BIO-DATA



BIO-DATA

1. Name: Anindita Ukil

2. Date of birth: December 25, 1975

3. Present Position: Assistant Professor (stage III)

4. Field of Specialization: Biochemistry, Cell Biology and Immunology with special reference to Macrophage Biology and Host-Parasite Interactions

5. Address: (a) Official (b) Residential

Department of Biochemistry 25/2B/1 Jheel Road, Dhakuria

University of Calcutta Kolkata-700031

35 Ballygunge Circular Road

Kolkata-700019

6. Phone: 91-33-2461-5455 Res: 033-24154235/91-9831319915

Fax: 91-33-2461-4849

E-mail: u.anindita@, aubioc@caluniv.ac.in

7. Academic Background:

B.Sc. (Chem. Hons) Calcutta University 1996

M.Sc. (Biochemistry) Calcutta University 1998

Ph.D. (Biochemistry) Calcutta University 2005

8. Date of joining the Institution (Designation & Scale) Assistant Professor, 1st April, 2009

9. Positions held earlier (in chronological order)

|S No |Period |Place of Employment |Designation |Scale of pay |

| | | | |Pay band-15,800-39,100, |

|1 |2009 April-2013 |University of Calcutta |Assistant Professor stage I |AGP-6000 |

| |April | | | |

| | | | | |

| | | | | |

| |2013 April - | | |Pay band-15,800-39,100, |

|2 | |University of Calcutta |Assistant Professor stage-II |AGP-7000 |

| |2018 April | | | |

| | | | | |

| | | | | |

|3 |2018 April -till |University of Calcutta |Assistant Professor stage III |Pay band-15,800-39,100, |

| |date | | |AGP-8000 |

| | | | | |

| | | | | |

10. Awards/Honours

• Invited by French National Research Agency (ANR) [pic], Govt. of France to act as a reviewer in the panel “CE15 - Immunologie, Infectiologie et Inflammation” for evaluating the generic call for proposals 2019.

• Received National Bioscience Award for Career Development by DBT for the year 2016.

• Received AN Bhaduri award by SBC (I) in 2017.

• Elected as a Fellow of National Academy of Sciences, Allahabad (FNASc) in 2017.

• Received Prof. B.K. Bachhawat Memorial Young Scientist Lecture Award by National Academy of Sciences, India (NASI) in 2014.

• Received SERB Women Excellence Award by DST in 2013.

• Received Young Scientist Award in Biomedical Sciences by National Academy of Sciences, Allahabad (NASI) in 2010.

• Received Indo-Israel Collaborative Project funded jointly by The Israel Science Foundation (ISF) and the University Grant Commission (UGC) in 2016.

• Acted as reviewer in reputed peer-reviewed journals like FASEB Journal, Journal of Infectious Diseases, PLoS Neglected Tropical Diseases etc.

11. Assignments

Member of Departmental Board of Studies.

Member Secretary for Departmental Animal Ethics Committee.

Regular teaching assignments such as University semester examination work as per duties allotted (invigilation, evaluation of answer scripts, setting of question papers for M.Sc. and B.Sc.(hons)-Head Examiner for Graduate course in Microbiology and Biochemistry).

Coordinator for B.Sc. (Hons.) Microbiology and Biochemistry.

12. Research guidance:

Number of researchers awarded Ph.D degrees: Four

Number of researchers submitted thesis: Two

Number of summer training completed: Eight

Number of students undertaking short-term projects: Three

Number of Ph.Ds presently supervising: Two

13. Research grant received:

Completed projects:

1. Received DST project Rs. 18 Lakhs (2013-2016)

2. Received DST project Rs. 37 Lakhs (2013-2016)

3. Received DST FAST TRACK project Rs. 15 Lakhs (2009-2012)

4. Received DBT project Rs. 76 Lakhs (2010-2013)

Current projects:

