Deciphering the functional roles of PE18 and PPE26 proteins in modulating Mycobacterium tuberculosis pathogenesis and immune response
IntroductionTuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), remains a leading cause of mortality worldwide. A crucial factor in Mtb's virulence is the ESX-5 secretion system, which transports PE/PPE proteins such as PE18 and PPE26. These proteins modulate host-pathogen interactio...
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Frontiers Media S.A.
2025-01-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2025.1517822/full |
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| author | Aquib Ehtram Mohd Shariq Neha Quadir Neha Quadir Salma Jamal Manjunath Pichipalli Sheeba Zarin Sheeba Zarin Javaid Ahmad Sheikh Nasreen Z. Ehtesham Seyed E. Hasnain Seyed E. Hasnain |
| author_facet | Aquib Ehtram Mohd Shariq Neha Quadir Neha Quadir Salma Jamal Manjunath Pichipalli Sheeba Zarin Sheeba Zarin Javaid Ahmad Sheikh Nasreen Z. Ehtesham Seyed E. Hasnain Seyed E. Hasnain |
| author_sort | Aquib Ehtram |
| collection | DOAJ |
| description | IntroductionTuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), remains a leading cause of mortality worldwide. A crucial factor in Mtb's virulence is the ESX-5 secretion system, which transports PE/PPE proteins such as PE18 and PPE26. These proteins modulate host-pathogen interactions, immune responses, and intracellular survival mechanisms. Despite their importance, the roles and molecular interactions of PE18 and PPE26 in Mtb pathogenesis require further investigation.MethodsWe explored the roles of PE18 and PPE26 using recombinant Mycobacterium smegmatis (Msmeg) as a model organism. Protein-protein interactions were analyzed biochemically to identify partners within the ESX-5 secretion system, including EspG5 and other PE/PPE proteins. Subcellular localization of these proteins was assessed via cell fractionation studies. Functional assays, including in vitro cytokine production and antigen presentation studies, were performed using TLR2/Myd88 knockout and wild-type macrophages. In vivo experiments were conducted to assess effector T-cell activation and intracellular survival. Mechanistic insights into endosome-phagosome maturation and actin cytoskeleton dynamics were obtained through fluorescence microscopy.ResultsOur biochemical analyses confirmed interactions between PE18/PPE26, PE18/PPE27, PE19/PPE25, and EspG5/PPE, highlighting their involvement in ESX-5-mediated secretion. Cell fractionation studies revealed that PE/PPE proteins predominantly localize to the cell wall, with PE18 also secreted extracellularly. In vitro and in vivo experiments demonstrated that PE18 and PPE26 activate cytokine production and antigen presentation via TLR2/Myd88-dependent signaling pathways, inducing robust effector memory T-cell responses. Recombinant Msmeg expressing PE18, PPE26, or their combination exhibited enhanced intracellular survival by disrupting endosome-phagosome maturation, likely through interference with actin cytoskeletal organization.DiscussionOur findings elucidate the pivotal roles of PE18 and PPE26 in Mtb pathogenesis, emphasizing their contributions to immune modulation and intracellular persistence. The observed disruption of actin dynamics and endosome-phagosome maturation underscores a novel mechanism by which Mtb evades host defenses. The ability of PE18 and PPE26 to induce effector T-cell responses highlights their potential as targets for host-directed therapies or vaccine development against TB. Further studies focusing on their structure-function relationships and interactions with host proteins could accelerate the development of innovative therapeutic strategies. |
| format | Article |
| id | doaj-art-dbfafa129fc64268a9a165763bd1267d |
| institution | Kabale University |
| issn | 1664-3224 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Immunology |
| spelling | doaj-art-dbfafa129fc64268a9a165763bd1267d2025-01-30T06:23:00ZengFrontiers Media S.A.Frontiers in Immunology1664-32242025-01-011610.3389/fimmu.2025.15178221517822Deciphering the functional roles of PE18 and PPE26 proteins in modulating Mycobacterium tuberculosis pathogenesis and immune responseAquib Ehtram0Mohd Shariq1Neha Quadir2Neha Quadir3Salma Jamal4Manjunath Pichipalli5Sheeba Zarin6Sheeba Zarin7Javaid Ahmad Sheikh8Nasreen Z. Ehtesham9Seyed E. Hasnain10Seyed E. Hasnain11Kusuma School of Biological Sciences, Indian Institute of Technology Delhi, New Delhi, IndiaGITAM School of Science, Gandhi Institute of Technology and Management (GITAM) University, Hyderabad, Telangana, IndiaInflammation Biology and Cell Signaling Laboratory, ICMR-National Institute of Pathology, New Delhi, IndiaJamia Hamdard Institute of Molecular Medicine, Jamia Hamdard, New Delhi, IndiaJamia Hamdard Institute of Molecular Medicine, Jamia Hamdard, New Delhi, IndiaInflammation Biology and Cell Signaling Laboratory, ICMR-National Institute of Pathology, New Delhi, IndiaJamia Hamdard Institute of Molecular Medicine, Jamia