Research Groups
Mammalian Biology: Immunology
Research Interests and Description
Staff Research Scientist: Gobardhan Das
Group Leader: Kanury V.S. Rao
Group MembersResearch 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 host’s immune responses. 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 Th1 to Th2 phenotype. In susceptible mice, Th2 response is mounted which inhibit 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 the 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 is prevailed 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 recently 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 its 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. The three specific goals are: (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.