1. Received DST project Rs. 60.28 Lakhs (2017-2020)

2. Received UGC-UPE-II project Rs. 13.5 Lakhs (2017-2019)

3. Received India-Israel Joint collaboration Research project Rs. 77.7 Lakhs (2016-2019)

4. Received WB-DBT project Rs. 20.68 Lakhs (2015-2018)

Student’s placements:

|Name of scholars | |Designation |

|Dr. Kuntal Ghosh | |National Post-doctoral |

| | |Fellow at Dept. of |

| | |Biochemistry and |

| | |Biophysics, University of |

| | |Kalyani |

|Dr. JayeetaGiri | |Research associate at Dept. |

| | |of Medicine , University of |

| | |Wisconsin, Madison, USA |

| | | |

|Dr. Purnima Gupta | |Post-Doctoral Fellow, |

| | |Infections and Cancer |

| | |Biology Group, |

| | |International Agency for |

| | |Research on Cancer, 69372 |

| | | | | | |

| | |Lyon CEDEX 08, France |

| | | | |

|Dr. Amrita Saha | |Research associate at |

| | |Infectious diseases and |

| | |Immunological Division, |

| | |Indian Institute of Chemical |

| | |Biology |

|Shriya Saha | |Thesis submitted |

|Moumita Basu | |Thesis submitted |

14. List of nominee's 10 most significant publications

• Basu M, Gupta P, Dutta A, Jana K and Ukil A. (2020) Increased host ATP efflux and its conversionto extracellular adenosine is crucial for establishing Leishmania infection. J Cell Sci. [in press]. (Impact factor 4.43).

• 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: 827-840. (Impact factor 4.92)

• Saha, A., Basu, M. and Ukil, A. (2018). Recent Advances in Understanding LeishmaniadonovaniInfection: the Importance of Diverse Host Regulatory Pathways. IUBMB Life. 70: 593–601. (Selected by the Editor to be featured in a short highlight at the front of the Issue)

• Gupta, A. K., Ghosh, K., Palit, S., Barua, J., Das, P. K and Ukil, A. (2017) Leishmaniadonovani inhibits inflammasome-dependent macrophage activation by exploiting the negative regulatory proteins A20 and UCP2. FASEB J. 31:5087-5101.(Impact factor 5.04)

• 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)

• Giri J., Srivastav S., Basu M., Palit S., Gupta P. and Ukil A. (2016) Leishmania donovani exploits myeloid cell leukemia 1 (MCL-1) protein to prevent mitochondria dependent host cell apoptosis J. Biol. Chem. 12: 3496-3507 (Impact factor 4.57)

• Gupta P., Das PK. and Ukil A. (2015) Antileishmanial effect of 18β-glycyrrhetinic acid is mediated by TLR dependent canonical and noncanonical p38 activation. Antimicrob. Agents Chemother. 59: 2531-2539. (Impact factor 4.48)

• Saha A., Biswas A., Srivastav S., Mukherjee M., Das PK. and Ukil A. (2014) Prostaglandin E2 negatively regulates the production of Th1/Th17 cytokines and proinflammatory chemokines in visceral leishmaniasis. J. Immunol. 193: 2330-2339. (Impact factor 4.92)

• Gupta P., Giri J., Srivastav S., Chande AG., Mukhopadhyaya R., Das PK.and Ukil A. (2014) Leishmania donovani negatively regulates TLR4 mediated host response by preventing ubiquitination dependent degradation of TRAF3. FASEB J. 28: 1756-1768. (Impact factor 5.04)

• Ghosh K., Sharma G., Saha A., Kar S., Das PK. and Ukil A. (2013) Successful therapy of visceral leishmaniasis with curdlan involves T-helper 17 Cytokines J. Infec. Dis. 207: 1016–1025. (Impact factor 6.01)

15. Complete list of publications in standard refereed journals:

1. Saha S, Dutta A, Jana K and Ukil A. (2020) Leishmania donovani targets host transcription factor NRF2 to activate anti-oxidant enzyme HO-1 and transcriptional repressor ATF3 for establishing infection. (Under revision in FASEB J)

2. Basu M, Saha S and Ukil A (2020). Spectrophotometric Assessment of Heme Oxygenase-1 Activity in Leishmania-infected 1 Macrophages. Bioprotocol (in press)

3. Basu M, Gupta P, Dutta A, JanaK and Ukil A. (2020) Increased host ATP efflux and its conversionto extracellular adenosine is crucial for establishing Leishmania infection. J Cell Sci.