Hamdard, New Delhi, IndiaDepartment of Life Science, School of Basic Sciences and Research, Sharda University, Greater Noida, Uttar Pradesh, IndiaDepartment of Biotechnology, Jamia Hamdard, New Delhi, IndiaDepartment of Life Science, School of Basic Sciences and Research, Sharda University, Greater Noida, Uttar Pradesh, IndiaDepartment of Life Science, School of Basic Sciences and Research, Sharda University, Greater Noida, Uttar Pradesh, IndiaDepartment of Biochemical Engineering and Biotechnology, Indian Institute of Technology Delhi, New Delhi, IndiaIntroductionTuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), remains a leading cause of mortality worldwide. A crucial factor in Mtb's virulence is the ESX-5 secretion system, which transports PE/PPE proteins such as PE18 and PPE26. These proteins modulate host-pathogen interactions, immune responses, and intracellular survival mechanisms. Despite their importance, the roles and molecular interactions of PE18 and PPE26 in Mtb pathogenesis require further investigation.MethodsWe explored the roles of PE18 and PPE26 using recombinant Mycobacterium smegmatis (Msmeg) as a model organism. Protein-protein interactions were analyzed biochemically to identify partners within the ESX-5 secretion system, including EspG5 and other PE/PPE proteins. Subcellular localization of these proteins was assessed via cell fractionation studies. Functional assays, including in vitro cytokine production and antigen presentation studies, were performed using TLR2/Myd88 knockout and wild-type macrophages. In vivo experiments were conducted to assess effector T-cell activation and intracellular survival. Mechanistic insights into endosome-phagosome maturation and actin cytoskeleton dynamics were obtained through fluorescence microscopy.ResultsOur biochemical analyses confirmed interactions between PE18/PPE26, PE18/PPE27, PE19/PPE25, and EspG5/PPE, highlighting their involvement in ESX-5-mediated secretion. Cell fractionation studies revealed that PE/PPE proteins predominantly localize to the cell wall, with PE18 also secreted extracellularly. In vitro and in vivo experiments demonstrated that PE18 and PPE26 activate cytokine production and antigen presentation via TLR2/Myd88-dependent signaling pathways, inducing robust effector memory T-cell responses. Recombinant Msmeg expressing PE18, PPE26, or their combination exhibited enhanced intracellular survival by disrupting endosome-phagosome maturation, likely through interference with actin cytoskeletal organization.DiscussionOur findings elucidate the pivotal roles of PE18 and PPE26 in Mtb pathogenesis, emphasizing their contributions to immune modulation and intracellular persistence. The observed disruption of actin dynamics and endosome-phagosome maturation underscores a novel mechanism by which Mtb evades host defenses. The ability of PE18 and PPE26 to induce effector T-cell responses highlights their potential as targets for host-directed therapies or vaccine development against TB. Further studies focusing on their structure-function relationships and interactions with host proteins could accelerate the development of innovative therapeutic strategies.https://www.frontiersin.org/articles/10.3389/fimmu.2025.1517822/fullmacrophage activation markerphagosomehost-pathogen interactionTh1 immune responseimmune modulationproinflammatory cytokine |
| spellingShingle | Aquib Ehtram Mohd Shariq Neha Quadir Neha Quadir Salma Jamal Manjunath Pichipalli Sheeba Zarin Sheeba Zarin Javaid Ahmad Sheikh Nasreen Z. Ehtesham Seyed E. Hasnain Seyed E. Hasnain Deciphering the functional roles of PE18 and PPE26 proteins in modulating Mycobacterium tuberculosis pathogenesis and immune response Frontiers in Immunology macrophage activation marker phagosome host-pathogen interaction Th1 immune response immune modulation proinflammatory cytokine |
| title | Deciphering the functional roles of PE18 and PPE26 proteins in modulating Mycobacterium tuberculosis pathogenesis and immune response |
| title_full | Deciphering the functional roles of PE18 and PPE26 proteins in modulating Mycobacterium tuberculosis pathogenesis and immune response |
| title_fullStr | Deciphering the functional roles of PE18 and PPE26 proteins in modulating Mycobacterium tuberculosis pathogenesis and immune response |
| title_full_unstemmed | Deciphering the functional roles of PE18 and PPE26 proteins in modulating Mycobacterium tuberculosis pathogenesis and immune response |
| title_short | Deciphering the functional roles of PE18 and PPE26 proteins in modulating Mycobacterium tuberculosis pathogenesis and immune response |
| title_sort | deciphering the functional roles of pe18 and ppe26 proteins in modulating mycobacterium tuberculosis pathogenesis and immune response |
| topic | macrophage activation marker phagosome host-pathogen interaction Th1 immune response immune modulation proinflammatory cytokine |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2025.1517822/full |
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