofilms, antimicrobials resistance Flashcards

HC 14, 15, 16

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1
Q

HC14: Character N. meningitidis

A
  • Gram-negative diplococcus
  • Natural habitat: human nasopharynx
  • At 5-30% it is culturable from population > not pathogenic > carriers
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2
Q

Carriage N. menigitidis is associated with age: peak at ..

A

Around 19 y/o: asymptomatic carriage

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3
Q

Peak of carriage N. meningitidis at age because

A

Behaviour, not age (19)
> crowds, kissing, bar/disco, active and passive smoking
> risk factors are strongly and independently linked to risk for meningococcal carriage
> whole relationship with age is gone when adjusted for behaviour.

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4
Q

Changes is risk factors N. meningitidis over years

A
  • Less smoking
  • Less crowding
  • Carriage decreased among teenagers
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5
Q

In 0.01% of Nm carriers: invasive pathogenesis and disease:

A

Septicemia (blood disease) and meningitis (meninges inflammation)

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6
Q

Invasion Nm

A

From nasopharyngeal cavity across epithelium to blood
> septicemia or even further to reach cerebrospinal fluid: meningitis

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7
Q

Meningococcemia

A

Meningococci in bloodstream
> sepsis
> petechial rash: round spots in skin from bleeding: cannot be pushed away: problematic stage
> Disseminated intravascular coagulation (DIC): abnormal blood clotting
» ischemic tissue damage, purpura fulmicans, too little blood to extremeties: dies off, amputations
> meningitis

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8
Q

High morbidity rate in IMD (invasive meningococcal disease), why>

A

Residual damage after cured
> limb loss
> cognitive deficits
> hearing loss
> seizure disorders

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9
Q

Is there vaccination for Nm?

A

Yes, in national program

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10
Q

Spread from adolescents peak incidence Nm to risk groups:

A

Eldery and infants

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11
Q

Effect COVID-19 on Nm incidence

A

Decreased > more distance held

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12
Q

Surveillance Nm disease in Netherlands

A
  • Mandatory notification
  • Laboratory surveillance
    > look at characteristics of disease and monitor it
    > isolates from blood or CSF (cerebrospinal fluid)
    > Antibiotics given to patients immediately
    > negative CSF culture > Molecular methods like PCR
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13
Q

Is there a link between the notifications of Meningococcal disease and laboratory data?

A

Yes, all linked and mandatory
> coverage >90%

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14
Q

Serogroups Nm

A

Based on chemical composition of polysaccharide capsule
> protects against effects immune system
> 13 serogroups
> A, B, C, X, Y and W cause >95% of IMD
> in Europe: B and C most prevalent

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15
Q

Typing methods Nm

A
  • Phenotype
    > serogroup, PorA epitope sequencing, FetA epitope sequencing
  • Genotype
  • Multi locus sequence typing using MLST
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16
Q

PorA

A

Protein in gram negatives like Neisseria meningitidis
> on outer membrane: porine A protein
» transport nutrients, transmembrane protein
> two variable loops in PorA: VR1 and VR2
» mutates constantly to hide from immune system with different epitope
» use foward and reverse primers for both VR1/2 to deteminate them
» into public database

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17
Q

FetA

A

Outer membrane protein of Nm
> one variable epitope: VR (variable region)
> beta barrel in membrane, VR loop sticks out

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18
Q

Typing of Nm isolates: annotation

A

Nm: B: P1.7,4:F5-1
> Nm: Neisseria meningitidis
> B: serogroup
> P1 (PorA) 7,4 > VR1 type 7, VR2 type 4
> F5-1 > ForA type 5-1

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19
Q

Multi Locus Sequence Typing (MLST)

A
  • Sequence seven loci
    > housekeeping genes: essential genes for viability and are present in all strains because essential
    > number assigned for each allele
    > combination of allele numbers > sequence type (ST) > a number like ST81
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20
Q

When different ST

A

When one of the housekeeping genes has a different allele

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21
Q

Single Locus Variant (SLV): example stain 2 of strain 1

A

Differs only one of the alleles from strain 1 (original)

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22
Q

Clonal complexes (CCs)

A

Any ST that matches the central genotype at 4 or more loci considered in the MLST.

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23
Q

Visualize the relatedness in MLST

A

BURST algorithm
> Circle is the CC, around the dots, the STs
> everything within the circle is from the CC

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24
Q

In the BURST pictures of MLST database, there are (within CCs) big dots with a flower like circle around it. What is it.

