Abstract
With the advent of synthetic biology in medicine many synthetic or engineered proteins have made their way to therapeutics and diagnostics. In this paper, the downstream gene network of CD14-TNF-EGFR pathway in leishmaniasis, a tropical disease, is reconstructed. Network analysis showed that NFkB links the signaling and gene network, used as a point of intervention through a synthetic circuit embedded within the negative autoregulatory feedback loop. A chimeric protein kinase C (PKC) is incorporated in the synthetic circuit, under the transcriptional regulation of Lac repressor and IPTG, as an inducer. The chimeric PKC_ζα via IκKb phosphorylation activates NFκB, and modulates the gene expression from an anti-inflammatory to a pro-inflammatory phenotype in in vitro L. major infected macrophage model. This is the first ever report of a synthetic device construction in leishmania.
Highlights
Another possible avenue for inducing plasticity of macrophage phenotype could be using synthetic biology approach to rewire signalling with novel molecular functions
Since there are no direct evidence for the transcription factors (TFs) and their corresponding transcription genes (TGs) in leishmaniasis, knowledge from various databases and literature were collected and a graph based analysis was implemented on the reconstructed transcription-factor target gene (TFTG) network
The TFTG network had 71 genes and 134 TF-TG pairs, from which important TFs and their TGs were selected based on network matrices of closeness centrality (CC) and edge betweeness
Summary
With the advent of synthetic biology in medicine many synthetic or engineered proteins have made their way to therapeutics and diagnostics. The chimeric PKC_ζα via IκKb phosphorylation activates NFκB, and modulates the gene expression from an anti-inflammatory to a pro-inflammatory phenotype in in vitro L. major infected macrophage model. This is the first ever report of a synthetic device construction in leishmania. This work exemplifies the use of a chimeric protein kinase C (PKC) embedded within a negative autoregulatory synthetic circuit for immune modulation via activation of NFκB which could result in phenotypic change of the Leishmania infected macrophages. The reconstructed TFTG network would be the effector system of the activated signal transduction and we begin with its analysis followed by the design and verification of the synthetic circuit and it’s in vitro effect on parasite survival
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