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ORIGINAL RESEARCH article

Front. Immunol.
Sec. Microbial Immunology
Volume 16 - 2025 | doi: 10.3389/fimmu.2025.1517822

Deciphering the Functional Roles of PE18 and PPE26 Proteins in Modulating Mycobacterium tuberculosis Pathogenesis and Immune Response

Provisionally accepted
Aquib Ehtram Aquib Ehtram 1Mohd Shariq Mohd Shariq 2Neha Quadir Neha Quadir 3Salma Jamal Salma Jamal 4MANJUNATH PICHIPALLI MANJUNATH PICHIPALLI 3Sheeba Zarin Sheeba Zarin 5Javaid Ahmad Sheikh Javaid Ahmad Sheikh 6Nasreen Zafar Ehtesham Nasreen Zafar Ehtesham 5Seyed Ehtesham Hasnain Seyed Ehtesham Hasnain 5,7*
  • 1 Kusuma School of Biological Sciences, Indian Institute of Technology Delhi, New Delhi, NCT of Delhi, India
  • 2 Gandhi Institute of Technology and Management (GITAM), Visakhapatnam, Andhra Pradesh, India
  • 3 National Institute of Pathology (ICMR), New Delhi, Delhi, India
  • 4 Institute of Molecular Medicine, Jamia Hamdard University, New Delhi, Delhi, India
  • 5 Department of Life Sciences, School of Basic Science and Research, Sharda University, Greater Noida, Uttar Pradesh, India
  • 6 Department of Biotechnology, Jamia Hamdard University, New Delhi, NCT of Delhi, India
  • 7 Indian Institute of Technology Delhi, New Delhi, India

The final, formatted version of the article will be published soon.

    Mycobacterium tuberculosis (Mtb) utilizes the ESX-5 secretion system to transport virulence-causing PE/PPE proteins, including PE18 and PPE26, to modulate host-pathogen interactions. Here, we investigated the roles and interactions of PE18 and PPE26 in modulating immune responses and enhancing intracellular survival of recombinant Mycobacterium smegmatis (Msmeg). Our biochemical analyses revealed interactions between PE18/PPE26, PE18/PPE27, PE19/PPE25, and EspG5/PPE, suggesting their involvement in ESX-5-mediated secretion. Cell fractionation studies indicated that PE/PPE proteins are primarily localized to the cell wall, with PE18 also being secreted. In vitro and in vivo experiments demonstrated that PE18 and PPE26 stimulate cytokine production and antigen presentation via TLR2/Myd88-dependent signaling pathways, leading to the induction of effector memory T-cell responses. Additionally, we observed that these proteins enhance intracellular survival of recombinant Msmeg containing PE18, PPE26 and PE18+PPE26 by impeding endosome-phagosome maturation, likely through the disruption of actin cytoskeletal dynamics. Taken together, our findings suggest that PE18 and PPE26 play pivotal roles in Mtb pathogenesis, immune modulation, and intracellular persistence, highlighting their potential as therapeutic targets for tuberculosis (TB) treatment.

    Keywords: Activation marker, phagosome, host-pathogen interaction, TH1 immune response, Immune Modulation, Proinflammatory cytokines (TNF- alpha, IL-1 beta, IL-6)

    Received: 27 Oct 2024; Accepted: 07 Jan 2025.

    Copyright: © 2025 Ehtram, Shariq, Quadir, Jamal, PICHIPALLI, Zarin, Sheikh, Ehtesham and Hasnain. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence: Seyed Ehtesham Hasnain, Indian Institute of Technology Delhi, New Delhi, India

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