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Biology of Salmonella
Dr Sophie Helaine
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Human diseases
Typhoid (S. entericaTyphi and S. Paratyphi):17 million casesand 600,000 deaths/yr - increasing multiple drug resistance recurrence infection
on-typhoidal (e!g S. entericaTyphimurium)" 1!# $illioncases and # million deaths/yr (ma%or pro$lem in su$-&arahan'frica)
Salmonellapathogenesis
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SalmonellaTyphi andhuman typhoid
Typhoid prevalence, 2006
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Transmission (faecal-oral)
SalmonellaTyphi andhuman typhoid
Chronic carrier stateTyphoid Mary
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S.Typhi S.Typhimurium
h (10 days)
T0
1* days
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Human diseases
Typhoid (S. entericaTyphi and S. Paratyphi):17 million cases
and 600,000 deaths/yr - increasing multiple drug resistance recurrence infection
on-typhoidal (e!g S. entericaTyphimurium)" 1!# $illioncases and # million deaths/yr (ma%or pro$lem in su$-&arahan
'frica)
Salmonellapathogenesis
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S.Typhimurium in+asion of cells
olonisation of Peyer.s
Patches, mesenteric lymphnodes
atal $acteraemiantracellular replication in spleen and li+e
macrophages (up to 10 $acterial cells/org
implies 2#0 rounds of cell di+ision)
Murine model of Typhoidfever
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3stimates suggest appro4! of S.Typhimuriumgenome
5uired for +irulenceS.Typhimurium has 600 s 82 appro4! +irulence gen
ppro4! genes identi9ed to dateost are present on Pathogenicity slands/islets (2 60)
:ut, $iochemical and physiological functions of manyemain un;no
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!i"erent virulence genes act atdi"erent stages of S. Typhimurium
virulencestage of environmental response virulenceinfection stimulus genes
stomach low pH acid tolerance fur, atr
small osmotic stress motilityintestine anaerobiosis adhesion flg, lpf and pef
epithelium anaerobiosis invasion many (e.g.inv/spa)penetration cell contact
blood- complement serum resistance rfb, rfc, rckstream antimicrobial peptide resistance sap, htr
peptides
macrophage low pH, low Mg comple! many(pag, "#$-%, spv)
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Salmonella-containing vacuoles in spleen cells
Salmonellaan intracellularpathogen
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isteriahigella
SalmonellaMycobacteria
Coxiella
Salmonellaan intracellularpathogen
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#ntracellular replication in macrophages($6 h)
%ild-type
Dhar and McKinney, Current Opinion in Microbiology 2007
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pDiGi
pDiGc
Helaine et al, PNAS 200
Measuring replication y &luorescence!ilution
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Helaine et al, PNAS 200
!one"#arro$ deri%ed#acrophage&
' h
Non"replicating bacteria ( )0 *
Measuring replication y &luorescence!ilution
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Many bacterial species form persisters - highly tolerant to antibiotics
Persistent bacterial infections pose significant public-health problems
Typhoid fever in humans - 1! of treated patients suffer a relapse
" ma#or brea$through %as the discovery that E. coli in vitro persisters are non-
replicating bacterial cells &Balaban et al' Science ())*+
'acterial persisters
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Per&i&ter& are tran&iently tolerant to A! treat#ent
+nteraction $ith ho&t M=, e%en tran&ient, enhance& the or#ation oper&i&ter cell& o Salmonella to- dierent cla&&e& o A!
Survival of Salmonella to AB treatment
Salmonellapersisters induced y contact%ith host M
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. *
2 *
Antibiotic tolerant bacteria / non"ly&ed by epo&ure to beta"lacta#
Ho&t induced per&i&ter& are non"replicatingbacteria
total intracellular
population
)
()
*)
,)
)
1))
!
ofMa.
1))
1)1
1)(
1)/
1)*
0P
total intracellular
population
intracellular
persisters
)
()
*)
,)
)
1))
!
ofMa.
