Insight into human alveolar macrophage
and M. tuberculosis interactions via
metabolic reconstructions
macrophage
phagosome compartment
M. tuberculosis
Bordbar, A., Lewis, N. E., Schellenberger, J., Palsson, B. Ø. & Jamshidi, N. Insight into
human alveolar macrophage and M. tuberculosis interactions via metabolic
reconstructions. Mol. Syst. Biol. 6, 422 (2010).
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Tubercle bacillus
• About one-third of the world's population is
infected!
• Only a 10% lifetime chance that the latent
infection will progress to overt
• 9.27 million new cases and 1.76 million deaths
in 2007 (WHO, 2009)
the prevalence of TB per 100,000 people was
highest in sub-Saharan Africa, and was also
relatively high in Asia
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Tubercle bacillus
• Tuberculosis typically attacks the lungs
hematogenous transmission can also
spread infection to more distant sites, such
as peripheral lymph nodes, the kidneys,
the brain, and the bones
• Antibiotic resistance is a growing problem in multiple drugresistant tuberculosis (MDR-TB) infections.
• Classic symptoms of active TB infection are a chronic
cough with blood-tinged sputum, fever, night sweats,
and weight loss
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Key aspects of TB’s pathogenicy
• The environment of the Phagosome is
nutrient poor, hypoxic, nitrosative and
oxidative
• In order to survive TB accumulates mycolic
and fatty acids on its cell wall.
• It also stops biomass accumulation
• fatty acids/lipids are the main carbon sources
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Modeling the interaction
MAC:= Alveolar macrophage host model
TB:= Mycobacterium tuberculosis model
• 4 steps:
• 1) Construction of the MAC (I-MAT and GMME)
• 2) Adaptation of the TB (modified biomass rxn)
• 3) Integration of the 2 into TB-MAC model
• 4) Analysis TB-MAC model in different contexts
(latent and infectious stages )
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Constructing the human alveolar
macrophage, iAB-AMØ-1410
X 2
Combined model
+
•
Biomass maintenance reaction- represents the turn
over of Lipids, proteins, RNA , etc
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Macrophage model - Results
• ATP production- 96.1% agreement with invitro experiments
• Nitric oxide production ~ 98% accuracy
• High glucose oxidation leading to High rate of
lactate production (like Warburg effect) .
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Results: Macrophage model vs. Recon1
• Majority of genes and reaction
are preserved
• Small reduction in Reaction count
but Large reduction of metabolic
Functions is due to exchange
constrains and removal of key
reactions for Recon 1
• Important Carbohydrate and central
metabolism were well preserved as
expected but Peripheral functions
were not preserved
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Infection in silico
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Tweak the Biomass Reaction
example (?):
Original Biomass reaction = ATP_COEF * ATP + 20 * NADH + 4 * Valine+ 7 * etc
Where ATP_COEF=40
A) iterative sampling for each Biomass component
1) Set: biomass rxn flux >= 0.75 * max biomass flux 6
2) Preform Monte Carlo sampling in order to
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determine mean ATP flux.
ATP flux
3) Set new ATP_Coef and return to 1)
2
0
B) Figure out the connection between flux and GE data (?) 1
Coef
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20
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C) Based on the results of A above the function from B
Find new_ATP_COEF to achieve the best fit between ATP flux and GE Data
D) Final biomass function = new_ ATP_COEF * ATP + new_NADH_COEF * NADH + 7 * etc
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Modifications of the original iNJ661 biomass objective
function to produce the final infectious state
TB objective function
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Macrophage-TB combined modelResults:
• The integration radically decreases major objective
function fluxes of the Macrophage:
51% reduction of the mean reaction flux span
• Max ATP, nitric oxide, NADH fluxes in the Macrophage:
reduced by 75%,55%, 70% respectively.
• Bottom line: Macrophage solution space was
substantially decreased without adding any additional
constrains on its the internal reactions.
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Integration and results of the alveolar macrophage
(iAB-AMØ-1410) and Mycobacterium
tuberculosis (iNJ661) reconstructions
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Results: Changes in reaction activity of TBA shift toward non carbohydrates usage
--
Gluconeogenesis is up regulatedGlucose is generate
from non-carbohydrates
Glyoxylate shunt is up regulatedAcytyl-Coa generated from fatty acids
Glycolysis is suppressed
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Increased accuracy of gene deletion tests
tests
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Infection-specific models:
latent, pulmonary, and meningeal tuberculosis
Projection of Macrophage GE
Latent Infection
Active infection
Macrophage
Tuberculosis
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Thanks !
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Three infection-specific models
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