Core Focus:
Biomedical big data analytics platforms with focus on understanding infection and rare disease biology for better therapeutics and diagnostics
A few ongoing projects under the broad theme of Antimicrobial Resistance (AMR) are presented below
Antimicrobial resistance (AMR), the phenomenon of clinically relevant pathogens developing multi-drug resistance (particularly to antibiotics), has emerged as a grave threat to public health that could plunge the world into a ‘post-antibiotic era’. Neglecting AMR would result in global annual loss of 10 million lives and trillions of dollars by 2050 (2015 O’Neil). The Global Action Plan for AMR has identified five objectives to address this scourge.
The first two objectives “(a) Improve awareness and understanding of antimicrobial resistance through effective communication, education and training and (b) Strengthen the knowledge and evidence base through surveillance and research”. Our lab focusses on these two verticals.
Genomics based Machine Learning Models to Predict MIC in Pathogens & Identification of Novel Antimicrobial Resistance Mechanisms
Under this major project objective we are working on two category of pathogens
a. Acinetobacter baumannii
Acinetobacter baumannii (AB), is known to cause a plethora of diseases, especially in hospital settings. It can survive in the environment and is resistant to multiple classes of antimicrobial agents and labeled as the most critical priority pathogen by the WHO (WHO, 2017). Recent reports indicate that the rate of carbapenem-resistant Acinetobacter cases has increased by 35% from 2019 to 2020 (CDC, 2022). The results from Antimicrobial Testing Leadership and Surveillance (ATLAS) program, 2012-2019 showed significant differences in the prevalence of carbapenem resistant AB among countries in the Asia-Pacific region (Lee et al., 2022).
b. Nontuberculous mycobacteria (NTM)
NTMs include more than 200 ubiquitous Mycobacterium species that do not cause tuberculosis or leprosy. NTMs are present in the environment (water or soil) and can infect humans or animals leading to a range of pathological conditions like pulmonary, skin, bone, joint, and disseminated diseases. NTM species are gaining visibility due an increasing number of strains responsible for treatment-resistant diseases. NTMs are taxonomical diverse and increasing number of new species offer challenges in identification of NTMs in clinical settings. NTM species like Mycobacterium abscessus are now recognized as a major threat and FDA identified NTMs as their focus disease area in 2016-17. It is crucial to know the NTM species and drug-resistant status for prescribing treatment options as the disease presentation and clinical investigation parameters are very similar to Tuberculosis. Moreover, there are species-specific differences from context of resistance to different antibiotics and recent studies do report differences in drug resistant determinants from various drug classes between TB and NTMs. The current proposal entitled ‘G-MOTT’ aims to develop a comparative genomics pipeline to identify genomic signatures of drug resistance in Mycobacterium abscessus
Precision medicine with specific focus on Human Mitochondrial Diseases
The Human mitochondrial DNA (mtDNA) encodes a set of 37 genes which are essential structural and functional components of the electron transport chain. Over 3000 genes are encoded by the nuclear DNA (nDNA) with potential role in mitochondrial functioning. Variations in these genes have been implicated in a broad spectrum of diseases and are extensively reported in literature and various databases. Genotype-phenotype correlations in human mitochondrial dysfunction are inherently complex to predict not only because the structural components are encoded both by nuclear and mitochondrial DNA but also due to the involvement of mitochondria in multiple cellular processes. Over the years, our lab has published several methods, databases and studies towards analysis and prioritization of genomic variations for disease association studies.
Host-Pathogen Interactions
The significance of Human mitochondria in normal and clinical contexts is extensively reviewed over the last few decades. Mitochondria not only play a central role in several cellular functions but also are key regulators of immune responses against viral and bacterial infections. Mitochondrial reprogramming occurs when cellular microenvironment is challenged and when there are mutations either in the mitochondrial genome or the nuclear genome encoding mitochondrial proteins. The human mitochondria harbors several mitochondrial DNA (mtDNA) and despite being a small genome encoding 37 genes which are essential structural and functional components of the electron
transport chain, the human mitochondria is gaining interest for its role in understanding complex disease phenotypes and also its role in host-pathogen interactions. The complexity further deepens given the fact that there are over 3900 proteins encoded by the nuclear DNA (nDNA) with potential role in mitochondrial function. Given that patients with mitochondrial disease often experience more frequent and severe infections, they are advised to obtain their immunologic profile as they might have decreased white blood cells and
antibodies required to fight infections. This indicates that mitochondrial dysfunction plays a significant role in infectious disease predisposition. To the best of our knowledge, there is no systematic evaluation performed till date to correlate genomic variations in primary mitochondrial diseases with infection predisposition to infections. It is also important to note that different immune signalling components are under strong purifying selection, therefore, evolutionary signatures of host mitochondrial proteome are also explored currently in the lab.
Video for generating awareness on pressing health issues
Our lab is keen on taking complex scientific concepts to young children through gamification techniques. In this direction, we released our indegeniously developed game ArMoR in 2021. We are in the process of building more such games.