Abstract
Macrophage phenotype plays a crucial role in the pathogenesis of Leishmanial infection. Pro-inflammatory cytokines are the key regulators that eliminate the infection induced by Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway. Suppressor of cytokine signaling (SOCS) is a well-known negative feedback regulator of JAK/STAT pathway. However, change in expression levels of SOCS in correlation with the establishment of infection is not well understood. Mathematical modeling of IL6 signaling pathway have helped identified the role of SOCS1 in establishment of infection. Furthermore, the ratio of SOCS1 and SOCS3 has been quantified both in silico as well as in vitro, indicating an immune axis which governs the macrophage phenotype during L. major infection. The ability of SOCS1 protein to inhibit the JAK/STAT1 signaling pathway and thereby decreasing pro-inflammatory cytokine expression makes it a strong candidate for therapeutic intervention. Using synthetic biology approaches, peptide based immuno-regulatory circuit have been designed to target the activity of SOCS1 which can restore pro-inflammatory cytokine expression during infection.
Competing Interest Statement
The authors have declared no competing interest.
Abbreviations
- AIF
- Anti-inflammatory factor
- CMV
- Cytomegalovirus
- CT
- Comparative threshold
- CTI
- Control + Transfected + Infected
- CTIM
- Control + Transfected + Infected + Miltefosine
- DAPI
- 4′,6-diamidino-2-phenylindole
- DMEM
- Dulbecco’s Modified Eagle Medium
- DSM
- Diseased State Model
- EDTA
- Ethylenediaminetetraacetic acid
- EV
- Empty Vector
- GFP
- Green Fluorescent Protein
- HSM
- Healthy State Model
- IFNγ
- Interferon gamma
- IPTG
- Isopropyl β- d-1-thiogalactopyranoside
- iGEM
- International Genetically Engineered Machine
- iNOS
- Inducible nitric oxide synthase
- IL6
- Interleukin 6
- IL1β
- Interleukin 1 beta
- IL10
- Interleukin 10
- JAK/STAT
- Janus kinase/signal transducer and activator of transcription
- LACR
- Lactose Repressor
- LPS
- Lipopolysaccharide
- MOGA
- Multi-objective genetic algorithm
- ODE
- Ordinary differential equation
- PBC
- Periodic boundary condition
- PCA
- Principal component analysis
- PFA
- Paraformaldehyde
- PGN-SA
- Peptidoglycan from Staphylococcus aureus
- PEI
- Polyethylenimine
- RPMI
- Roswell Park Memorial Institute
- RMSD
- Root-mean-square deviation
- RMSF
- Root mean square fluctuation
- SH2
- Src Homology 2
- SOCS
- Suppressor Of Cytokine Signaling
- TIP3P
- Transferable intermolecular potential with 3-point
- TLR
- Toll like Receptors