K. Natarajan

Sr. Professor

Infectious Disease Immunology lab
Email: krishnatraj@gmail.com

In an effort to decipher the immune responses to mycobacteria, our group has been characterizing the interactions of M. tuberculosis with key players of the innate immune system including dendritic cells (DCs), macrophages and the effects thereof on regulating effector T cell responses. We have earlier demonstrated that many M. tuberculosis antigens strategically induce differentiation of DCs that induce suppressor responses to mycobacteria by downregulating the expression of pro-inflammatory cytokines and chemokines. This leads to poor recruitment and activation of antigen specific T cells leading to the induction of suppressor responses. These DCs also serve as depots for mycobacterial multiplication and survival by down-modulating oxidative burst and interfering with the activation status of key intracellular signaling molecules. Conditioning antigen differentiated DCs with pro-inflammatory chemokines and cytokines leads to effective clearance of an established M. tuberculosis infection in vivo in mice. Differential triggering of protective and inhibitory receptors on DCs and macrophages govern cytokine responses during M. tuberculosis infection by induced expression and selective recruitment of SOCS1 to the receptors that lead to defective clearance of the pathogen from macrophages. In addition, M. tuberculosis indeed expresses antigens as a function of infection, that employ different and yet complementary mechanisms to keep the immune responses suppressed thus contributing to long-term establishment of infection. A key feature that regulated the above responses was calcium mobilization in infected cells. By deciphering calcium homeostasis in infected cells we have developed a new approach to treating multiple and extensively drug resistant M. tuberculosis infections in mice and guinea pigs. Using RNA interference, we identified specific genes in the calcium-calmodulin and cysteine protease pathways that play a regulatory role in mediating immune responses and survival of M. tuberculosis inside dendritic cells.

Further characterization of calcium homeostasis revealed that it fine tunes protective responses to HIV-Mycobacterium tuberculosis co-infections and Streptococcus pneumonia infections. Differential influx and efflux of Calcium played a contrasting role in regulating protective responses in a Toll-Like Receptor-2, ROS and the transcription factor CREB dependent mechanism. We identified, for the first time, the role of Neddylation during Mycobacterium tuberculosis infections. We identified Rv3529c, an antigen that bears homology to the death domain of TLR intermediate MyD88. Incubation of macrophages with Rv3529c attenuates TLR2 signaling with determinant effects of defense responses and bacterial burden.

Ongoing Projects:

1. 1. Deciphering macrophage functions during human immunodeficiency virus and mycobacterium tuberculosis co-infection. (Funded by DBT)
   
   
2. 2. Deciphering the role of Neddylation dendritic cell activation during Mycobacterium tuberculosis infection by RNA interference. (Funded by DBT)
   
   
3. 3. Investigations into chemokine and chemokine receptors levels in macrophages following Mycobacterium tuberculosis antigenic challenge: role of calcium and Toll Like Receptors. (Funded by DU)
   
   

Selected Recent Publications:

1. 01. Singh, A., Singh, A., Saraswati, S. S. K., Rana, A. K., Singh, A., Verma, C., Sinha, V., Kalra, K., & Natarajan, K. (2024). Suppressive effects of Toll-Like Receptor 2, Toll-Like Receptor 4, and Toll-Like Receptor 7 on protective responses to Mycobacterium bovis BCG from epithelial cells. Microbes and infection, 105428. Advance online publication. https://doi.org/10.1016/j.micinf.2024.105428
   
   
2. 02. Sinha V, Singh A, Singh A, Saraswati SSK, Rana AK, Kalra K, Natarajan K. Potassium ion channel Kir2.1 negatively regulates protective responses to Mycobacterium bovis BCG. J Leukoc Biol. 2024 Sep 2;116(3):644-656. doi: 10.1093/jleuko/qiae068. PMID: 38489665.
   
   
3. 03. Rana AK, Kumar Saraswati SS, Anang V, Singh A, Singh A, Verma C, Natarajan K. Butyrate induces oxidative burst mediated apoptosis via Glucose-6-Phosphate Dehydrogenase (G6PDH) in macrophages during mycobacterial infection. Microbes Infect. 2024 Mar-Apr;26(3):105271. doi: 10.1016/j.micinf.2023.105271. Epub 2023 Nov 29. PMID: 38036036.
   