A

A central genotype (ST) with SLVs (single locus variants) around it.

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25
Q

Which CCs overrrepresented in IMD patients

A

CC41/44 and CC32
> specific characteristics that make them more virulent

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26
Q

CC53 and CC35 are almost never in IMD patients, why?

A

Often unencapsulated: vulnerable for immune response

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27
Q

The CC distribution among IMD patients is…

A

Dynamic, CCs disappear and appear in IMD patients
> different dominant clones
> is related to epidemiology (number of cases)

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28
Q

Are the strains of Nm identical to a certain outbreak? How to increase resolution to answer the question

A

Whole genome MLST > identify different strains
first: identify clusters or outbreaks

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29
Q

Which phenotypic and genotypic analyses are prerequisite to investigate vaccine effectiveness and coverage?

A
  • Social behaviour including coronal regulations affect meningococcal carriages and IMD incidence
  • Meningococcal surveillance: typing provides insight into epidemiology
  • Fine typing of meningococci to identify clusters or outbreaks
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30
Q

HC15: Around 2000, peak incidence in … and decrease in …

A

MenC peak
MenB started to decrease

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31
Q

First accepted Nm vaccine

A

Against MenC

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32
Q

Vaccines Nm

A

Capsular polysaccharide conjugate vaccines
> Nm cultured > CPS (capsule polysaccharide) extracted > coupled to protein carrier
- Develop immunological memory
- Class switching and affinity maturation
- High affinity IgG
- Effective in infants (not yet developed to react to antigens on sugars, so protein carrier)

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33
Q

MenC vaccination, who?

A

Infants, 14 mo/o
> and adolescents: herd protection by reducing carriage reservoir: protect infants and eldery: follow up campaign

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34
Q

Continuous caution for Nm is required: rise of IMD cases with serogroup …

A

W

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35
Q

MenW origin

A

From England
> MenW CC11 (linked to IMD) from South America to England (not big outbreak) and genetic switch to UK-2013 strains > CC11 UK2013 > spread across Europe (increased chance of carriage)

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36
Q

Meningococcal ACWY multivalent vaccine

A

CPS conjugated to protein carrier
> MenW peaks cass at infants, adolescents and eldery
> also take mortality rates into account: highest for adeolescents
> Replacement MenC for MenACWY vaccine for 14 mo/o, all 15-18 y/o called up in 2019 and 14 y/o now also in vaccination program
> decreased MenW cases after vaccination

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37
Q

Why did the MenW cases decrease in non-vaccinated groups after vaccination program?

A

Herd immunity, less carriers and transmission

38
Q

MenY and MenB cases after the ACWY vaccine

A

MenY: decrease trend
MenB: no effect

39
Q

Why is MenB unaffected by vaccinations?

A
  • Capsule polysaccharide is problematic for vaccines
  • poorly immunogenic due to mimicry (identical sialic acid in nerve tissue > no auto-immunity wanted)
  • different vaccine composition: protein vaccine antigens
40
Q

Possible solutions against MenB

A
  • Use outer membrane vesicles
  • Use other vaccines
41
Q

Outer membrane vesicle (OMV) strategy for MenB

A
  • Small vesicles of outer membrane which contain components of outer membrane on them contains bacterial components as well
    > vesicles used (OMVs), isolate and used for vaccination
    > PorA as important protective antigen (however: variable)
    » strain specific immunity
    » protection from antibodies directed against VR1/2 loops
    » include as many PorA as possible in meningococcus and isolate their OMVs
    » 3 PorA variants made and 3 strains used: NonaMen
    > 80-85% of circulating strains are covered, but vaccine not accepted
42
Q

Use other vaccines for MenB: Reverse vaccinology

A

Reverse vaccinology
> Use genome meningococcus
> Genomic-based approach to vaccine development
> Test for antibody response in mice
> Test if they are on surface of meningococcus bacterium
> check if antibodies kill the bacterium
> 3 antigens selected: fHbp, NadA, NHBA

43
Q

Registered MenB vaccines

A
  • Baxsero
    > three components and OMVs
  • trumenba
    > One component, but important variant
44
Q

Baxsero and antigenic components

A

4 antigenic components
> fHbp: factor H binding protein: for bacterial survival
> NadA: adhesin, promotes adherence to and invasion of human epithelial cells
> NHBA: heparin-binding: binds heparin, which promotes bacterial survival in blood
> OMV with one variant of PorA in it
» decrease pathogenesis on different steps to help optimize MenB vaccine effectiveness

45
Q

Trumenba

A

Single antigenic component but 2 subfamilies
> Subfamily A: 30%
> Subfamily B: 70%
> all meningococcus B targeted: 1 variant of subfamilies A and B
> only fHbp targeted

46
Q

Is there herd immunity with MenB vaccines?