133(7). pii: jcs239939. doi: 10.1242/jcs.239939. (Impact factor 4.43). Selected for inclusion in the ‘Research Highlights’ section of JCS.

4. ChatterjeeT, Pattanayak R, Ukil A, Chowdhury S and Bhattacharyya M (2019). Autophagy protects peripheral blood mononuclear cells against inflammation, oxidative and nitrosative stress in diabetic dyslipidemia. Free Radical Biol. Med. 143:309-323.(Impact factor 5.9).

5. Roy S, SahaS, 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. 132 [E-pub ahead of print].(Impact factor 4.43).

6. 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. 202:827-840.(Impact factor 4.92)

7. DowariP, 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.19:3994-4002. (Impact factor 5.73) * Co-corresponding author.

8. Saha A, Basu M and Ukil A. (2018). Recent advances in understanding Leishmania donovani infection: the importance of diverse host regulatory pathways. IUBMB Life. 70:93–601. (Selected by the Editor to be featured in a short highlight at the front of the Issue)

9. Singha N, Gupta P, Pramanik B, Ahmed S, *Dasgupta A, *Ukil A Hydrogelation of a naphthalene diimide appended peptide amphiphile cell-imaging and intracellular pH sensing. Biomacromolecules.18: factor 5.34) * Co-corresponding author.

and *Das D. (2017) and its application in 3630-3641. (Impact

10. Gupta, AK, Ghosh, K, Palit S, Barua J, Das PK and Ukil A. (2017) Leishmania donovani inhibits inflammasome-dependent macrophage activation by exploiting the negative regulatory proteins A20 and UCP2. FASEB J.31: 5087-5101. (Impact factor 5.04).

11. RoyS, Gupta P, PalitS, BasuM, Ukil A and Das PK. (2017) The role of PD1 in regulation of macrophage apoptosis and its subversion byLeishmania donovani. Clin. Translational Immunol. 6: e137; doi:10.1038/cti.2017.12.(Impact factor 7.2)

12. Gupta P, Srivastav S, Saha S, Das PK and Ukil A. (2016) Leishmaniadonovaniinhibits 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)

13. Giri J, Srivastav S, Basu M, Palit S, Gupta P and Ukil A. (2016) Leishmania donovani exploits myeloid cell leukemia 1 (MCL-1) protein to prevent mitochondria dependent host cell apoptosis J. Biol. Chem. 291: 3496-3507(Impact factor 4.57)

14. Srivastav S, Saha A, Barua J, Ukil A and Das PK. (2015) IRAK-M regulates the inhibition of TLR-mediated macrophage immune response late during in vitro Leishmania donovani infection. Eur. J. Immunol. 45: 2787-2797. (Impact factor 4.51)

15. Gupta P, Das PK and Ukil A. (2015) Antileishmanial effect of 18β-glycyrrhetinic acid is mediated by TLR dependent canonical and noncanonical p38 activation. Antimicrob. Agents Chemother. 59: 2531-2539. (Impact factor 4.48)

16. Saha A, Biswas A, Srivastav S, Mukherjee M, Das PK and Ukil A. (2014) Prostaglandin E2 negatively regulates the production of Th1/Th17 cytokines and proinflammatory chemokines in visceral leishmaniasis. J. Immunol. 193: 2330-2339. (Impact factor 4.92)

17. Gupta P, Giri J, Srivastav S, Chande AG, Mukhopadhyaya R, Das PK and Ukil A. (2014) Leishmaniadonovani negatively regulates TLR4 mediated host response by preventing ubiquitination dependent degradation of TRAF3. FASEB J. 28: 1756-1768. (Impact factor 5.04)

