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macrophage

Insight into human alveolar macrophage and  M. tuberculosis  interactions via metabolic reconstructions. macrophage. phagosome compartment.

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macrophage

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  1. Insight into human alveolar macrophage and M. tuberculosis interactions via metabolic reconstructions macrophage phagosome compartment 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). M. tuberculosis

  2. 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

  3. 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 drug- resistant tuberculosis (MDR-TB) infections.  • Classic symptoms of active TB infection are a chronic cough with blood-tinged sputum, fever, night sweats, and weight loss 

  4. 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 acidson its cell wall. • It also stops biomass accumulation • fatty acids/lipids are the main carbon sources

  5. 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 )

  6. Constructing the human alveolar macrophage, iAB-AMØ-1410 X 2 Combined model + • Biomass maintenance reaction- represents the turn over of Lipids, proteins, RNA , etc

  7. Macrophage model - Results • ATP production- 96.1% agreement with in-vitro experiments • Nitric oxide production ~ 98% accuracy • High glucose oxidation leading to High rate of lactate production (like Warburg effect) .

  8. 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

  9. Infection in silico

  10. Tweak the Biomass Reactionexample (?): 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 2) Preform Monte Carlo sampling in order to determine mean ATP flux. 3) Set new ATP_Coef and return to 1) B) Figure out the connection between flux and GE data (?) 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

  11. Modifications of the original iNJ661 biomass objective function to produce the final infectious state TB objective function

  12. Macrophage-TB combined model- Results: • 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.

  13. Integration and results of the alveolar macrophage (iAB-AMØ-1410) and Mycobacterium tuberculosis (iNJ661) reconstructions

  14. Results: Changes in reaction activity of TB- Ashift toward non carbohydrates usage-- Gluconeogenesis is up regulated- Glucose is generate from non-carbohydrates Glyoxylate shunt is up regulated- Acytyl-Coa generated from fatty acids Glycolysis is suppressed

  15. Increased accuracy of gene deletion tests tests

  16. Infection-specific models: latent, pulmonary, and meningeal tuberculosis Projection of Macrophage GE Active infection Latent Infection Macrophage Tuberculosis

  17. Thanks !

  18. Three infection-specific models

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