Page 9 - CSIR-IGIB Annual Report 2020-21

approaches to model disease and therapeutic potential of small molecular modifiers. Here she reports
on a model of inflammation induced fatty liver disease in zebrafish and ongoing efforts in reversing this
phenotype using small molecules. T.N. Vivek’s lab has been using the zebrafish model to understand
melanocyte migration, an important development step for patterning. Here he reports on the cognate
semaphorin-semaphorin receptor pair that is crucial for melanoblast migration in the developing fish.
Parallel approaches in B16 melanocytes enable molecular understanding of the migration cues.

Central pathways that regulate the switch from health to disease can best be understood using “simpler”
model systems such as bacteria, and even further clarity with purified components of a pathway in the
test tube. Kausik Chakraborty’s lab reports on a genetic approach undertaken in E. coli to address the
role of metabolism in buffering mutational landscape across model proteins. Complementing this
approach with biophysical studies, his lab is on the path to identify how metabolites can buffer specific
mutations, thereby achieving proteostasis.

Establishment of fine structure-function relationships is the cornerstone of biology and changes as small
as single amino acid alterations impact response to life saving antibiotics. Bhupesh Taneja’s lab has
several programs linked by this common theme with the aim to offer solutions to the development of
antimicrobial resistance in bacteria and fungi that cause skin infections. He reports on the identification
of methyltransferase based mechanisms for development of resistance to ribosome-targeting antibiotics
in mycobacteria. His lab is also applying global transcriptome analysis and making way in fungal gene
targeting to address mechanisms of terbinafine resistance in case of dermatophytes.

With the rise of drug resistance to existing drugs, and the threat of emergence of resistance against new
antimycobacterials, host directed therapies offer several benefits in Tuberculosis. Tuning the host
inflammatory response elicited by infection towards a host-favourable, antimicrobial response is one of
the validated preclinical approaches for TB control. Vivek Rao’s lab reports on the discovery of a clinically
approved anti-depressant-Sertraline as an adjunct therapy for tuberculosis using resistant and
susceptible models of infection. The fact that this was identified by searching for inhibitors of the Type I
IFN axis, has motivated his lab’s current efforts towards a more comprehensive understanding of this
pathway with potential for other FDA-approved drugs to be included in the pre-clinical pipeline against
TB. Choice of metabolic arms for energy production seem to be crucial regulators of the innate immune
defense against mycobacteria. Findings from Vivek’s lab identify a mitochondrial protein to be a
determinant of innate cell activation state. While mitochondria are destinations for oxidative
degradation of fatty acids, lipid droplets are a storehouse for them. The unusually high abundance of
lipid droplets within TB lesions has been the focus area of Sheetal Gandotra’s lab. Here she reports on
the role of this lipid in a susceptible mouse model of infection, delineating the dual role played by
triglyceride synthesis in regulating eicosanoid levels as well as transcriptional control in tuberculous
lungs. This study not only points to the potential benefit of targeting granuloma triglyceride synthesis, it
also points towards the need to understand lipid droplet biology in macrophages. Her group is focussing
efforts on Mycobacterium tuberculosis induced alteration to the lipid droplet proteome.

Targeting lung tissue for precise delivery of specific nucleic acids when the lung is secreting large
quantities of mucus is challenging. Dr Munia Ganguli’s lab reports on the development of a mucus
penetrating peptide based nanocarrier capable of delivering plasmid DNA or siRNA to the inflamed lung
tissue. This approach has been tested in a quartz-induced mouse fibrosis model developed in her lab and
is a promising approach to be tested for other lung diseases. Besides this, her lab also reports on a novel
topical delivery method for skin that could be developed for photoprotection from UV irradiation.

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