18. Srivastav S, Basu Ball W, Gupta P, Giri J, Ukil A and Das PK. (2014) Leishmaniadonovaniprevents oxidative burst mediated apoptosis of host macrophages through selective induction of suppressors of cytokine signalling (SOCS) proteins. J. Biol. Chem. 289: 1092-1105. (Impact factor 4.57)

19. Ghosh K, Sharma G, Saha A, Kar S, Das PK and Ukil A. (2013) Successful therapy of visceral leishmaniasis with curdlan involves T-helper 17 Cytokines J. Infec. Dis. 207: 1016–1025. (Impact factor 6.01)

20. Ukil A, Kar S, Srivastav S, Ghosh K and Das PK. (2011) Curative effect of 18β-glycyrrhetinic acid in experimental visceral leishmaniasis depends on phosphatase-dependent modulation of cellular MAP kinases. PLoS ONE, e29062 (Impact factor 3.54)

21. Kar S, Ukil A and Das PK. (2011) Cystatin cures visceral leishmaniasis by NF-kB mediated proinflammatory response through co-ordination of TLR/MyD88 signaling with p105-Tpl2-ERK pathway. Eur. J. Immunol. 41: 116-127. (Impact factor 4.51)

22. Kar S, Ukil A, Sharma G and Das PK. (2010) MAPK directed phosphatases preferentially regulate pro- and anti-inflammatory cytokines in experimental visceral leishmaniasis: involvement of distinct protein kinase C isoforms. J. Leukocyte Biol. 88: 9-20. (Impact factor 4.16)

23. *Kar S, *Ukil A and Das PK. (2009) Signaling events leading to the curative effect of cystatin on experimental visceral leishmaniasis: involvement of ERK1/2, NF-?B and JAK/STAT pathways. Eur. J. Immunol. 39: 741-751 (*Equal contribution). (Impact factor 4.51)

24. Mukherjee S, Ukil A and Das PK. (2007) Immunomodulatory peptide from cystatin, a natural cysteine protease inhibitor, using leishmaniasis as model macrophage disease. Antimicrob. Agents Chemother. 51: 1700-1707. (Impact factor 4.48)

25. Ukil A, Maity S and Das PK. (2006) Protection from experimental colitis by theaflavin-3,3'-digallate correlates with inhibition of IKK and NF-kappaB activation. Br. J. Pharmacol. 149: 121-131. (Impact factor 4.84)

26. *Ukil A, *Maity S and Das PK. (2006) Biodistribution and pharmacokinetics of theaflavin-3,3`-digallate, the major antioxidant of black tea, in mice. Int. J. Pharmacol. 2: 240-246. (* Equal contribution)

27. Karmakar S, Ukil A, Mukherjee S and Das PK. (2006) Regulation of guanylyl cyclase by intracellular Ca2+ in relation to the infectivity of the protozoan parasite Leishmaniadonovani. Int. J. Biochem. Cell Biol. 38: 1277-1289.(Impact factor 3.91)

28. Ukil A, Biswas A, Das T and Das PK. (2005) 18 Beta-glycyrrhetinic acid triggers curative Th1 response and nitric oxide up-regulation in experimental visceral leishmaniasis associated with the activation of NF-kappaB. J. Immunol. 175: 1161-1169. (Impact factor 4.92)

29. Maity S, Ukil A, Karmakar S, Datta N, Chaudhuri T, Vedasiromoni JR, Ganguly DK and Das PK. (2003) Thearubigin, the major polyphenol of black tea, ameliorates mucosal injury in trinitrobenzene sulfonic acid-induced colitis. Eur. J. Pharmacol. 470: 103-112. (Impact factor 2.73)

30. Ukil A, Maity S, Karmakar S, Datta N, Vedasiromoni JR and Das PK. (2003) Curcumin, the major component of food flavour turmeric, reduces mucosal injury in trinitrobenzenesulphonic acid-induced colitis. Br. J. Pharmacol. 139: 209-218. (Impact factor 4.84)

a) Books/ book chapters :

1. Srivastav S, Ukil A and Das PK. (2015) Elucidating the strategies of immune evasion by Leishmania in: Leishmania: Current Biology and Control, Chapter 6, pp 93-106, Eds. S. Adak and R. Datta, Caister Academic Press, Norfolk, UK.

