Significant Contribution |
1. Roy S, Saha S, Gupta P, Ukil A, and Das PK. (2019) . Crosstalk of PD-1 signaling with SIRT1/FOXO-1 axis in progression of visceral leishmaniasis. J.Cell Sci. 226274. doi:10.1242/jcs.226274.(Impact factor 4.43)
2. Saha S, Basu B, Guin S, Roy A, Gupta P, Mitterstiller AM, Weiss G. Jana K and Ukil A. (2019). Leishmania donovani exploits macrophage heme oxygenase-1 to neutralize oxidative burst and TLR signalling dependent host defense. J Immunol. 202(3):827-840. (Impact factor 4.92)
3. Dowari,P., Saha S, Pramanik B, Ahmed S, Singha N, Ukil A and Das D. (2018).Multiple cross-linking strategy to form size tuneable bio-polymer with efficient cell adhesion and proliferation property. Biomacromolecules. 19(10):3994-4002. (Impact factor 5.73)
4. Gupta P., Srivastav S., Saha S., Das PK. and Ukil A. (2016). Leishmania donovani inhibits macrophage apoptosis and pro-inflammatory response through AKT-mediated regulation of β-catenin and FOXO-1. Cell Death Differ.23: 1815-1826(Impact factor 8.46)
5. Dutta S, Lahiri S, Banerjee A, Saha S, Dasgupta D.(2015).Association of antitumor antibiotic Mithramycin with Mn2+ and the potential cellular targets of Mithramycin after association with Mn2+. J Biomol Struct Dyn. 33(2):434-46. (Impact factor 3.1)
6. Saha S, Roy S, Dutta A,Jana K and Ukil A.(2021). Leishmania donovani targets host transcription factor NRF2 to activate anti-oxidant enzyme HO-1 and transcriptional repressor ATF3 for establishing infection. (Accepted in Infection and Immunity, DOI: 10.1128/IAI.00764-20)
7. Saha S*, Basu B* and Ukil A (*contributed equally to this work).(2020). Spectrophotometric Assessment of Heme Oxygenase-1 Activity in Leishmania-infected Macrophages. Bioprotocol. 10(7), DOI: 10.21769/BioProtoc.3578.
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Bio |
In my first study, screening of macrophage antioxidant enzymes during infection revealed marked upregulation of the heme-degrading enzyme, heme oxygenase-1 (HO-1). Moreover, HO-1 inhibition increased superoxide production and decreased parasite survival in infected RAW macrophages. HO-1 induction further decreased cellular heme content, thereby inhibiting the heme-dependent maturation of gp91phox, a catalytic component of major ROS–producing enzyme NAD(P)H oxidase. Decreased gp91phox expression resulted in reduced stability of p22phox, another component of the catalytic center of NAD(P)H oxidase. In my next study, we aimed to gain mechanistic understanding of the molecular events used by the parasite to upregulate HO-1. Analysis of macrophage stress responsive transcription factors of HO-1 revealed that infection upregulates nuclear factor erythroid 2 (NFE2)-related factor 2 (NRF2) and silencing of NRF2 significantly reduced HO-1 expression and parasite survival. Infection led to dissociation of NRF2 from its cytosolic inhibitor KEAP1 leading to its phosphorylation-dependent nuclear translocation. This suggested NRF2 mediated HO-1 activation helps in ROS neutralization. After neutralization of ROS, the pathogen gains access to the interior of the macrophage where establishment of an anti-inflammatory milleu is required for the pathogen persistence. In my next study we showed that Leishmania exploits transcriptional repressor activating transcription factor 3(ATF3) to inhibit proinflammatory responses. CHIP assay demonstrated that NRF2 induces ATF3 gene activation. Silencing of ATF3 resulted in decreased parasite survival and increased pro-inflammatory cytokine production without affecting ROS level. Infection-induced ATF3 interacted with histone deacetylase 1 (HDAC1) and recruited HDAC1 into the promoter sites of TNF-α and IL-12 gene. Deacetylated histones interfered NFκB binding and reduced transcription of inflammatory cytokines. Collectively we documented that Leishmania upregulates NRF2 to activate antioxidant enzyme HO-1 and epigenetic modulator ATF3 to inhibit ROS and pro-inflammatory cytokine production necessary for propagating infection. Overall this work dissects the survival strategies adopted by the parasite which will help in development of newer generation of drugs and also shed light on the host-pathogen interaction which can be extended to other intramacrophage pathogens.
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