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Microbiota On Mucosal > L8/9- Salmonella > Flashcards

L8/9- Salmonella Flashcards

1
Q

What type of bacteria are they

A

Gram -ve dacultative intracellular (don’t need to be)

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2
Q

What 2 types are there

A

Salmonella enterica serovar typhimurium or typhi

Typhi causes typhoid fever and can go systemic and lethal

Tm causes salmonellosis and is local

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3
Q

How have some adapted to not be killed in acidic stomach

A

Acid shock proteins activating at sensitive ph

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4
Q

What are pathogenicity islands and spi1/2

A

Gene clusters needed for virulent factors
T3ss1 is for invasion inside affecting family of rho gptases
2 is for survival inside a scv

Both have needle complex, basal body and translocon

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5
Q

By systemic, where can typhi disseminate

A

Spleen,ln,liver,gall bladder

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6
Q

Why are m cells preferred route of salmonella

A

No mucus
Plus it can be take n up by mac or dc where it can migrate to mln and escape out to disseminate

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7
Q

What else can sample lumen and take them up

A

Crocs epi dc

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8
Q

What in mucus helps regulate inflammation

A

Trefoil peptides

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9
Q

Which types of phagocytes cna carry salmonella to the circulation for dissemination

A

Cd18+
Can use this indep of its t3ss

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10
Q

What happens when they eventually want to get released from macrophages

A

Cause inflammation eg via Il1b release from mac

Then either get killed ef by neutrophils or enter epi cells absolaterally

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11
Q

Which protein family regulates tight junctions because they have effect on the cytoskeleton

A

Rho gtpases

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12
Q

Disrupting their function would cause what

A

Change in junction organisation and cell membrane actin to promote entry

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13
Q

What are gaps

A

Gtp activating proteins

Hydrolyse gtp inactivating the gtpases

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14
Q

Give 3 members of the family and what they do

A

Rho - formation of focal adhesions (ecm to actin) and stress fibres

Rac- forming extrusions/lamellipodia from plasma membrane

Cdc42- forming finger extrusions (filopodia)

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15
Q

What do the extrusions from rac and cdc42 need

A

Actin polymerisation

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16
Q

What effects can tm have that doesn’t affect these rhos for their entry (by their effectors)

A

Down reg of zo-1 and dephos of occludins

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17
Q

What are the effector proteins which induce the ruffling of the membrane/ structural changes

A

Sipa,sipc, sopb, sope, sope2

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18
Q

What does sopb do

A

It’s a phosphatase needed for macropinosome formation

It indirectly stimulates cdc42 activity allowing extensions filopodia of membranes needed for macropinosome/pinocytosis

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19
Q

What do sope and e2 do

A

Act as gef activating rac1 and cdc42 to induce cutokskeletal extrusions for bac uptake

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20
Q

What do sipa and c do

A

Bind with actin and cause bundling to help with macropinocytosis

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21
Q

Which protein is recruited by cdc42 and rac1 for actin polymerisation for extrusions

A

Actin related protein arp 2/3

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22
Q

What late acting effector proteins (released after entry) help reverse cytoskeetal arrangements

A

Spt P

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23
Q

What does late acting avra do

A

Stabilise tj again
and inhibits inflammation response quickly by ikb blocking degradation

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24
Q

Which spi2 protein blocks mhc2 presentation on dc

A

SteD

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25
Q

How do scv acquire nutrients when inside cell

A

SifA induces tubules which provide nutrients to them

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26
Q

Which immune receptors key in early stages of salmonella and how do they induce proinflam cytokines

A

Prr
Myd88
Activate mapk signalling pathway and activate ap1 nkfb tf

Proinflam cytokines exp like Il1b,23,18,tnf,12,ifny

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27
Q

How can stm also induce compelsmtn

A

C3 recognises o-antigen on its lps

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28
Q

Which tlr shown v important in esrly process to stop invasion of mln

A

Flagellin tlr5

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29
Q

What does tlr1/2 recognise

A

Curli ligand in the ecm of salmonella biofilms

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30
Q

What does lps bind to on cell surface

A

Lps binding protein which then interacts with
Cd14 gpi anchored which interacts with tlr4

