Research Groups

Mammalian Biology: Immunology

Research Interests and Description

Staff Research Scientist: Gobardhan Das, PhD

Research Interests

Mycobacterium tuberculosis, T cell responses, innate immunity, pathogenesis.

Description of Research

M. tb invades, survives, and replicates within the mononuclear phagocytes of susceptible hosts by evading the host’s immune responses. The neutralization of lysosomal acidic environment, and inhibition of phagosome-lysosome fusion are the key modifications engineered by this intracellular pathogen for avoiding destruction by phagocytes. The hallmark of mycobacterial infection is the alteration of the balance of T helper (Th) cell responses from the Th1 to Th2 phenotype. In susceptible mice, a Th2 response is mounted, which inhibits protective Th1 responses during the progression of the disease. Thus, the pathogenic tuberculoid organisms survive and replicate unhindered within the susceptible hosts. On the other hand, resistant hosts are invulnerable to modification engineered by mycobacteria, thus, a Th1 response is mounted and the mycobacteria are eliminated from the body. Previously, we have shown that M. tb alters the expression of co-stimulatory molecules to ensure that the state of anergy occurred in a protective Th1 cell. Thus, a biased Th2 response prevails in susceptible hosts. Further studies show that mycobacteria inhibit IL-12 production in macrophages, a key cytokine required for the generation of Th1 cells. Soluble factors direct the differentiation of T regulatory (Tr) cells, which inhibit cellular immune responses. We have demonstrated that innate like lymphocytes (ILLs), such as NKT cells and MHC class Ib restricted CD8+ T cells, are involved in the polarization of Th1/Th2 responses. On the other hand CD8+ ILLs that are restricted by MHC class Ib molecules produce an early burst of IFN-γ that helps in the differentiation of Th1 cells, and play a critical role in the initiation and progression of type I autoimmune diseases, namely type I diabetes and inflammatory bowel disease.
Immunomodulation of adaptive immune responses in tuberculosis infection is initiated and directed by the infected macrophages. Macrophages recognize pathogens through toll like receptors (TLRs), which bind pathogen- associated molecular pattern (PAMP). Thus, this pathway plays a critical role in the initiation of disease, an area, which has not been explored in depth. Our aim is to study the role of TLRs in the modulation of innate and adaptive immune responses during the mycobacterial infection to (i) evaluate the role of TLR mediated signaling in the modulation of innate immune responses during mycobacterial infection; (ii) study the potential role of innate like lymphocytes in mycobaterial infection in presence and absence of TLR signaling, and (iii) study the role of Th17 in tuberculosis infection in animal models.
In parallel, we are also investigating the molecular basis of susceptibility and resistance in murine models of tuberculosis. It is well known that helper T (Th) cell subsets play a central role in the outcome of TB pathogenesis. While Th1 and Th17 cells confer resistance, Th2 and T regulatory cells enhance disease progression. However, the precise activity of these subsets of Th cells during the progression of infection has not been well studied. We are investigating the activity of different Th subsets in reporter knock-in and knock-out animals and their co-relation with disease progression.

Recent Publications

Chatterjee, S., Prakash, V., Dwivedi, Vora, H., Siddiqui, I., Kumar, P., Sharma, P., Van Kaer, L., Das, G. 2011. Early Secreted Antigen ESAT-6 of Mycobacterium tuberculosis Promotes Protective T Helper 17 Cell Responses in a Toll-Like Receptor-2-dependent manner. PlosPathogens In Press

Kumar, P., Agarwal, R., Siddiqui, I., Vora, H., Das, G., Sharma, P. 2011. ESAT6 differentially inhibits IFN-γ-inducible class II transactivator isoforms in both a TLR2-dependent and -independent manner. Immunol Cell Biol doi: 10.1038/icb.2011.54. [Epub ahead of print] PubMed link

Tousif, S., Singh, Y., Van Kaer, L., Das, G. 2011. Programmed Death-1-deficiency Exacerbates Mycobacterium tuberculosis Infection in Mice. PLoS One 6, 19864

Chandele, A., Mukerjee, P., Das, G., Ahmed, R., Chauhan, V.S. 2010. Phenotypic and functional profiling of malaria-induced CD8 and CD4 T cells during blood-stage infection of Plasmodium yoelii. Immunology 132, 273-286 PubMed link

Jayaswal, S., Kamal, A., Dua, R., Gupta, S., Majumdar, T., Das, G., Kumar, D., Rao, K.V. 2010. Identification of host-dependent survival factors for intracellular Mycobacterium tuberculosis through an siRNA Screen. PLOS Pathogen 6, e1000839 PubMed link

Raghuvanshi, S., Munnawar, A., Singh, S., Van Kaer, L., Das, G. 2010. Mycobacterium tuberculosis evades host immunity by recruiting mesenchymal stem cells. Proc Natl Acad Sci 107, 21653-21658 PubMed link