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Targeting host immune pathways for for efficient control of the invading microbe. We
therapeutics have unravelled a novel mechanism of Mtb
Pathogens like Mycobacterium tuberculosis induced type I IFN response of macrophages,
(Mtb) have developed numerous ways to dependent solely on transit of bacteria via the
manipulate the host immune response to host cell phago-lysosome machinery. This
support infection. By activating the type I activation of the type I IFN axis is critical to the
interferon response, Mtb has achieved host cell inflammatory response against Mtb
suppression of the bactericidal innate responses and intersects with the regulation of the cellular
of host macrophages. By targeting this axis, we sterol (25- hydroxy cholesterol) biosynthetic
intend to revert this suppression thereby pathway. We have now embarked upon
bolstering the ability of host defense systems to defining newer interconnections between
overhaul the infection better. Interestingly, phagocyte metabolism and the response to
anti-psychotics have an inherent property to bacterial infections (Immuno-metabolism). We
dampen macrophage type I interferon demonstrated that macrophages encountering
responses. We demonstrated that repurposing Mtb infection activate the type I IFN response
an FDA approved anti- depressant- Sertraline rapidly. Infection induces several novel
(SRT), enhances macrophage control of Mtb transcriptional changes; we have identified
invitro. Sertraline synergized with frontline TB TILTs (TLR4 and Infection induced Long
drugs to further augment bactericidal Transcripts) as novel non-coding RNAs that
properties. Addition of SRT to standard ATT respond to macrophage stimulation by bacterial
significantly augmented bacterial control in infection and TLR4 stimulation. We found that
murine models of TB, leading to shortening of the TILT locus also expresses a mitochondrial
treatment duration. Adjunct SRT based therapy resident kinase CMPK2 that controls
regimen also afforded better protection to the mitochondrial architecture and function and
host from infection induced mortality. The plays a dominant role in establishing basal
combination was also efficient in conditions of inflammation homeostasis in macrophages,
antibiotic dysfunction. We are working towards thereby linking the Type IFN response with
elucidating the molecular mechanism of SRT cellular homeostasis. Changes in mitochondrial
mediated antibiotic reinforcement in cells. This function/ dynamics were also found to be
will help us in more precise targeting of host associated with infection. Our work
innate responses against infections in future. demonstrates that mitochondrial function
dictates the metabolic fate of infected
Cross-talk of immune signalling with macrophages. We are working towards
metabolism molecular basis of mitochondria- metabolism-
Immune cells efficiently adapt to infection by inflammation nexus in Mtb infected
activating responses and altering their macrophages.
metabolism significantly to suit requirements
Annual Report 2020-21 158