1))
1)1
1)(
1)/
1)*
0P
luorescence
Host induced Salmonellapersisters arenon-replicating
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21 hin #acrophage&
ceotai#e 200 g3#4
arabino&e
gfp dsRed
+P56"inducible arabino&e"inducible
Proportion o the non"replicatingbacteria re&u#e gro$th
1))
1)1
1)(
1)/
1)*
31-H
1)
)
1)1
1)(
1)/
1)*
13(-H
8e&pon&i%e non"replicating bacteriaater 21 h in #acrophage&
0P
Ds2ed
1))
1)1
1)(
1)/
1)*
31-H
1)
)
1)1
1)(
1)/
1)*
13(-
H
8egro$ing non"replicating bacteriaater 21 h in #acrophage&
Ds2ed
0P
responding
regro%ing
on-replicating acteria*egro%th
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21 hin #acrophage&
ceotai#e 200 g3#4
arabino&e
Non replicating bacteria9 re&er%oir or relap&e o inection
1))
1)1
1)(
1)/
1)*
1))
1)1
1)(
1)/
1)*
1))
1)1
1)(
1)/
1)*
1))
1)1
1)(
1)/
1)*
Ds2ed
8e&pon&i%e per&i&ter& a,ter 21 h in +:Nacti%ated C)7 #acrophage&
8e&pon&i%e and regro$ing per&i&ter& inC)7 #acrophage&
Ds2ed
0P 0P
on-replicating acteria*egro%th
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Bacterial actors 4 Host signals 4
Heterogeneity of intracellular population
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Human diseases
Typhoid (S. entericaTyphi and S. Paratyphi):17 million cases
and 600,000 deaths/yr - increasing multiple drug resistance recurrence infection
on-typhoidal (e!g S. entericaTyphimurium)" 1!# $illioncases and # million deaths/yr (ma%or pro$lem in su$-&arahan
'frica)
Salmonellapathogenesis
Salmonella an intracellular
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+#-$mediates in+asion of host cells
andintestinal secretory and in?ammatoryresponses
+#-2is re5uired for $acterial replicationand immune modulation
Salmonellaan intracellularpathogenT%o T++
Salmonella an intracellular
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Adhesion Invasion SCV formation SCV maturation Replication
SP5-1 T/SS SP5-( T/SS
6.tracellular 5ntracellular
Salmonellaan intracellularpathogenT%o T++
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e@ectors induce actin polymerisation,
mem$rane ruAing and $acterial internalisation
Salmonellainvasion of epithelialcells occurs
via the +#-$ type ### secretion
system
3@ector
Salmonella an intracellular
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Adhesion Invasion SCV formation SCV maturation Replication
SP5-1 T/SS SP5-( T/SS
6.tracellular 5ntracellular
Salmonellaan intracellularpathogenT%o T++
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effectors &Sif"' Sse7' Sse0' etc+
translocon pore &Sse8' SseD+
translocon &SseB+
vacuolar membrane
bacterial outermembrane
bacterial innermembrane
Ssa9
Ssa8
secreton needle
Ssa7
H:
H:
H:
H:
H: H:
H:
SsaM
Spi8
Ssa3
cidic pH triggerssecretion
ssaVmutantis null for+#-2 function
+#-2 Type ###
cretion system
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#ntracellular replication defect of a +#-2null mutant in macrophages ($6 h)
%ild-type +#-2 mutant
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."ectors of the +#-2 T++
rom igueira and Holden' Microbiology' ()1(
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."ectors of the +#-2 T++
rom igueira and Holden' Microbiology' ()1(
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."ectors of the +#-2 T++
:igueira et al, #anu&cript in preparation
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Human diseases
Typhoid (S. entericaTyphi and S. Paratyphi):17 million casesand 600,000 deaths/yr - increasing multiple drug resistance recurrence infection
on-typhoidal (e!g S. entericaTyphimurium)" 1!# $illioncases and # million deaths/yr (ma%or pro$lem in su$-&arahan'frica)
Salmonellapathogenesis
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yphoidal Salmonella in H#/-infected frican
T& (S.Typhimurium and 3nteritidis)"
Predominantly cause self-limiting gastroenteritis:BTma%or cause of in+asi+e disease in 'frica, young
children and CD-infected adults
on speci9c fe+er (E/- diarrhea) :acteremiaase fatalities (**-> F)': resistanceo +accine
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&2eddy 6"' et al; Lancet Infect Dis ()1)+
Salmonellaeare the commonest causeof acterial loodstream infection in
frica
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yphoidal Salmonella in H#/-infected frican
;oro, et al. ature Genetics, *01*
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yphoidal Salmonella in H#/-infected frican
Cost resistance to Salmonellarelies on"
- cell-mediated immunity (macrophages, Ps, Hcells)
- complement ;illing (induced $y 'nti$odies Ps)
CD-uninfected sera CD-infected sera
34posure to serum (min)Iog10changeinSalmone
lla(cfu/ml)
Iac; of '$J
acIenan, et al. &cience, *010
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yphoidal Salmonella in H#/-infected frican
CD-uninfected sera CD-infected sera
Total anti- &almonella gG titerIog
10changein
Salmonella(cfu/ml)
acIenan, et al. &cience, *010
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yphoidal Salmonella in H#/-infected frican
nhi$itory factor" IP& gG
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yphoidal Salmonella in H#/-infected frican
nhi$itory factor" IP& gG
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yphoidal Salmonella in H#/-infected frican
nhi$itory factor" IP& gG
Ki+erting complement deposition a
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Salmonella enterica di@erent diseases, typhoid and non-typhoidal
eplicates in macrophages in mem$rane-$ound +acuoles
Persists chronic infection, carriers/shedders
&P-1 and &P-* Type secretion systems are important
+irulence components" &P-1 for in+asion and &P-* forreplication
+ummary
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