emergence and robustness of multicellular behavior in bacteria
TRANSCRIPT
Emergence and robustness of
multicellular behavior in bacteria
Joao B. Xavier
Computational and Systems Biology
Memorial Sloan-Kettering Cancer Center
Bacteria have many examples of social
interaction
What prevents evolutionary cheating?
Cooperator
Public good
"cheater"
+
•Strength by numbers
•Secretion of virulence factors
•Biofilm formation
•Quorum sensing
Swarming benefits the colony but requires
biosurfactant synthesis by cells
What prevents
evolutionary
cheating?
With: Wook Kim, Kevin Foster
Different genotypes are distinguishable
using neutral colors
GFP RFP mix
GFP RFP mix
ce
lls
in
co
lon
y
2x10 10
1x10 10
Biosurfactant secretion is uncheatable
• Non-cooperators do
better than when alone…
• Not enough to distinguish
who wins, WT or rhlA-
• …but at expense of wild-
type
Measured relative fitness:
0.99 0.05
rhlA expression is delayed until
stationary phase
[h]
rhlAB expression ON rhlAB expression OFF
P. aeruginosa
PA14 rhlAB-GFP
Expression of biosurfactant synthesis is
favored at lower nitrogen source levels
Carbon source: Glycerol (C3H5(OH)3)
Nitrogen source: (NH4)2SO4
rhlA regulation ensures
metabolic prudence
But only if there s a quorum
N
N C
C C
C
C
Medium both carbon
and nitrogen but
carbon is in excess
C C
CCC
C
C C
Cells grow while
there s
nitrogen…
C
C
C
…then use excess
carbon to secrete
rhamnolipids
Inducible rhlAB bypasses
metabolic pudence mechanism
No inducer
(behaves like non-
cooperator)
Inducer present
(strict cooperator)
Single dose of clindamycin can perturb
mice microbiota up to 28 days…
Phylotype color scheme:
Ileum (Clindamycin treated mice)
Cecum (Clindamycin treated mice)
Rela
tive a
bun
dance
R
ela
tive a
bun
dance
Ileum (control)
Cecum (control)
Rela
tive a
bun
dance
R
ela
tive a
bun
dance
With: Charlie Buffie, Eric Pamer
…and greatly increases the risk of
Clostridium difficile colitis
Rela
tive a
bun
dance
R
ela
tive a
bun
dance
Clindamycin treated mice
Control mice
Phylotype color scheme:
Ileum (clindamycin + C. difficile)
Cecum (clindamycin + C. difficile)
Antibiotic therapy and competition explain multi-
stability and hysteresis in intestinal microbiota
(competitive ability of sensitives)
(sensitiv
ity to a
ntibio
tic)
Problem:
Noise-free model predicts dominance states can last indefinitely. Can noise
describe return to sensitive dominated state?
Simulation time Simulation time
Exposure to environmental microbes
explains microbiota recovery
(No noise)
Antibio
tic p
uls
es
Antibiotic tolerants
Antibiotic sensitives
DN=3.3x10-4
(noise level)
DN=1x10-3
(noise level)
Can we test the model with
metagenomic data?
Dethlefsen & Relman (2011) PNAS
Question:
Can we separate OTUs into sensitives and tolerants according to their
response to ciprofloxacin?
Antibiotic sensitive or antibiotic tolerant dynamics
identified from singular value decomposition
Data from subject D Data from subject E Data from subject F
Sample (day) Sample (day) Sample (day)
OTUs that
correlate with
PC1
OTUs that
correlate with
PC2
Summary
• Social interaction is key in microbial evolution and ecology
• Multicellular cooperative traits are open to exploitation…
• …and therefore must have evolved with mechanisms for robustness
• We can find the mechanisms stabilizing bacterial multicellularity such as metabolic prudence
• Next gen sequencing and ecological modeling can unveil the human microbiome
• And lead to applications for human health
Clinical application:
the microbiome of bone marrow transplantation
Microbiota states: Timelines of bone marrow transplants:
State transitions:
With: Ying Taur, Eric Pamer
Xavier lab at MSKCC (est Dec 2009):
Dave van Ditmarsch
Vanni Bucci
Will Chang
Laura de Vargas Roditi
Carlos Carmona-Fontaine
Kerry Boyle
http://cbio.mskcc.org/xavierlab/
Foster lab at Oxford:
Kevin Foster
Wook Kim
Acknowledgments Eric Pamer
Charlie Buffie
Carles Ubeda
Ying Taur
Serena Bradde (now at Curie Institute)
Giulio Biroli (Institut Physique Theorique Saclay)
Thanks also to:
Peter Greenberg, Pradeep Singh,
Deborah Hogan, Les Dethlefsen
Lucille Castori Center for Microbes Inflammation
and Cancer
Funding: