hannover medical school january 25 th 2010 salmonella enterica serovar typhimurium exploits...
TRANSCRIPT
Hannover Medical School
January 25th 2010
Salmonella enterica serovar Typhimurium exploits inflammation
to compete with the intestinal microbiota
Stecher et al.,
PLoS Biol 5(10): e244
2007
Hannover Medical School
Salmonella enterica
• Gram-negative, rod-shaped, motile bacterium
• typically acquired by the oral ingestion of contaminated food or water
• many different serovars
1) typhoid enteric fever
• e.g. serovar Typhi or Paratyphi
2) non-typhoid gastroenteritis
• e.g. serovar Typhimurium
Hannover Medical School
Intestinal microbiota
• more than 1000 species with a collective
weight of about 1kg in human intestine
• symbiotic relationship with the host:
1. structual functions
• e.g. immune system development
2. metabolic functions
• e.g. synthesize vitamins
3. protective functionschanged from O´Hara et al., EMBO reports, 2006
Role of inflammation for Salmonella colonization and competition against intrinsic microbiota
Hannover Medical School
Colonization efficiency of Salmonella enterica serovar Typhimurium (S. Tm) in the streptomycin mouse model
1 dayStreptomycin mouse model
S. Tmwt wild-type
S. Tmavir mutant that lacks virulence-associated type III secretion systems
S. Tmwt but not S. Tmavir can colonize the intestine and cause colitis
Hannover Medical School
Colonization efficiency of S. Tmwt and S. Tmavir in the streptomycin mouse model
sm = streptomycin; L = cecum lumen
fluorescence microscopy of cecum tissue sections
S. Tmavir but not S. Tmwt is outcompeted by re-growing commensal microbiota
Hannover Medical School
Microbiota manipulation by S. Tm in the streptomycin mouse model
16S rRNA gene sequencing of intestinal microbiota
sm = streptomycin
Hannover Medical School
Microbiota composition of individual mice (streptomycin mouse model)
mo
use
sm = streptomycin
16S rRNA gene sequencing of intestinal microbiota
S. Tmwt infection alters the composition of intestinal microbiota
Hannover Medical School
Competitive infection with Lactobacillus reuteri in the streptomycin mouse model
alteration of microbiota composition by S. Tmwt can be demonstrated at the level of a single bacterial strain
L. retueri RRRif a commensal bacteria of mouse intestine
L. retueri RRRif infection 1 day p.i. with S. Tm
Hannover Medical School
Influence of S. Tmwt induced inflammation on colonization of S. Tmavir in the streptomycin mouse model
S. Tmwt triggered colitis creates favourable conditions in the intestinal lumen that rescues S. Tmavir colonization
• Mixed infection with S. Tmwt also complements the colonization defect of S. Tmavir in a chronic Salmonella colitis model (129Sv/Ev mice)
Hannover Medical School
Influence of cecal inflammation per se on S. Tmavir colonization
C3H/HeJBirIL10-/- mice
lack anti-inflammatory IL-10; develop colitis spontaneously
• similar results were made using a C57Bl/6IL10-/- mouse model
Intestinal content
Hannover Medical School
Influence of intestinal inflammation in the VILLIN-HACL4-CD8 mouse model on S. Tmavir colonization
VILLIN-HACL4-CD8 mouse model
Intestinal content
inflammation
per se can
enhance S. Tmavir
colonization
VILLIN-HA mice express HA from influenza virus under the control of enterocyte-specific VILLIN promotor
CL4 transgenic mice express TCR that recognize HA epitope
Hannover Medical School
Microbiota composition in the VILLIN-HACL4-CD8 mouse model
16S rRNA gene sequencing of intestinal microbiota
4 days post adoptive transfer
inflammation per se does
not drastically change the gut
flora composition
Hannover Medical School
Summary
S. Tmavir (T3SS deficient mutant) but not S. Tmwt is
outcompeted by re-growing commensal microbiota in the
streptmycin mouse model
Inflammation triggered by specific S. Tm virulence factors
(T3SS), by genetic predisposition (IL10-/-), or by T cell-inflicted
damage (VILLIN-HACL4-CD8 model) can enhance S. Tmavir
colonization
Hannover Medical School
Microbiota-pathogen-host interaction model
• S. Tm virulence factors trigger colitis• Inflammation shifts the growth competition in
favour for the pathogen:
a. inhibitory effects on the microbiota- release of antimicrobial factors- disruption of commensal network
b. improved growth conditions for the pathogen- altered nutrient mix
symbiotic interaction
• resident microbiota mediates colonization resistance against incoming S. Tm
Hannover Medical School
Thank you for your
attention!