A

No, there is no protection for non-vaccinated people as the carriage or transmission is not decreased, just the pathogenesis.

47
Q

HC16: Which organ is the first barrier for bacteria and fungi

A

The skin

48
Q

Which components of the skin are susceptible for infection

A
  • Sweat glands
  • Sebaceous glands near hair follicles
  • Hair follicles
    > can cause infection with penetrance
49
Q

The composition of microbiota differs per …. of the skin

A

Location

50
Q

Human antimicrobial peptides : where and how

A

In the cells > epithelium, endothelium, leukocytes, platelets
> rapid: storage and secretion, also for intracellular killing when phagocytosis

51
Q

Human Antimicrobial Peptides are inducible. Transcription after:

A
  • Tissue damage
  • Inflammation
  • Bacterial products (TLR mediated)
    » thus: physiologically very first line of defense
52
Q

Skin Human Antimicrobial peptides at:

A
  • Sweat glads
  • Epidermis
  • Sebocytes
  • Mast cells
53
Q

Antimicrobial peptides work … and protective enzymes at the skin barrier work …

A

Directly ; indirectly

54
Q

Not all bacteria are reached by disinfectants, what can happen when skin damage

A

Bacteria release and cause problems > for example under the hair when pulled out

55
Q

Skin infections in who

A

Immunocompromised patients

56
Q

Local skin infections sources

A

Surgical wound, infuse, oedema, eczema

57
Q

Systemic skin infection inducing factors

A

Diabetes, Prednison (immune suppression), leukopenia (low white blood cells)

58
Q

Impetigo

A

Krentenbaard
> skin surface infection by S. aureus or Streptococcus pyogenes (Group A streptococcus, GAS) or mixed

59
Q

Folliculitis

A
  • Infection of hair follicle
  • Infection by staphylococcus aureus
60
Q

Furuncle

A

Acute necrotic form of folliculitis (S. aureus)

61
Q

Erysipelas (belroos, wondroos)

A
  • Deeper in skin than Furuncle
  • Close to deeper tissues
  • Lymphatics can be infected as well
  • Mostly legs, sometimes arms and face
  • Via skin defect, GAS: streptococcus pyogenes
  • eldery, diabetes, edema
  • hard to get rid of.
62
Q

Cellulitis

A

Infection into dermis and subcutaneous fat
> via skin defect
> S. aureus, GAS

63
Q

Necrotising fasciitis and myositis

A

Flesh eating bacteria, into deeper layers

64
Q

Type 1 Necrotising fasciitis and myositis

A

From inside out
> post-surgery
> necrosis from fasci (bindweefsel) towards the skin
> initially no skin signs
> often GAS
> also mixed infection aerobe and anaerobe with GAS

65
Q

Type 2 Necrotosing fasciitis and myositis

A

Outside in: from skin (cellulitis) to fascii
> mono-infection GAS
> patient severely ill
> extremely painful
> surgery and antibiotics
> 1/3 die

66
Q

Important skin pathogens

A

Staphylococcus aureus
Group A streptococcus like Streptococcus pyogenes

67
Q

Major component S. aureus cell wall

A

Protein A
> prevents opsonation from occuring
> bind Fc tails of antibodies
> bind antibodies upside down and prevent recognition by immune cells

68
Q

S. aureus extotoxins

A
  • Exfoliatin cause scalded skin syndrome (SSSS)
  • Panton Valentine attracts and destroys leukocytes
  • TSST-1 Toxic Shock Syndrome
69
Q

S. aureus toxins

A

TSST-1, enterotoxins, alpha hemolysin and others

70
Q

S. aureus exoenzymes

A

In order to enter and penetrate
> Hyaluronidase destroys tissues
> Hemolysins destroy red blood cells and release iron
> Coagulase clot formation: form shell of platelets around bacterium to hide from immune cells
> Staphylokinase: dissolves clots when inside their shell to release and propagate pathogen

