K. Natarajan


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. 1. 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).

  2. 2. Sharma D., B.K. Tiwari, S. Mehto, C. Antony, G. Kak, Y. Singh and K. Natarajan. 2016. Suppression of protective responses upon activation of L-type Voltage Gatwd Calcium Channel in macrophages during Mycobacterium bovis BCG infection. PLoS One 11(10). e0163845.

  3. 3. Mehto, S., Antony, C., Khan, N., Arya, R., Selvakumar, A., Tiwari, B.K. Vashishta, M., Singh, Y., Jameel, S., & Natarajan, K. (2015). Mycobacterium tuberculosis and human Immunodeficiency virus type 1 cooperatively modulate macrophage apoptosis via Toll Like receptor 2 and calcium homeostasis. PLoS One 10(7), e0131767.

  4. 4. Vashishta, M., Khan, N., Mehto, S., Sehgal, D., & Natarajan, K. (2015). Pneumococcal surface protein A (PspA) regulates programmed death ligand 1 expresion on dendritic cells in a Toll-Like receptor 2 and calcium dependent manner. PLoS One 10(7), e0133601.

  5. 5. Chadha, A., Mehto, S., Selvakumar, A., Vashsita, M., Kamble, S.K., Popli, S., Raman, R., Singh, Y., & Natarajan, K. (2015). Suppressive role of neddylation in dendritic cells during Mycobacterium tuberculosis infection. Tuberculosis (Edin.) 95, 599-607.

  6. 6. Pandey, S., Singh, S., Anang, V., Bhatt, A.V., Natarajan, K., & Dwarakanath, B.S. (2015). Pattern Recognition Receptors in Cancer Progression and Metastasis. Cancer Growth and Metastasis 8, 25-34.

  7. 7. Selvakumar A., C Antony, J Singhal, BK Tiwari, Y Singh and K. Natarajan 2014. Reciprocal regulation of reactive oxygen species and phosphor-CREB regulates voltage gated calcium channel expression during Mycobacterium tuberculosis infection. PLoS One 9(5): 96427

  8. 8. Singhal J., N Agrawal, M Vashishta, N G Priya, B K Tiwari, Y Singh, R Raman and K. Natarajan 2012. Suppression of dendritic cell mediated responses by genes in the calcium and cysteine protease pathways during Mycobacterium tuberculosis infection. J. Biol. Chem. 287: 11108-11121.

  9. 9. Srivastava, V, M Vashishta, S Gupta, R Singla, N Singla, D behera and K. Natarajan. 2011. Suppressors of cytokine signaling inhibit effector T cell responses during Mycobacterium tuberculosis infection Immunol. Cell Biol. 89: 786-791.

  10. 10. Gupta D, S Sharma, J Singhal, A T Satsangi, C Antony and K Natarajan. Suppression of TLR2 Induced Interleukin-12, Reactive Oxygen Species, Inducible Nitric Oxide Synthase Expression by Mycobacterium tuberculosis Antigens Expressed Inside Macrophages During the Course of Infection. J. Immunol 184: 5444-5454,2010.