CDFD :: Molecular Cell Biology

Broad Research Area:

Molecular dissection of the changes in innate and adaptive immune responses signaling networks of the host by invading pathogens and/or stress.

The activation of macrophage leads to production of a wide range of inducible gene products that are essential in developing innate and subsequent acquired immune phenotypes like T helper type 1 (Th1) or Th2 responses. The major goals of our laboratory encompass from understand ing the cell signaling networks that are important for macrophage activation to elucidating how expression of various genes are modulated during various pathophysiological conditions leading to establishment of diseased states using state of the art molecular biology procedures like recombinant DNA technology, yeast two hybrid system, proteomics and immunological techniques. In particular, we are looking at the immunomodulation during tuberculosis and stress. These studies are intended to develop novel immunomodulatory drugs with therapeutic potential against tuberculosis and other health problems like ageing and cancer. Our main research interests include,

The free radicals like nitric oxide (NO) and reactive oxygen species (ROS) and their by-products cause oxidative damage of cellular components like lipids, proteins, DNA, and eventually leads to cell death. Despite the well known activity of NO/ROS in antibody independent cellular cytotoxicity, the effect of excess NO/ROS in modulating the homeostasis of the immune system is not well documented. Our studies for the first time provide evidence that, free radicals can act as secondary signaling cues that can modulate macrophage effector functions and adaptive immune response of the host. We have demonstrated that these molecules could target the calmodulin-c-rel signaling cascades to subsequently inhibit interleukin-12 (IL-12) induction in activated macrophages. Production of free radicals is known to be a primary defensive mechanism elicited by the host because of their potent cytotoxicity on pathogens and considered to be an important component of the innate immunity. However, our work clearly highlights that excess free radicals produced under certain pathophysiological conditions actually can surpass their beneficial role to cause immunosuppression thus preventing desirable forward amplification of the defensive immune responses and may favor survival of intracellular pathogens and/or cause other problems like ageing and neoplasia.

We are currently studying alterations of macrophage effector and APC functions by NO/ROS and cell signaling pathways involved in such modulations. Also we are studying the immunore-gulatory role of NO/ROS during stress and infection (tuberculosis). Since NO/ROS cause for senescence associated losses in physiological functions including the immune system, a research in this area is likely to help us designing effective interventions for improving deteriorated immune functions in elderly people or people exposed to chronic oxidative stress during infection (tuberculosis).

Tuberculosis (TB) is declared a global emergency by the WHO, the first disease to be so desig-nated which kills about 3 million people a year. The bacillus Mycobacterium tuberculosis re-mained the leading cause of mortality in the world, even when we are entering into the new millennium of technical and medical excellence. An extremely resilient cell wall, very slow growth, highly contagious nature and a number of cunning strategies adopted by the pathogen to evade host immune attack make it one of the least tractable organisms to work with. The rapid spread of tuberculosis in AIDS patients and emergence of multidrug resistant strains renders the situation still grave. The bacterium has a very sophisticated signal transduction systems and potentialities to adapt into a variety of hostile environments. There have been extensive attempts worldwide to identify the mycobacterial components that have an important role in the establishment of the infection. But till date only little information is available regarding the molecular basis of mycobacterial virulence. Development of vaccines is getting hampered because of the facts that the host-bacilli interactions and molecular basis of pathogen invasion are not well understood yet. Identification and functional characterization of the set of genes expressed by the M. tuberculosis bacilli during interaction with macrophage will be helpful to increase our understanding of pathogenic mechanisms that result in disease and may provide insights into potential vaccine strategies and novel drug targets.

The macrophage mediates the first line of defense in the host. The M. tuberculosis bacilli play various strategies to suppress the macrophage-innate effector and APC (antigen presenting cell) functions and use the host's defense weapon as its comfortable home. In various projects we are approaching to identify and characterize the mycobacterial ORFs/proteins that enable the bacilli to survive and multiply within the macrophages. We also approach to identify the down-stream signal transduction pathways in macrophages modulated during TB infection, which is important to understand how the bacterium invades the macrophage cells successfully and this work will provide new insights about the detrimental endogenous immune responses triggered by the mycobacterium bacilli and shed some light on the molecular basis of pathogenesis of this dreadful pathogen. We have demonstrated that some of the candidate PE/PPE family proteins are involved in the pathogenesis of tuberculosis (filed USA Patent-1, 2008) and thus constitute potent drug targets.

In the area of tuberculosis diagnosis, it is important to identify suitable antigens that can differentiate active tuberculosis patients from BCG-vaccinated individuals. Since many PE/PPE proteins are present only in the pathogenic mycobacteria like M. tuberculosis and few of these are found to be overexpressed in macrophages during infection, it is possible that these proteins are highly sensitive to detect patients with active tuberculosis. We have identified one candidate protein which displays stronger and specific immunoreactivity against the sera obtained from clinically active TB patients compared to PPD, ESAT-6 and hsp60 and could differentiate TB-patients from the BCG-vaccinated controls (filed USA Patent-2, 2008). We are interested to identify potent markers that can be used to differentiate active tuberculosis patients from BCG-vaccinated individuals since currently used Mantoux test cannot distinguish such differences reliably.

Our long-term aspiration is to develop suitable therapeutic interventions to control diseases like tuberculosis and aging to eradicate human sufferings.