DBT’s support for research on tuberculosis has seen significant milestones in the development of diagnostic test for the diseases which was adopted under the government’s Revised National Tuberculosis Control Programme and also development of new approaches to vaccine development.
Crystal TB jointly produced by DBT and M/s Span Diagnostics was adopted as a confirmatory test under Govt.-run RNTCP program.
The department’s support for TB vaccine project has led to the generation of BCG mutants with respect to bioA, thiE and mbtE genes due to their role in attenuation. The mutants are few steps away from animal studies.
Multiple approaches to vaccines receives support
A vaccine project focusing on development of alternative methods for the selection and maintenance of the resulting recombinant BCG85C strain in vitro in the absence of antibiotic selection pressure is being supported at University of Delhi, South Campus. The team has succeeded in generating the BCG mutants with respect to bioA, thiE and mbtE genes due to their role in attenuation.
In addition, the curing of plasmid pJV53 from these mutants has been achieved and unmarking of the mutants has been carried out. The complementation proficient plasmids are under preparation. Subsequently, after complementation of these mutants with Ag85C gene along with the target gene such as bioA / thiE /mbtE, the recombinant strains will be subjected to expression studies before finally embarking on the animal studies.
Another novel approach for generating a vaccine against TB through antigens presented by macrophages infected with Mycobacterium tuberculosis has been identified jointly at ICGEB, New Delhi and UDSC, New Delhi.
When immunized in the form of DNA vaccines they conferred significant protection against a subsequent challenge with the pathogen and reduced the period of chemotherapy, in the background of BCG vaccination. The inhibitor discovery component of the work has resulted in the identification of some promising inhibitors against Mycobacterium tuberculosis.
In another approach aimed at interventions against Mycobacterium tuberculosis at University of Hyderabad in collaboration with six institutions, protein and molecular markers for diagnosis of pulmonary TB were identified. Further they have identified proline-glutamate (PE)/ proline-prolineglutamate (PPE) gene as possible candidate vaccine antigen and a chemical entity that inhibits Mycobacterium tuberculosis chorismate mutase enzyme, absent in human host, as possible new candidate drug.
Host- pathogen interaction needs understanding
Incomplete understanding of mechanisms involved in the host-pathogen interaction constrains the efforts in eliminating tuberculosis. In vitro granuloma model has been optimized by a research team at National Institute of Biomedical Genomics (NIBMG), Kalyani by infecting the isolated peripheral blood mononuclear cells with live Mycobacterium tuberculosis, which enhanced feasibility to imitate early human responses against the pathogen.
Data obtained for the recruited 87 healthy individuals suggested high inter-individual variation in the degree of granuloma formation and rate of bacterial growth.
In an ongoing study at IISc Bangalore, scientists have demonstrated that M. tuberculosis H37Rv induced expression of several signaling components of Wnt pathway in time as well as dose dependent manner in macrophages upon infections. In addition, they have also identified that mycobacterial cell wall antigen induces Wntsignaling thus serving as an important signaling cohort and molecular regulator during mycobacterial infection.
The crystal structure of the pepsin-like domain of Rv0977, a protein from Mycobacterium tuberculosis belonging to the PE family has been determined by X-ray crystallography by researcher at IISc Bangalore. This is the first structural report of a pepsin-like protein from any procaryotes. The structure has provided an evolutionary link between the eucaryotic and retroviral pepsin structures. The structure also provided a new peptide sequence to be tested as an inhibitor for pepsins.
India TB forum
In a joint initiative between DBT, ICMR, Central TB Division/MOH&FW, DBT is planning to set-up an India TB Research Forum with a purpose to undertake activities pertaining to diagnostics/treatment/prevention of TB/MDR-TB on a long term basis. Placed under an “Expert Committee”, the forum would be collective Indian Voice on Tuberculosis in all National & Global meetings/fora. It would review the achievements under TB research and identify strengths and gaps; convene joint meetings/ consultations to formulate India specific guidelines for the programme; formulate guidelines for multi-disciplinary research contributing to TB elimination and pool the resources and promote funding in Innovative Research.
DBT has been funding research on Tuberculosis for the past two decades with focus on diagnostics, vaccine development, Immuno-modulation, Basic Biology; and early & late stage drug-development.
There are about 60 on-going R & D projects covering above aspects. In order to convert scientific leads into products, DBT has signed an MoU with ICMR/DHR on “Validation of indigenously developed technologies for diagnosis of pulmonary tuberculosis and multi-drug resistant tuberculosis” with an aim to replace imported kits with locally developed technologies. Four major institutions and two Indian companies are involved in a tightly governed exercise.