2. Gupta P, Ukil A and Das PK. (2016). Bioactive components of Licorice as an antileishmanial agent in: Research of Licorice in the Past, present and Future - Preparation of Various Bioactive Extracts as Alternative Medicines, Chapter 10, pp 147-163, Ed. Hiroshi Sakagami, INTECH .

3. Saha A and Ukil A. (2017) Leishmania exploits host’s defense machineries for survival: a tale of immune evasion. in Molecular Biology of Kinetoplastid Parasites. Ed. Majumder, H.K., pp 107-120, Caister Academic Press, Norfolk, UK. .

16. List of invited lecture:

• Delivered motivational lecture at Jhargram Raj College, Government of West Bengal on “Women in

Charge: Breaking through barriers” at 28th February, 2020.

• Delivered motivational lecture at JBNSTS, Kolkata on “Infection, Disease and Immunity: Crises and the savior!!! at 30th March, 2018.

• Delivered Invited lecture at IISER, Kolkata on “You can do it“, My journey as a women and a researcher...” on the occasion of International Women’s Day celebration at 8th March, 2018.

• Delivered Invited lecture at Second Annual Meeting on “Infectious Diseases” organized by Centre for

Infectious Disease Research (CIDR) on 23rd November, 2017 at IISC on “Suppresion of host defence responses through PGE2 dependent cAMP signaling during infection by the protozoan parasite Leishmania donovani “

• Delivered A.N. Bhaduri Award lecture by Society of Biological Chemists (SBC) India at the 86th SBC annual meeting held on JNU, New Delhi on 16th Nov, 2017 on “Taking control: Hijacking of host defense mechanism by the unicellular protozoan parasite Leishmania donovani “

• Delivered invited lecture at Refresher Course in Biotechnology at the department of Biotechnology, University of Calcutta on The Immune System: Orders and Disorders” on 13th Nov, 2017

• Delivered invited lecture at T.H.K. Jain College in the Department of Microbiology for the under-graduate students on “Understanding The Immune System: Orders and Disorders” on 1st Nov, 2017

• Delivered invited lecture at “Microbiology in the new Millennium: from Molecules to Communities (MNM 2017)” Kolkata organized by Bose Institute on 27th-29th October, 2017 on “Role of lipid mediator in modulation of host defence by the protozoan parasite Leishmania donovani”.

• Delivered invited lecture at Mini Symposium on Host Parasite Relationship under INDO-TRIT Networking project in the frame of the Indo-Belgian Research and Technology Cooperation at Floatel, Kolkata (organized by CSIR-IICB) on 6th and 7th February, 2017 on “Neutralization of macrophage defense machinery by Leishmania parasites”.

• Delivered invited lecture at Jagadis Bose National Science Talent Search (JBNSTS), Kolkata for the Inspire

Internship Science Camps on “Immune System: Diseases, Disorders & Function” on 07.02.2017.

• Delivered invited lecture at Indo- Brazil Symposium on the Biochemistry of Kinetoplastid Parasites held at CSIR-Indian Institute of Chemical Biology (CSIR-IICB), Kolkata on september 19 and 20, 2016 on

“Inside story! Hacking of macrophage host defense by Leishmania parasites”.

• Delivered invited lecture at Jagadis Bose National Science Talent Search (JBNSTS), Kolkata for the Inspire

Internship Science Camps on “How we defend ourselves against intruding pathogens: Our own immune system” on 19.03.2016.

• Invited lecture delivered at Dinabandhu Mahavidyalaya, Bongaon , on 27th August, 2015.

