Transcription Factor Target Gene Network governs the Logical Abstraction Analysis of the Synthetic Circuit in Leishmaniasis

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.

Mechanobiology of immune cells: Messengers, receivers and followers in leishmaniasis aiding synthetic devices

“…Rewiring of signaling pathway is also achieved by engineering chimeric proteins to target ligand receptor interaction. PKC is a protein kinase C (PKC) that is incorporated inside a negative autoregulatory synthetic circuit for immunological modulation via NF-κB activation, which could lead to phenotypic changes in leishmania infected macrophages ( Mol et al, 2018 ).…”

Synthetic biology tools for engineering Goodwin oscillation in Trypanosoma brucei brucei

“…The Kinetoplastid Leishmania tarentolae is already an established niche recombinant protein production platform ( Klatt et al., 2019 ). Mol et al. (2018) have paved the way for applying synthetic biology approaches to Leishmania major by building synthetic networks in the organism to investigate the aetiology of the pathology it can cause in humans.…”

Perspectives From Systems Biology to Improve Knowledge of Leishmania Drug Resistance

“…One possible approach is the integration of public available RNAseq data depicting the resistance phenomena in gene regulatory networks (Andrade et al, 2020). Such approach has demonstrated how genes interact with each other and how changes in their expression levels may result, for example, in different immunological responses promoting distinct disease outcomes including leishmaniasis (Mol et al, 2018).…”