Page 36 - Biennial Report 2018-20 Jun 2021

Further exploratory investigations of this gene might be valuable in understanding of its
physiological and biological roles. The blockade of these selective adhesions, which have
potential to bind with host molecules, could be a therapeutically useful approach for tracking
survival and pathogenic mechanism of M. tuberculosis. It is essential to have a better
understanding of host-pathogen interaction if the tuberculosis epidemic must be controlled. The
complex interconnected network of proteins and host molecules may open gates to find the
effective and potential approach for new drug targets.

ADIPOCYTE MODEL OF TUBERCULOSIS INFECTION

Research from Sheetal Gandotra’s group at IGIB, with the support of DBT-Wellcome Trust India
Alliance and CSIR, has revealed novel aspects of how Mycobacterium tuberculosis (Mtb) survives
inside the lipid rich environment of the host cells. Excess host derived fatty acids are routed to
bacterial triglycerides with accompanying increased resilience to oxidative stress, without
affecting bacterial growth.

Macrophage and adipocyte models were used to understand the physiology of M. tuberculosis
in a lipid rich environment. The adipocyte model was found to exhibit key features of the
extracellular necrotic lipid rich environment. It was found that the bacilli are able to utilize fatty
acids in this infection model. As a control, preadipocytes were used. Importantly, across these
cellular models of infection, it was found that neither depletion of triglyceride levels, nor
providing excess triglycerides altered bacterial growth. However, when bacterial lipid profiling
and transcriptional profiling was carried out from the adipocyte and preadipocyte model, distinct
physiological states of the bacilli were identified.

Excess fatty acids in case of adipocytes were found to be stored by mycobacteria in the form of
triglyceride. Oleic acid is a fatty acid that promotes triglyceride storage in mammalian cells and
forms a major component of the fatty acid pool of host triglycerides. One of the major findings
of this work was that growth in the presence of oleic acid, as in the extracellular caseous necrotic
environment, led to reduction of the bacterial cytosol, thereby conferring increased resilience to
oxidative stress. This is accompanied by an increase in expression of genes involved in lipid
storage and the oxidative stress response.

A key signature was downregulation of iron acquisition genes which are known to be induced
under conditions of iron starvation. Complementary to this, both the adipocyte model and in
vivo murine caseous granulomas were found to be iron rich, establishing an association between
host lipid accumulation and iron availability. M. tuberculosis deleted for both its bacterioferritins
becomes sensitive to oxidative stress. This strain was found to be impaired in the preadipocyte
model of infection while it grew unaffected in the adipocyte model of infection. These data
suggest that targeting bacterial oxidative stress mitigation pathways may be important under
conditions of the caseous granuloma. Because of the similarities of the adipocyte model of
infection to caseous granulomas, this model would be extremely valuable in developing assays
for drug screening against M. tuberculosis.

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