Research Projects

Tuberculosis, caused by M.tb, is a major health concern being the top infectious killer in the world surpassing COVID-19 in 2023, where 10.8 million active TB cases were reported including ~1.25 million deaths. In 2023, India alone contributed to 26% of the global TB cases. With a quarter of the world’s population infected with latent TB, no vaccine for HIV yet, the HIV-TB remains a field of significant scientific challenge. The current treatment approaches for TB-HIV co-infected patients includes simultaneous treatment with anti-TB antibiotics and anti-retroviral drugs. This is complicated by drug-drug interactions, drug toxicity, and TB-associated immune reconstitution inflammatory syndrome (TB-IRIS); thereby posing enormous challenges for clinical interventions. To address these issues, we propose to: • Identify novel compound/s, with improved efficacy and reduced toxicity and lesser drug-drug interactions against M.tb and HIV. • Establish a new therapeutic intervention/s which is/are capable of enhancing immunity without worsening immunopathology. This dual therapeutic aim will be achieved by exploring host-directed therapies that rectifies underlying pathogenic mechanisms in infected cells/tissues, in spite of targeting immune cells. The human PBMC based 3-D granuloma model that we propose to use for testing our potential therapeutics has many advantages in preliminary screening for candidate compounds; understanding mechanistic details of host-signaling pathways, finding new therapeutic targets, facilitating study of co-morbidities such as HIV. These are low-cost models with easy scale-up capacity to enable high throughput screening for discovering novel therapeutics. The efficacy results with this model will be translated to a greater extent in humans. For drug evaluation, we will use libraries of FDA approved compounds/ drugs which will be tested for their anti-Mtb and anti-HIV activities; immune responses; structural and organizational changes in granuloma and ability to prevent reactivation of M.tb within the granuloma. We will do transcriptomics and proteomics studies to get detailed insight into the changes occurring inside host cells upon M.tb-HIV co-infection and upon subsequent treatment with prospective compound candidate/s. Since, TB treatment in co-infected individuals with MDR/XDR TB in a major concern, we will employ various combinations of existing drugs and our novel candidate/s as adjunct therapies in in vitro co-infection models followed by ex vivo experiments in alveolar macrophages and lymphocytes isolated from TB/HIV infected patients. Utilizing already licensed FDA-approved drugs/compounds is cost-effective and less time-consuming than developing new drugs. This will fasten the drug discovery process for TB-AIDS comorbidity and drug resistant-TB, thereby contributing to National Mission of TB elimination and prospectively improving the treatment quality for millions of patients suffering from TB and HIV worldwide.