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31
Q

What do nod1 and nod2 also recognise if intracellular

A

Dap acid (nod1)

Muramyl dipeptide (nod2)

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32
Q

How do they activate nkfb also

A

Through rip2 adapter protein

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33
Q

When we’re nod 1/2 crucial for in mice salmonella

A

Crucial in infection when salmonella expressed their spi2 t3ss - ie intracellular

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34
Q

Which t3ss1 proteins can be delivered and activate nlrc4 receptor

A

Prgj from needle complex
And flagellin can be injected

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35
Q

What does this do

A

Associate with caspase1 and asc protein and allows cleavage Il1b and il18 to active forms by caspases 1

= drives neutrophil response and il18 drives ifny = mac activation

= inflammation

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36
Q

Which bacteriophage derived effector protein can some strains have that can activate caspase 1 by unknown mechanism

A

Sope

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37
Q

Which chemoattractant from salmonella induced macrophages causes basolateral influx of neutrophils from circulation

A

Il8

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38
Q

What does hepoxilin hxa3 do instead

A

Allows migration to the apical/lumen of neutrophils through tj

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39
Q

Which effector causes production of hxa3

A

It is an arachidonic metabolite

SipA induced lipid signal cascade , activation of pkc, and release of arachidonic acid from plasma membrane

Converted into hxa3 by 12 lipooxygenase

40
Q

Why would sipA induce it’s own inflammation against salmonella

A

Thrives in it

41
Q

How can neutrophils bind basolateral through rolling and adhesion

A

Their B2 integrins

42
Q

What is the hypothesis of watery diarrhoea

A

Spi1 effector induced inflammation and rapid neutrophil influx (via sipA) causes impaired barrier and leakage of extra vascular fluid

Also neutrophils migration can lead to Cl sexretion by epi cells which causes influx of water for osmolarity

43
Q

What is extrusion

A

Cell mechanism to signal they are dying and other cells induce actomyosin ring releasing dying cell into the lumen

44
Q

Why is this bad

A

Can cause salmonella escape to lumen, and either infect other cells or exit host in transmission cycle

45
Q

Which amp forms nano nets around salmonella and stops adhesion instead of killing them

A

Hd6

46
Q

Which illness is there a deficit of this

A

Ibd crohns

47
Q

Activation of caspases can cause what type of killing of macrophages (inducing the release of more inflammation or killed by neutrophils)

A

Pyroptosis

48
Q

Which chemokines produced in the nkfb activation pathways eg nod or tlr cause neutrophil recruitment

A

Il23 inducing th17 inducing il17= chemokine
Il1b
TNFa

49
Q

Which 2 induce ifny macrophage activation pathway

A

Il12 and 18

50
Q

What from th17 by il23 from nkfb can cause release of amps and lipocallin2

A

Il22

51
Q

What pathogenicity island important for effector blocks lysosomal trafficking when salmonella inside

A

SpiC

52
Q

How do typhi cause gallstones

A

Associated with biofilm formation

53
Q

Other than general gut barrier. Give 2 chemicals form Microbiota needed for colonisation resistance

A

Bacteriocins - gram-ve rna,dna and protein disruption

Indole - works with scfa to downregulated spi1 gene cluster exp

54
Q

What other things physically stop colonisation

A

Carbon source limitation
Iron limitation eg via nissle 1917 (largest siderophore acquisition)
Adhesion competition
and physical adhesion since there’s around 10^11 in colon

55
Q

Which genes found in salmonella crucial for early colonisation in mice- through mice studies with 500 mutants and screened which ones did not survive after mutants made

A

Chemotaxis, lps genes,
niFe-hydrogenase subunit genes hybA and hybF
FrdA fumarate reductases complex encoding

