NON-COMMUNICABLE DISEASES / Immunology
Research Interests
Adaptive immunity to Mycobacterium tuberculosis, Vaccine formulation against Tuberculosis, T cell biology, Immunotherapy for Tuberculosis.
Description of Research
The lab mainly focuses on understanding the host protective immunity against Tuberculosis (TB) specifically adaptive immunity. The only TB vaccine available, BCG, fails to provide protection in adult pulmonary Tuberculosis since it not only induces protective immunity but also induces other responses, which are involved in pathogenesis. As T helper cell subsets are cross regulatory, the resultant protective responses induced by BCG are inadequate for host resistance. Thus, an ideal vaccine should not be a whole organism but should consist of Mycobacterium tuberculosis (the causative agent of TB, M.tb) derived antigens/epitopes that can selectively induce protective responses. A variety of recently designed vaccines, including subunit, and DNA vaccines, may induce protective responses, but these are delivered through conventional routes, which generate protective immune responses in the periphery but not in lung. In addition, mucosal sites are generally immunotolerant, and thus T cells that migrate to mucosal sites acquire tolerance. Consistent with this notion, M.tb mostly colonizes in the mucosal/Immunotolerant sites, such as lung and intestine. Therefore, conventional strategies for the generation of the immune response may not yield an effective TB vaccine. We are engaged in the development of new vaccines for TB by using a novel approach that can induce the host protective immune responses at the local site of infection, i.e. the lung. We are planning to generate a mimic of M.tb, which can be potentially immunogenic in the lung and that can be delivered directly into the lung and generate protective long-lasting immunity.
The lab is also involved in understanding the factors and mechanism involved in the migration of T cells from blood vasculature to lung parenchyma during TB pathogenesis. These factors will be further studied for their ability to modulate the protective immune responses during M.tb infection.
Another aspect of our research is to enhance existing TB therapy using various immunomodulatory compounds as adjunct therapeutics.
The Group has recently generated and patented an immunogenic complex against Mycobacterium tuberculosis, consisting of promiscuous T cell epitopes and TLR ligands which significantly enhance the BCG vaccine efficacy (Life Sciences 2020; JCI Insight, 2021). We have also shown that various bioactive phytochemicals/immunomodulators could be employed as an adjunct therapy together with traditional anti-tuberculosis therapy (J Biol Chem. 2019; J Ethnopharmacol. 2019; Int Immunopharmacol. 2020; Front Immunol. 2021; Meddcom, 2021).
Use of novel immunomodulators as an adjunct therapy against TB. As an immunomodulator, Bergenin activates MAPK signaling pathways in the macrophages leading to the induction of NF-κB, which in turn results in the expression of protective pro-inflammatory cytokines and iNOS. The NO thus produced mediates the killing of intracellular mycobacteria and the pro-inflammatory cytokines activate Th cells, which mediates further protection.
Recent Publications
Kumar, S., Sharma, C., Kaushik, S.R., Kulshreshta, A., Chaturvedi, S., Nanda, R.K., Bhaskar, A., Chattopadhyay, D., Das, G., Dwivedi, V.P. 2019. The phytochemical bergenin as an adjunct immunotherapy for tuberculosis in mice. J Biol Chem 24, 8555-8563 PubMed link
Dwivedi, V.P., Bhattacharya, D., Yadav, V., Singh, D.K., Kumar, S., Singh, M., Ojha, D., Ranganathan, A., Van Kaer, L., Chattopadhyay, D., Das, G. 2017. The phytochemical bergenin enhances T helper 1 responses and anti-Mycobacterial immunity by activating the MAP kinase pathway in macrophages. Front Cell Infect Microbiol 7, 149 PubMed link
Singh, D.K., Dwivedi, V.P., Ranganathan, A., Bishai, W.R. Van Kaer, L., Das, G. 2016. Blockade of the Kv1.3 K+ channel enhances BCG vaccine efficacy by expanding central memory T lymphocytes. J Infect Dis 214, 1456-1464 PubMed link
Bhalla, K., Chugh, M., Mehrotra, S., Rathore, S., Tousif, S., Dwivedi, V.P., Prakash, P., Samuchiwal, S.K., Kumar, S., Singh, D.K., Ghanwat, S., Kumar, D., Das, G., Mohmmed, A., Malhotra, P., Ranganathan, A. 2015. Host ICAMs play a role in cell invasion by Mycobacterium tuberculosis and Plasmodium falciparum. Nature Commun 6, 6049 PubMed link
Rahman, M.A., Sobia, P., Dwivedi, V.P., Sharma, P., Moodley, P., Van Kaer, L., Bishai, W.R., Das, G. 2015. Mycobacterium tuberculosis TlyA negatively regulates Th1 and Th17 differentiation and promotes tuberculosis pathogenesis. J Biol Chem 290, 14407-17 PubMed link
Bhattacharya, D., Dwivedi, V.P., Kumar, S., Reddy, M.C., Van Kaer, L., Moodley, P., Das, G. 2014. Simultaneous inhibition of T helper 2 and T regulatory cell differentiation by small molecules enhances Bacillus Calmette-Guerin vaccine efficacy. J Biol Chem 289, 33404-11 PubMed link