• Motivational lecture delivered at DST-INSPIRE Internship Science Camp, organized by Jagadis Bose National Science Talent Search (JBNSTS), on 24thJuly, 2015.

• Professor B.K. Bachhawat Young Scientist Award Lecture (NASI) delivered on 26thMarch, 2015 at the Bose Institute, Kolkata.

• Invited lecture delivered at Molecular Immunology Forum on 16thJanuary, 2015 in the Institute of Life Sciences, Bhubaneswar.

• Invited lecture delivered at Molecular Immunology Forum on 9thJanuary, 2014 in Bose Institute, Kolkata.

• Delivered invited plenary talk at IMMUNOCON 2013, organized by Indian Immunological Society in Delhi from November 15-17, 2013 on “Leishmania donovani Negatively Regulates TLR4 Mediated Host Response by Preventing Ubiquitination Dependent Degradation of TRAF3.

• Invited lecture on “The Emerging World of RNA: Paradigm Shift in Modern Biology” in Ramkrishna Mission Vidyamandira, Belur, on 29thSeptember, 2010.

• Invited lecture on “Macrophage signaling in host defense: a pivotal regulator of immunity and pathogenesis”in St. Xavier’s college on 6thOctober, 2010.

17. GENERAL AREA OF SCIENTIFIC INTEREST

During my research career, I tried to address fundamental issues pertaining to macrophage biology that have provided conceptual leads towards identification of novel and effective chemotherapeutic targets and formulations of better therapy against macrophage-associated diseases. I have used visceral leishmaniasis (VL) as model macrophage disease caused by the protozoan parasite, Leishmania donovani. In order to establish infection, intra-macrophage pathogens need to inhibit complex host defense signal transduction pathways culminating in the production of robust defence parameters including inflammatory cytokines, reactive oxygen and nitrogen species, inflammasome formation and apoptosis. I am trying to identify the key molecules and steps of macrophage signaling pathways manipulated by Leishmania donoveni during various phases of infection to ensure their successful survival and replication. My research group is primarily interested in

1. Identifying molecular events associated with the early phase entry of the parasite inside the host macrophages.

Toll-like receptors (TLRs), which recognize pathogen-associated molecular pattern (PAMP), are the means for first line of host defense leading to pathogen clearance via enhanced pro-inflammatory response. However, this potent defense mechanism of the host cell puts strong selective pressure on Leishmania parasites, which have, in turn, evolved strategies to modulate the host TLR signaling cascade in their own favor. I tried to elucidate the molecular mechanisms associated with this down-regulation of TLR4 pathway in L. donovani infection and identified that the key molecule associated with this event is tumor necrosis factor receptor–associated factor (TRAF) 3, a negative regulator of TLR pathway (Gupta et al., FASEB J, 2014, 28: 1756-1768.). Apart from TLR, another important host defense mechanism is to produce reactive oxygen species (ROS) to eliminate the pathogens. Our research showed that Leishmania inhibited mitochondrial ROS to neutralize inflammasome activation (Gupta et al., FASEB J, 2017, 31: 5087-5101) and activate anti-oxidant enzyme heme oxygenase 1 (HO-1), which by degrading heme prevents maturation of major macrophage

ROS producing enzyme NADPH oxidase (Saha S et al, J Immunol, 2019, 202:827-840)

2. Identifying late phase host modulators exploited by the parasite for their successful survival and replication inside the hostile macrophage environment.