56
Q

Why would niFe dehydrogenase be needed for early colonisation to overcome cr

A

Allows to use dihydrogen released from Microbiota femenrtariln as an alternative electron source in anaerobic conditions = promotes growth

57
Q

Is this only relevant before inflammation induced fitness

A

Yes! Early colonisation before inflammatory help

58
Q

What is the evidence for inflammation being the fitness advantage using spi1/2 mutants

A

Mutants in spi1/2 who cannot induce inflammation themselves werent able to outcompete / grow Microbiota in a dss-colitis mouse model

Less than 1% of colonisers if mutant

90 fold increase in colonisation when compared with wt salmonella

59
Q

What from fermentation by Microbiota can be converted to tetrathionate and give the steps

A

H2s

Converted to thiosulfate by colonic epi cells bc it is toxic

This can react with the migrated chemotaxtic neutrophils via hxa3 ros they release

Causes oxidation of thiosulfate into tetrathionate

60
Q

Why does tetrathionate matter in our competition

A

Used as an alternate electron acceptor in anaerobic conditions , allowing them to grow on poor carbon sources

Tetrathionate more efficient for energy than normal fermentation is = our growth

61
Q

How does il22 from inflammation also cause outcompetition

A

Induces release of amp lipocallin2 which will block iron acquisition of commensals like ecoli but salmonella is immune because they have a modified siderophore (salmochellin)

62
Q

How is host nitrate produced by inflammation

A

Effectors recognised like sopE (nlrp3) can induce release of proinflam ifny (from il18 by caspases) = induces production of NO by inos

Also induced dual oxidase 2 activity forming hydrogen peroxide (ros)

Ros will react with NO to form peroxynitrite which isomerises to nitrate

63
Q

Why is this important

A

Can be also used as alternative electron acceptor (same as tetrathionate but nitrate is higher in hierarchy as has more redox potential) = more energy generated

64
Q

Why are the aea important

A

Because they are not used by obligate commensals anaerobes

65
Q

Give a potent poir carbon source only respired during production of alternative resp electron acceptors

A

Ethanolamine part of lipid membrane shed during epi cell turnover

66
Q

What enhances salmonella fitness through chemotaxis

A

Flagella motility

67
Q

How does this work

A

Sense ligands inducing methylation of a receptor
in inflamed gut like sense new nitrate or tetrathionate and undergo growth blooms through chemotaxis movement by flagella

68
Q

Which proteins were crucial in this process when tested mutants in them on mice and nutrient agar plates

A

Methyl accepting chemotaxis proteins (mcp proteins)
Eg tsr and aer

Mutants had reduced fitness survival and lack of swarming to nitrate/tt

69
Q

How is it suggested HGT can occur during inflammation/Microbiota dysbiosis between commensal enterobacteraciae and pathogenic strains eg ones that are antibiotic resistant or stx

A

Because they are facultative anaerobes meaning they can use nitrate for respiration and out grow in inflammation (seen in conditions like Ibd)

There is therefore more chance they come into close contact with virulent strains

70
Q

Give some modes of hgt with close contact

A

Conjugation (exchange plasmids)
Transformation (uptake of naked dna)

71
Q

Which other fermentation product can be used as an alternative carbon source in both aerobic and anaerobic s.tm respiration

A

1,2 propanediol

72
Q

Fermentation of what produces this

A

Rhamnose or fucose

73
Q

What gene cluster do they have for degradation of 1,2 propanediol

A

PduA-X

74
Q

Which aea during inflammation allowed to use this as carbon source under anaerobic conditions

A

Tetrathionate

75
Q

Which enzyme mutation involved in aerobic respiration alongside mutation in moa (for synthesis of molybdopterin required for enzymes which allow use of tt/nitrate as electron acceptors) proved that it is a combo of aerobic and anaerobic respiration salmonella uses for 1,2 propanediol use

A

Cytochrome bd oxidase II

76
Q

Why did they find Microbiota needed to be present to generate this for growth advantage

