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Deciphering the role of PE_PGRS45 (Rv2615c) protein of Mycobacterium tuberculosis in host macrophage apoptosis: Possible effector for persistence
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  • Monika Sharma,
  • * Medha,
  • * Priyanka,
  • Sadhna Sharma
Monika Sharma
University of Delhi Miranda House

Corresponding Author:[email protected]

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* Medha
University of Delhi Miranda House
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* Priyanka
University of Delhi Miranda House
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Sadhna Sharma
University of Delhi Miranda House
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Abstract

Mycobacterium tuberculosis has co-evolved with its host to evade and modulate host cellular processes. Few PE/PPE proteins of Mycobacterium have been reported to modulate cell death pathways and determine the infection outcome. This study investigates role of one such uncharacterized protein PE_PGRS45/Rv2615c in host cell death and immuno-modulation. In-silico analysis predicted similarity of Rv2615c with APAF1-apoptosome and involvement in Cysteine-type endo-peptidase activation during apoptosis. In-vitro experiments with THP-1 macrophages confirmed the Caspase-dependent apoptosis inducing potential of Rv2615c. Several PE_PGRS proteins have been reported to be TLR-agonist. Docking showed preferential binding of Rv2615c with TLR4 than TLR2. Up-regulation of TLR4-HLA-DR-MyD88-NF-ƙB-TNF‐α in Rv2615c-stimulated THP-1 macrophages was observed. To investigate the mechanism underpinning the apoptotic function, a thorough sequence scan of Rv2615c revealed the presence of eukaryotic CARD-like domain in it. In-silico studies showed binding affinity of Rv2615c’s CARD-like domain with APAF1-CARD and Caspase9-CARD, attributing Rv2615c’s role in apoptosis. Since, Rv2615c is reported to be upregulated in dormancy which suggest that it may be one of the unexplored effectors employed by Mtb for its persistence via silent cell-to-cell spread of infection by inducing macrophage apoptosis. Additionally, Rv2615c’s interaction with TLR4 implicates its engagement in host-pathogen interaction.
25 Jan 2023Submitted to Molecular Microbiology
26 Jan 2023Submission Checks Completed
26 Jan 2023Assigned to Editor
31 Jan 2023Reviewer(s) Assigned
20 Feb 2023Review(s) Completed, Editorial Evaluation Pending
21 Feb 2023Editorial Decision: Revise Minor