The overall objective our laboratory is to understand biological responses to different stimuli. For this purpose, we utilize microbial systems as well as the host encoded immune system. Over the years, we have established a diverse array of models and expertise that help us to understand the roles of various genes and signals in modulating microbial and host encoded responses. Broadly, the twin areas of interests of our laboratory are:
A) Studying novel microbial genes during stress and infection
Cytosolic protein degradation is important for regulation of several cellular processes and can be divided into two parts: ATP-dependent and ATP-independent. Giant enzymes known as proteasomes are required for the majority of cytosolic protein degradation in eukaryotes. Several years back, our laboratory identified Peptidase N (PepN), the sole M1 family member in E. coli and S. typhimurium to be a major aminopeptidase. Over the years, we have studied the roles of this enzyme during stress and infection, using a combination of genetics, microbiology, biochemistry and immunology.
Some aspects of structure-functional relationship of PepN with respect to its biochemistry and function and roles of other proteases and peptidases during stress responses are on going. However, the emphasis now will be on functional roles of novel genes during stress responses and infections.
B) Understanding the host encoded immune responses
There are two subordinate areas under this heading.
T cell biology:
T cells are required for cellular immunity and play key roles during the adaptive immune response. Host immunity is greatly compromised if CD4+ T cells are absent or lowered, as seen in AIDS patients. We have established a primary CD4+ T cell culture system and can modulate their activation (low versus high) using different stimuli, e.g. anti-CD3 stimulation, combinations of a phorbol ester and different amounts of Ionomycin etc. This is, in essence, known as the strength of signal. Efforts are geared towards studying the mechanistic aspects, especially the roles of different species of free radicals, in modulating T cell responses. In addition, we are studying the roles of small molecules in modulating CD4+ T cell activation and survival and attempting to understand their mechanism/s of action. As far as in vivo T cell responses are concerned, we have shown the role of heat killed Mycobacterium indicus prannii (an adjuvant) in inducing anti-tumor T cells to reduce tumor growth.
T cell differentiate in the thymus and the loss of thymocytes resulting in thymic atrophy, is known to occur during many infections. We have standardized a model of thymic atrophy using a model of oral infection by Salmonella enterica serovar Typhimurium, an intracellular pathogen. We are studying multiple aspects during this process, including, expression of cell surface markers, death markers, the roles of different signalling pathways etc. The mechanistic insights uncovered in this study may be important in designing effective strategies to reduce thymic atrophy during infections. This aspect is important as enhancement of thymic output will increase the numbers and diversity of thymic T cell emigrants in the periphery to boost host responses during infections.
Inflammatory and Interferon-gamma modulated responses:
Inflammation is important for host defense; however, too much of it is harmful as it can cause immunopathology, resulting in harm to the host. A key cytokine involved is Interferon-gamma (IFN-gamma) which is produced mainly by activated T cells and NK cells. Humans lacking IFN-gamma or its receptors are extremely susceptible to infections by intracellular pathogens, e.g. Mycobacterium tuberculosis, S. typhimurium etc. Our laboratory has been studying the roles of IFN-gamma and shown the roles of oxidative and nitrosative stress in modulating the expression of IFN-gamma-regulated genes. We have now extended this study to macrophages and are attempting to identify novel IFN-gamma regulated genes and responses that are modulated by Nos2. Current efforts are also directed towards understanding the expression and roles of novel IFN-gamma-regulated genes in cell growth suppression and modulation of intracellular growth of Salmonella enterica serovar Typhimurium.
Overall, our laboratory works at the interface of microbiology and immunology.
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