A

Loss in gf mice showed no advantage

B fragilis and theta did though generate it

77
Q

Explain how epithelial oxidation through antibiotic treatment occurs

A

Reduced clostridia butyrate production and therefore reduced b-oxidation and need to use glycosylis releasing oxygen

78
Q

How can this provide environment where salmonella grows rapidly just after antibiotic treatment

A

Have bd cytochrome oxidase II for the use of oxygen as a final electron acceptor (the most efficient way)

79
Q

After 4/5 days of antibiotics clostridia became present again but salmonella still grew , how? Also what 2 enzymes required for the most efficient transmission/shedding

A

T3ss induced inflammation was used instead to drive further dysbiosis where eventually butyrate will fall again (depletion of clostridia) - shown via mutants of spi
and grow on both nitrate and bd oxidase II electron acceptors

Nr and cytochrome bd oxidase were required for best transmission (shown through mutants)

80
Q

What we’re conclusions of this mice model experiment using mutants

A

Early antibiotic treatment = need oxygenation/low butyrate

Later = need inflammation, dysbiosis and can use both nitrate and bd oxidase for efficient transmission/shedding

81
Q

What was found to bloom in dysbiosis of colitis induced mice (3rd experiment example)

A

Enterobacteraciae / ecoli

82
Q

Why is this

A

Formate is found enriched in dysbiotic and inflamed gut

Can use formate oxidation as a growth fitness advantage

83
Q

Where does formate come from which isn’t present in the gf mice model of dss

A

Microbiota fermentation eg by b theta

84
Q

METAGENOMICS ANALYSIS EXAMPLE- Which 2 enzymes were necessary (upreg in inflamed gut) for the dysbiotic microbiome in dss-mice (majorly ecoli) to use formate to grow (formate oxidation) and why

A

formate dehydrogenase - allows coupling of electron acceptors (oxygen in this inflammatory environment) to the electron donor(formate)

and cytochrome bd oxidase for aerobic resp

85
Q

What was found the electron acceptor in formate oxidation

A

Oxygen as aerobic resp was found necessary (cytochrome bd oxidase needed)

(Inflammation is an oxidative state)

86
Q

What marker of inflammation (produced from nos reaction with ros) was shown to induce formate dehydrogenase so that ecoli can use formate as an electron donor in inflamed gut

A

Nitrate

87
Q

What does the spi-7 capsule vi on s typhi prevent

A

Complement fixation

88
Q

At which point according to colitis mouse models with s.tm ko of nod1/2 show it’s importance in dampening the survival of s.tm in cells

A

When they are expressing spi-2 effectors forming the scv

89
Q

Which d-alanine importer is important for salmonella survival against neutrophil D amino acid oxidase (DAO) which kills it via oxidative damage

A

DalS

90
Q

Which ecoli strain been proven probiotic for salmonella infections eg via siderophore and Curli ligand

A

Nissle 1917

91
Q

Which bacterial species important for toxin delivery to kill salmonella via t6ss

A

Bacteroides

92
Q

What is the evidence from 2 mouse studies that Microbiota are important for cr and reduced inflammation

A

Study 1-
Low shedder mice were treated with antibiotics and converged to super shedders showing increased colonisation/invasion and increased shedding of salmonella

Study 2-
Antibiotic treatment induced worse salmonella colonisation and inflammation. Even after 3 weeks from the antibiotic treatment this still was the case showing the long lasting effect a dysbiosis can have

93
Q

When spi1/2 mutants we’re introduced into il10- mice models of colitis what happened

A

We’re able to outcompete Microbiota again and overcome cr

Shows inflammation required

94
Q

What is ttrSR

A

Gene cluster of tetrathionate sensor and response regulator encoded by salmonella and some ecoli strains which permit use of tetrathionate as an aea via ttrBCA

95
Q

What is the ttr BCA cluster for

A

Encode tetrathionate reductase

Microbiota On Mucosal (22 decks)

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