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SARS-CoV-2 and Influenza co-infection turned out to be a huge threat in recent times. The clinical presentation and disease severity is common in both the infection condition. The present paper deals with studying co-infection model system through systems biology approaches. Understanding signaling regulation in COVID-19 and co-infection model systems aid in the development of network-based models thereby suggesting intervention points for therapeutics. This paper highlights the aim of revealing such perturbations to decipher opportune mediating cross talks characterizing the deadly viral disease. The comparative analysis of both the models reveals major signaling protein NFκB and STAT1 playing a crucial role in establishing co-infection. By targeting these proteins at cellular level, it might help modulating the release of potent pro-inflammatory cytokines thereby taming the severity of the disease symptoms. Mathematical models developed here are precisely tailored and serves as a first step towards co-infection model offering flexibility and pitching towards therapeutic investigation.

Macrophage phenotype plays a crucial role in the pathogenesis of Leishmanial infection. Pro-inflammatory cytokines signals through the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway that functions in parasite killing. Suppression of cytokine signaling (SOCS) is a well-known negative feedback regulator of the JAK/STAT pathway. However, change in the expression levels of SOCSs in correlation with the establishment of infection is not well understood. IL6 is a pleotropic cytokine that induces SOCS1 and SOCS3 expression through JAK-STAT signaling. Mathematical modeling of the TLR2 and IL6 signaling pathway has established the immune axis of SOCS1 and SOCS3 functioning in macrophage polarization during the early stage of Leishmania major infection. The ratio has been quantified both in silico and in vitro as 3:2 which is required to establish infection during the early stage. Furthermore, phosphorylated STAT1 and STAT3 have been established as an immunological cross talk between TLR2 and IL6 signaling pathways. Using synthetic biology approaches, peptide based immuno-regulatory circuits have been designed to target the activity of SOCS1 which can restore pro-inflammatory cytokine expression during infection. In a nutshell, we explored the potential of synthetic biology to address and rewire the immune response from Th2 to Th1 type during the early stage of leishmanial infection governed by SOCS1/SOCS3 immune axis.

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