IL12 and IL10 are two of the major cytokines which control the fate of Leishmaniasis. This paper presents two models healthy state and diseased state which shows how secretion of IL12 is responsible for parasite elimination and IL10 can jeopardize the parasite elimination and promote its survival. Epigenetic modification in the host IL12 and IL10 promoter can decide the fate of parasites. It was observed that reciprocal relationship exists between IL12 and IL10 and that is majorly controlled by a transcription factor NFAT5 from Rel family of transcription factors. By targeting this transcription factor at the cellular level, it might be possible to modulate the release of powerful pro-inflammatory cytokines, thereby reducing parasite survival. The mathematical models developed here serves as a step towards finding a key component that can pave a way for therapeutic investigation.

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Hallmark for macrophages is their ability to possess plasticity which enables them to respond to changing microenvironment. Leishmania takes use of the phenotypic plasticity of macrophages to create favorable position for intracellular survival and persistent infection through regulatory cytokine like IL10. However, these effector cells can eliminate infection through modulation of critical cytokines such as IL12 and key players involved in its production. Using sophisticated tool of single cell ATAC sequencing we analyzed the regulatory axis of IL10 and IL12 in time dependent manner for L.major infection in macrophages. We recognized the cellular heterogeneity post infection with the regulators of IL10 and IL12 and observed a reciprocal relationship between them. Our prominent findings also exposed sleepy macrophages and its role in IL10 and IL12 reciprocity. To summarize, role of NFAT5 was vital in identification of sleepy macrophages which is a transient state where transcription factors controlled the epigenetic remodeling and expression of genes involved in pro-inflammatory cytokine production and recruitment of immune cells.