Mission
We are interested in understanding how large multi-megadalton molecular machines integrated in the bacterial cell wall mediate Horizontal Gene Transfer (HGT) and Abortive Infection (Abi) in bacteria. Both these avenues of research have important implications on global efforts to fight infections caused by persistent pathogens and combating antimicrobial-resistance (AMR).
Motivation and Genesis
Conjugative systems in mycobacteria
The proposed research on mycobacterial secretion systems is a continuation of my scientific journey because it combines my experience studying mycobacterial-pathogenesis with my expertise in purifying and structurally characterising large membrane integrated secretion systems. My interest in mycobacterial secretion systems arose from the realisation that in Mycobacteriaceae, a clinically relevant family of gram-positive bacteria with serious implications for human health, the process of dissemination of antibiotic resistance-containing genes occurs through a novel form of HGT called Distributive Conjugal Transfer (DCT) rather than traditional conjugation. The key difference here is unlike classical conjugation which uses T4SS to send a single-stranded plasmid DNA, DCT involves transfer of double-stranded genomic DNA fragments using two T7SS (ESX-1 and ESX-4). Despite the differences, there are similarities similarities: both processes are contact dependent and necessitate membrane integrated secretion systems and dedicated ATPases for substrate pre-processing, recruitment and transport.
Abortive infection systems in bacteria
Horizontal gene transfer (HGT) mechanisms are the key drivers of genetic diversity and genome plasticity in bacteria. This flexibility allows bacteria to respond swiftly to environmental challenges by rapidly evolving their genetic diversity to thrive in physiologically challenging conditions. Genetic recombination through Integrative and conjugative elements (ICE) and bacteriophages underpins this process. Since these mobile genetic elements also pose a grave risk to bacteria by causing genomic instability bacteria have also evolved defence strategies to defend against these elements. One such example is that of the Abortive infection (Abi) system where the host cell actively prevents the completion of the viral life cycle, ultimately leading to the termination of the infection without production of new viral progeny. Research along these lines is interesting because studying these systems not only sheds light on the co-evolutionary arms race between bacterial and viruses but it also offers insights into the broader dynamics of host-pathogen interactions and allow us develop more efficient strategies to combat viral infections.