71
Q

Invasins of S. aureus

A

Coagulase, staphylokinase

72
Q

Adhesins

A

To attach to host proteins

73
Q

Inhibition phagocytosis by S. aureus

A
  • Protein A
  • Capsular polysaccharide
  • Clumping factor A (coagulase)
74
Q

GAS like Streptococcus pyogenes

A
  • Gram positive cocci in chains
  • In throat, infection which can propagate to blood
  • SPE A, B and C exotoxins cause the redness of people with this infection
  • High fever
  • Has M-protein: protein which sticks out against phagocytic cells
75
Q

Invasins and adhesins of GAS/ S. pyogenes

A

Invasins:
- Streptolysins; lyse cells
- Streptokinases and protease break structures around bacterium down
- Flesh eating bacteria have proteases which break down entire tissue
Adhesins
> adhere epithelium: Lipoteichoic acid (LTA)

76
Q

Sources examples Biomaterial-associated infection (BAI)

A
  • Hip prosthesis
  • Central venous catheter
  • CSF shunt
  • Heart valve
  • Breast implant
77
Q

Some biomaterials have higher chances of infection, why?

A

Connection between the outside and the inside
> like catheters
> need to be switched regularly

78
Q

Problem removing infected biomaterial

A

they may grow with the adjacent bone which needs to be removed as well

79
Q

BAI mostly by…

A

Often harmless skin bacteria becoming opportunistic like Staphylococcus epidermis

80
Q

There is a … load of S. aureus needed to cause infection when wound with sutures (hechtingen) than without them

A

Lower

81
Q

Elements of pathogenesis of BAI
1. Site of application of biomaterials
> name sites of applications

A
  • External: no surgical wound, no port d’entrée
    > urinary catheters
    > Endotracheal tubes
    > No penetrance of epithelium
  • Transcutaneous: surgical wound AND port d’entrée
    > Intravenous catheters, shunts
    > CAPD catheters
    > external fixation devices
    > like the pins for complicated fractures
  • Implanted: surgical wound, no port d’entrée
    > prosthetic joints like hips and knees
    > prosthetic heat valves or pieces
    > Pacemakers
    > Hydrocephalus shunts
    > Brought in, but then closed
82
Q

Transcutaneous device: intravascular catheter

A
  • Insertion site wound: port d’entrée for skin bacteria
    > possible extraluminal infection: from skin
    > possible hub contamination: intraluminal: inside catheter
    > possible hematogenous infection
    > possible contiguous infection from deeper tissues to biomaterial
83
Q

External device: urinary catheter

A
  • mostly infections on skin nearby
  • Natural defense: flushing with urine, but water flow is now removed
84
Q

Implanted device: total hip

A
  • Skin bacteria introduced during surgery
  • Hematogenous infecion possible: bacteria find the prosthetic
  • implantation site wound, no port d’entrée (nothing is brought in)
85
Q

Elements involved in pathogenesis of BAI
2 Biomaterial characteristics

A
  • Texture, surface, hydrophobicity, and charge determinants
    > adhesion host proteins and blood platelets
    > adherence of microorganisms, directly or to host proteins and blood platelets on the biomaterial.
    > biocompatibility: nature of foreign body response
86
Q

Elements of pathogenesis of BAI
3 Bacterial virulence factors

A

Adherence by specific adhesins of bacterium
- Biofilm initiated by quorum sensing
- production slime, polysaccaride intercellular adhesin PIA, enzymes from ica operon

87
Q

Biofilm formation by quorum sensing

A

Gene expression regulated by population density via paracrine signals
> quorum sensing molecule produced: encapsidation
> extracellular matrix made

88
Q

icaABCD operon

A

Intracellular adhesin operon
> insertion sequence transposon (IS256) can jump irregularly in a locus in ica cluster
> mutation to not produce the extracellular material
> from biofilm to no biofilm

89
Q

Elements of pathogenesis of BAI
4 Host factors predisposing for infection

A
  • Reduced neutrophil phagocytic and respiratory burst activity
    > due to presence foreign body (prosthetic): frustated phagocytosis
    > due to bacterial components such as Staphylococcus epidermidis extracellular polysaccharide slime
    » combined influence of bacteria and biomaterial reduce defense
90
Q

Elements of Pathogenesis of BAI

A
  1. Site of application of biomaterials
    2 Biomaterial characteristics
    3 Bacterial virulence factors
    4 Host factors predisposing for infection

Medical Microbiology (11 decks)

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