   
4. 04. Anang V, Singh A, Kumar Rana A, Saraswati SSK, Bandyopadhyay U, Verma C, Chadha A, Natarajan K. Mycobacteria modulate SUMOylation to suppresses protective responses in dendritic cells. PLoS One. 2023 Sep 29;18(9):e0283448. doi: 10.1371/journal.pone.0283448. PMID: 37773921; PMCID: PMC10540951.
   
   
5. 05. Pandey S, Anang V, Singh S, Seth S, Bhatt AN, Kalra N, Manda K, Soni R, Roy BG, Natarajan K, Dwarakanath BS. Dietary administration of the glycolytic inhibitor 2-deoxy-D-glucose reduces endotoxemia-induced inflammation and oxidative stress: Implications in PAMP-associated acute and chronic pathology. Front Pharmacol. 2023 May 10;14:940129. doi: 10.3389/fphar.2023.940129. PMID: 37234710; PMCID: PMC10206263.
   
   
6. 06. Saraswati SSK, Rana AK, Singh A, Anang V, Singh A, Natarajan K. HSP-27 and HSP-70 negatively regulate protective defence responses from macrophages during mycobacterial infection. Microbes Infect. 2023 Jul-Aug;25(6):105126. doi: 10.1016/j.micinf.2023.105126. Epub 2023 Mar 16. PMID: 36931492.
   
   
7. 17. Singh A, V Anang, C Verma, SS Saraswati, U Bandhyopadhyaya, AK Rana, A Chadha and K Natarajan. 2021. Bcl2 negatively regulates protective responses during mycobacterial infection. Biomolecular Concepts12: 94-109
   
   
8. 08. Kak G., Tiwari B.K., Singh Y. and Natarajan K. 2020. Regulation of Interferon-? receptor (IFN-?R) expression in macrophages during Mycobacterium tuberculosis infection. Biomol. Concepts. 11: 76-85
   
   
9. 09. Singh A., Anang A., Rana A.K., Verma C., Saraswati S.S.K., Kumari P., Singh A., and Natarajan K. 2020. Deciphering the role of calcium homeostasis in T cells functions during mycobacterial infection. Cell. Immunol. 357: 104198
   
   
10. 10. Verma C., Rana A.K., Anang V., Tiwari B.K., Singh A., Saraswati S.S.K., Shariff M. and Natarajan, K. 2020. Calcium Dynamics Regulate Protective Responses and Growth of Staphylococcus aureus in Macrophages. Biomol. Concepts. 11: 230-239
    
    
11. 11. Rana V,, S Popli, GK Saurav, K yadav A Kumar, S Sunil, N Kumar, OP Singh, K Natarajan and R Rajagopal. 2020. Aedes Aegypti Lachesin Protein Binds to the Domain III of Envelope Protein of Dengue virus-2 and Inhibits Viral Replication. Cellular Microbiology 22: e13200
    
    
12. 12. G Kak, BK Tiwari, Y Singh and K. Natarajan. 2020. Regulation of Interferon-? Receptor (IFN-?R) Expression in Macrophages During Mycobacterium Tuberculosis Infection. Biomolecular Concepts 11: 76-85
    
    
13. 13. Singh A, V Anang, A K Rana, C Verma, S S Toni, P Kumari, A Singh and K Natarajan 2020. Deciphering the role of calcium homeostasis during mycobacterial infection. Cellular Immunology 357: 104198
    
    
14. 14. Shweta S, G. Kumar, M. Vashishta, R. Pandey, S. Rathore, B.?K. Chourasia,J. Singhal, A. Deshmukh, Md KalamuddinG. Paul, A. Panda, S. Tatiya, K. Rawat, D. Gupta, A. Mohmmed, K. Natarajan and P. Malhotra. (2018) Biochemical characterization of Plasmodium complement factors binding protein for its role in immune modulation. Biochemical Journal 475: 2877-2891
    
    
15. 15. Bandyopadhyay U., A. Chadha, P. Gupta, B. T., K. Bhattacharyya, S. Popli, R. Raman, V. Brahamachari, Y. Singh, P. Malhotra, and K. Natarajan. 2017. Suppression of Toll Like receptor 2 Mediated Pro-Inflammatory Responses by Mycobacterium tuberculosis Protein Rv3529c. J. Leukoc. Biol. (In press).