SIRTUIN-DEPENDENT REGULATION OF TUBERCULOSIS AND HIV INTERACTIONS IN MACROPHAGES

Project: Research project

Project Details

Description

Macrophage activation is a complex immune response process involving orchestrated actions of signals from cytokines, chemokines, pathogen-associated molecular pattern molecules (PAMPs) and damage-associated molecular pattern molecules (DAMPS). Classically activated macrophages are pro-inflammatory macrophages and defined as M1-M? while alternatively activated macrophages are anti-inflammatory and defined as M2-M?s. Polarization between M1-M? and M2-M? is intelligently utilized by our immune system to safeguard extrinsic pathogen invasion by killing with M1-M? then apply anti-inflammatory M2-M?s to repair M1-M?s potentially-caused tissue damage. We have identified Sirt2 is highly expressed in M2-M?s while Sirt5 highly expressed in M1-M?s. Highly expressed Sirt2 promotes pathogen growth for both Mtb and HIV. However, the mechanism is unknown. We hypothesis that Sirt2 regulates tryptophan metabolism in the two parallel directions, the IDO catalyzing to kynurenine and IL4I1 oxidizing to indole-3-pyruvic acid, which controls the expression of anti-inflammatory genes including IL-10 through ARNT activation. In contrast, inhibition of Sirt2 suppresses the expression of IDO and IL4I1 resulting in the down-regulation of IL-10 and promoting polarization of M2 to M1, increasing autophagy to kill pathogens. In this submitted application entitled “SIRTUIN-DEPENDENT REGULATION OF TUBERCULOSIS AND HIV INTERACTIONS IN MACROPHAGES”, as an MPI, I will work with Dr. Chinnaswamy Jagannath and others not only to address the above hypothesis using multi-omics and various epigenetic methods.
StatusActive
Effective start/end date8/1/247/31/25

Funding

  • Houston Methodist Research Institute: $143,110.00

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