After initial entry and down-regulation of immediate host activation, Leishmania needs specific molecules that are either secreted by it or may activate macrophages to produce immunosuppressive molecules that render the host defense inactive. Our study showed that late phase parasite survival requires PGE2, a lipid mediator, which mediates its action by cAMP-dependent pathway and we have substantiated this hypothesis by both in vitro and in vivo inhibitor-based approach (Saha et al., J. Immunol, 2014, 193: 2330-2339). Furthermore, we have recently shown that the cAMP dependent pathway-mediated immunomodulation during infection by Leishmania is primarily executed through cAMP dependent protein kinase A (PKA), which consists of catalytic subunits C1 and C2 and regulatory subunits RI and RII. Specific substrate targeting of PKA is achieved by binding with scaffold proteins AKAP (A kinase-anchoring protein). Our detailed experimentation on the screening as well as the role of major AKAP proteins led to the observation that specific AKAPs associate with PKA during infection and revealed that Leishmania-induced immunosuppression was mediated by AKAP8-anchored PKA-RII for inflammatory cytokines and AKAP10-anchored PKA-RI subunit for inflammatory chemokines (Saha et al., communicated…..).

3. Identifying anti-apoptotic proteins used by the parasite to subvert macrophage apoptotic machinery, thus establishing its replicative

niche inside the host.

One of the major host defense mechanisms against intra-macrophage pathogens is to facilitate pathogen clearance by apoptosis of the host cells. Conversely, pathogen tries to save its niche for replication and multiplication and thus critically turn off the host apoptotic machinery for the same purpose. Our study revealed that Leishmania parasite employs suppressor of cytokine signaling (SOCS) group of proteins to subvert macrophage apoptotic machinery through participation of thioredoxin and protein tyrosine phosphatase (PTP) (Srivastav et al., J. Biol. Chem. 2014, 289:1092-105). Subsequently we identified host protein myeloid cell leukemia 1 (MCL-1), which plays an important role in inhibiting mitochondria-dependent macrophage apoptosis. Our detailed work has shown that infection by Leishmania induced translocation of MCL-1 to mitochondria, where it interacts with the major pro-apoptotic protein BAK and prevents BAK-BAK homo-oligomer formation thereby preventing cytochrome c release mediated mitochondrial dysfunction. (Giri et al., J. Biol. Chem, 2016, 291, 3496-3507).

4. Identification of a single macrophage regulatory protein which prevents both immune activation and apoptosis, essential for parasite survival.

Leishmania parasite dampens host defense mechanisms by regulating various parameters starting from modulation of cytokine and reactive oxygen and nitrogen species responses to inhibition of apoptosis. To modulate these various parameters it seemed appropriate for the parasite to take use of a master regulator thereby securing its niche with minimum effort. In our search for such a regulator, we came across with the identification of PI3K modulated AKT, whose role seems to be multifaceted. Leishmania exploits the master regulator AKT signalling in its favour by GSK-3β-mediated activation of β-catenin, an anti-apoptotic transcription factor, in one hand and by directly inactivating FOXO-1, a pro-apoptotic pro-inflammatory transcription factor, on the other hand thereby frustrating host cell defense (Gupta et al., Cell Death Differ. 2016, 23: 1815-1826).

5. Role of immunomodulators as an intervention therapy.

By way of immunomodulation therapy we have already shown the effective role of curdlan, a naturally occurring herbal immunomodulator that could completely cure experimental VL through significantly enhanced production of NO. Along with induction of disease-resolving Th1 cytokines, curdlan stimulates the production of IL-23, which helps in the stabilization and differentiation of Th17 cytokine, IL-17 (Ghosh et al., 2013, J. Infec. Dis, 207: 1016–1025). Our work also led to developing18β-glycyrrhetinic acid, a pentacyclic triterpene of licorice root, as highly effective anti-leishmanial agent, which has strong immunomodulatory potential for its use in general for macrophage-associated diseases (Gupta et al., 2015, Antimicrb. Agents Chemother. 59: 2531–2539; Ukil et al., PLoS ONE, e29062, 2011; Ukil et al., J. Immunol. 175: 1161-1169, 2005).

Our work thus provides important insights into the molecular mechanisms of how pathogens modulate macrophage defense signalling pathways to survive in phagocytes. Deciphering this intricate survival mechanism Leishmania has devised to frustrate the host defense system is a crucial contribution not only in understanding the biology of Leishmania but also suggests innovative target to arrest the infection process.

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