Infectious diseases are the leading causes of death of both humans and animals. Vaccination is one of the most effective methods to control many infectious diseases. The primary focus of my laboratory is to unravel the molecular mechanisms of infectious diseases to explore new drug targets and development of vaccines against pathogens.
Summary of Research:
Gram positive Clostridium perfringens is a major cause of human and veterinary enteric disease largely because this bacterium can produce several toxins when present inside the gastrointestinal tract. Epsilon toxin, produced by Clostridium perfringens types B and D is the key antigen implicated in the Enterotoxaemia or Pulpy kidney disease of domestic animals. It is the third most lethal of all clostridial toxins. Epsilon toxin functions by interacting with the surface of mammalian cells probably through receptor binding and oligomerizes to form pores. Our initial focus is to identify the residues important for receptor binding as well as residues involved in oligomerization. We envisage to isolate the receptor for epsilon toxin to understand this interaction in greater detail. Further, by site-directed mutagenesis we aim to study the role of various residues within the gene for its toxicity and immunogenicity. Another emphasis of our research is to develop recombinant protein and DNA based vaccines against C. perfringens, C. novyi, C. chauvoei and D. nodosus.
My laboratory is also interested in Mycobacterium tuberculosis. More than 2.5 million deaths every year make tuberculosis one of the most lethal infectious diseases. Recent years have seen an increase in incidence of tuberculosis in both developing and industrialized countries, and there is an immediate need to search for new molecules that can be used as future drug target(s).
In vivo growth studies of the organism have indicated that up to 70% of glucose metabolizes through the EMP pathway. Thus, glycolysis is central to the organism's survival and targeting the glycolytic enzymes, as potential drug targets to control M. tuberculosis may be feasible. My laboratory envisages cloning and expressing the genes of metabolic pathways beginning with the enzymes of EMP pathway. Subsequently genes encoding the enzymes of other metabolic pathways will be evaluated. Biochemical characterization of the recombinant enzymes will help in identifying the differences and similarities between the Mtb and human, which can be exploited for drug development. Further, production of large amounts of recombinant protein using efficient expression strategies would make it possible to carry out structural studies. This will help in defining the 3-dimensional structure of the enzymes ultimately leading to the rational development of new therapeutic interventions.
Sequencing of the complete genome of M. tuberculosis H37Rv has revealed that approximately 8% of the total genome codes for members of two large families of conserved proteins, the PE and PPE families. The uniqueness of the genes of the PE and PPE families is that these are specifically present in mycobacteria and are mainly restricted to the pathogenic strain. Despite their numerical abundance and interesting distinctiveness, function of these genes remains largely unknown. A true understanding of the gene products of a pathogen is essential for the successful control of disease. Functional characterization and defining the role of this unique family of proteins in mycobacterium biology may provide novel targets for chemotherapeutic intervention of tuberculosis.
Sachin Kumar Deshmukh, Himani, Shweta Chatrath, Vineet Kumar Gupta, Bharati Bhatia, Sweta, Moolchand Sigar, Sonam Takkar, K.P. Pandey