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Salmonella 2015 - BSC Blackboard
Salmonella 2015 - BSC Blackboard
Salmonella 2015 - BSC Blackboard
Dr Sophie Helaine
Salmonella pathogenesis
Human diseases
Typhoid (S. enterica Typhi and S. Paratyphi): 17 million cases
and 600,000 deaths/yr - increasing multiple drug resistance
recurrence infection
Non-typhoidal (e.g S. enterica Typhimurium): 1.3 billion
cases and 3 million deaths/yr (major problem in sub-Sarahan
Africa)
T0
48 h (10 days)
12 days
S. Typhi
Typhimurium
S.
Salmonella pathogenesis
Human diseases
Typhoid (S. enterica Typhi and S. Paratyphi): 17 million cases
and 600,000 deaths/yr - increasing multiple drug resistance
recurrence infection
Non-typhoidal (e.g S. enterica Typhimurium): 1.3 billion
cases and 3 million deaths/yr (major problem in sub-Sarahan
Africa)
Fatal bacteraemia
Colonisation of Peyers
Patches, mesenteric lymph
nodes
response
genes
stomach
low pH
small
intestine
osmotic stress
anaerobiosis
motility
adhesion
flg, lpf and pef
epithelium
penetration
anaerobiosis
cell contact
invasion
bloodstream
complement
antimicrobial
peptides
macrophage
virulence
many (e.g.inv/spa)
Salmonella an intracellular
pathogen
Salmonella-containing vacuoles in spleen cells
Salmonella an intracellular
pathogen
Listeria
Shigella
Salmonella
Mycobacteria
Coxiella
pDiGc
pDiGi
18 h
Bone-marrow derived
macrophages
Bacterial persisters
Many bacterial species form persisters - highly tolerant to antibiotics
Persistent bacterial infections pose significant public-health problems
Typhoid fever in humans - 15% of treated patients suffer a relapse
A major breakthrough was the discovery that E. coli in vitro persisters are nonreplicating bacterial cells (Balaban et al, Science 2004)
total intracellular
population
intracellular
persisters
% of Max
80
60
40
21 %
20
9%
0
0
10
10
10
GFP
10
10
Fluorescence
Host induced persisters are non-replicating
bacteria
arabinose-inducible
gfp
104
dsRed
10
+ arabinose
+arabinose
+ triton
103
DsRed
FL2-H
10
DsRed
FL2-H
IPTG-inducible
Non-replicating bacteria
Regrowth
102
101
+ cefotaxime
10
cefotaxime
0
O/N growth
10
10
100
+ IPTG
infect
101
102
FL1-H
103
GFP
Responsive non-replicating
after 24 h in macrophages
- IPTG
10
24 h
in macrophages
104
bacteria
10
10
10
FL1-H
103
103
DsRed
DsRed
104
10
102
10
100
100
102
101
101
102
GFP
103
104
100
100
responding
102
GFP
103
104
GFP
regrowing
4
10
10
Non-replicating bacteria
Regrowth
10
10
10
10
DsRed
DsRed
+arabinose
102
10
10
10
24 h
in macrophages
10
10
GFP
10
10
102
10
10
10
10
10
GFP
10
10
Figure5
Salmonella pathogenesis
Human diseases
Typhoid (S. enterica Typhi and S. Paratyphi): 17 million cases
and 600,000 deaths/yr - increasing multiple drug resistance
recurrence infection
Non-typhoidal (e.g S. enterica Typhimurium): 1.3 billion
cases and 3 million deaths/yr (major problem in sub-Sarahan
Africa)
Salmonella an intracellular
pathogen
Two T3SS
SPI-1 mediates invasion of host cells
and
intestinal secretory and inflammatory
responses
SPI-2 is required for bacterial replication
and immune modulation
Salmonella an intracellular
pathogen
Two T3SS
Adhesion
Invasion
SPI-1 T3SS
Extracellular
SCV formation
SCV maturation
SPI-2 T3SS
Intracellular
Replication
Salmonella an intracellular
pathogen
Two T3SS
Adhesion
Invasion
SPI-1 T3SS
Extracellular
SCV formation
SCV maturation
SPI-2 T3SS
Intracellular
Replication
acidic pH triggers
secretion
H+
H+
translocon (SseB)
H+
H+
H+
H+
H+
secreton needle
bacterial outer
membrane
SsaC
SsaJ
bacterial inner
membrane
SsaV
SsaM
SpiC
SsaL
ssaV mutant
is null for
SPI-2 function
wild-type
SPI-2 mutant
Salmonella pathogenesis
Human diseases
Typhoid (S. enterica Typhi and S. Paratyphi): 17 million cases
and 600,000 deaths/yr - increasing multiple drug resistance
recurrence infection
Non-typhoidal (e.g S. enterica Typhimurium): 1.3 billion
cases and 3 million deaths/yr (major problem in sub-Sarahan
Africa)
Lack of Ab?
HIV-uninfected sera
HIV-infected sera
Summary
More reading
Salmonella takes control: effector driven
manipulation of the host. McGhie et al., Curr
Opinion Microbiol 12: 117 (2009)
Salmonella interplay with host cells: Haraga et al.,
Nature Reviews Microbiol 6: 53 (2008)