BROAD RESEARCH FOCUS:Tuberculosis and acute lymphatic leukemia
Tuberculosis, caused by Mycobacterium tuberculosis (Mtb), is a serious human disease that infects one-third of the world’s population and kills more than 1.5 million people every year. The main reasons for downfall to curb Mtb infection are emergence of multidrug-resistant strains, lack of potent multi-target drugs, inadequate vaccine, and the ability of the pathogen to evolve mechanisms to avoid elimination by strong host immune responses. Our laboratory studies the molecular, genetical and immunological basis for mycobacterial pathogenesis and its interaction with host cells.
Mycobacterium Glycobiology
Mycobacterium tuberculosis (Mtb) glycoproteins play a critical role in host-pathogen interactions, antigenicity, and virulence determination, and are therefore, considered as potential drug and vaccine targets. The cell wall of Mtb dominantly contains sugars and lipids. Our recent In-silico analysis has predicted more than 200 glycoproteins and glycolipoproteins in Mtb cell wall. Using multilectin glyco-catch system we have identified several novel Mtb glycoproteins and glycolipoproteins. Now, we are trying to investigate the role of these glycoconjugates in host-pathogen interactions and modulation of host innate and adaptive immune responses using mice and zebrafish infection models. Some of these proteins were found to be highly antigenic in nature. We are also exploring them as potential drug and vaccine candidates.
Stem Cells
Mtb is evolved with plethora of evasion strategies against host immune responses. It is well established that alveolar macrophages are the primary infection sites for Mtb. However, recent studies have shown that Mtb can also infect and reside in bone marrow stem cells and use them as a safe niche to evade host immune responses. We are investigating the molecular mechanisms of Mtb dormancy in bone marrow stem cells and the implications of cross-talk between stem cells, macrophages and T-cells on the fate of Mtb infection.
Epigenetics
One of the prominent mechanisms employed by pathogenic bacteria to facilitate its survival in host cells involves induction of epigenetic modifications in the host DNA, histones and RNA. Mtb is known to induce several transcriptional activation and repression epigenetic changes to promote its replication, propagation and protection from host immune responses. However, very little is known about the dynamics and mechanisms of epigenetic changes during Mtb infection. Here, we are studying the molecular mechanisms of epigenetic modifications during Mtb infection and the effect of these modifications on macrophage, stem cells and T-cell immune functions.
Drug Delivery
Over the decades several anti-TB drugs have been developed, however, due to emergence of multidrug-resistant (MDR), extremely drug-resistant (XDR) and totally drug-resistant (TDR) Mtb strains most of these drugs became ineffective. Moreover, Mtb is an intracellular pathogen equipped with lipid rich cell wall. As a result most of the anti-TB drugs are not able to diffuse inside the Mtb cell wall to achieve effective killing. To overcome these challenges, we are synthesizing small compounds, antimicrobial peptides and delivering them at target sites using engineered nanocarriers, quantum dots and MOFs.
Acute Lymphatic Leukemia
treatment (ALL)
Asparaginases are central to the treatment of acute lymphatic leukemia (ALL), a disease that affects lymphocytes and its precursor cells in the bone marrow. However, current asparaginase drugs show several severe side effects such as immunogenicity, neurotoxicity, low stability and low therapeutic efficacy in primary and relapsed ALL. Through the protein engineering approach, we have developed novel asparaginase molecules that show better therapeutic efficacy. Our preclinical and pharmacological studies in ALL patient samples and mice models showed that these novel asparaginase molecules exhibit low immunogenicity, neurotoxicity and high stability. Moreover, these molecules do not bind to pre-existing antibodies present in ALL patients suggesting that these asparaginases can also be used in the treatment of relapsed ALL. These novel asparaginase molecules showed improved In-vivo pharmacokinetic properties than the wild type and commercial asparaginases. Also, all the asparaginase molecules showed significantly improved therapeutic efficacy in NOD/SCID xenograft mice models without exerting any acute or chronic toxicity in-vivo. Now in collaboration with Tata Memorial Hospital, ACTREC, Mumbai and D.K.Biopharma Pvt Ltd., Mumbai Maharashtra industry partner we have started for scale-up and phase-I/II clinical trial in patients with ALL at GMP facility, for which we have got the funding from Early Translator Accelerator (ETA), BIRAC, New Delhi.
Protein S-palmitoylation
S-palmitoylation is an important class of protein lipidation in which a 16-carbon fatty acid attached to Cys residue of the substrate protein. S-palmitoylation is catalyzed by Palmitoyl acyl transferase (PAT). Here, we are exploring the role of S-palmitoylation in diseases biology via multi-omics approach to develop effective therapeutic strategies.
Biosensing using SPIONs
We are working on development of a novel platform for rapid TB diagnosis, based on the superparamagnetic iron oxide nanoparticles (SPIONs) coupled with mycobacterium specific antibodies as a recognition element for detecting the Mycobacterium antigen with a fluorescence read out. Due to their unique magnetic and optical characteristics, such as high paramagnetism, low magnetic coercivity, and high Curie temperature, SPIONs show favorable characteristics compared to other types of magnetic nanocarriers. Magnetic properties of the SPIONs were also employed for the development of the contrast agents for the magnetic resonance imaging (MRI). Therefore, we are hopefull about developing a SPIONs based novel anti-tubercular MR contrast biosensor.