{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,28]],"date-time":"2026-10-28T23:13:02Z","timestamp":1793229182392,"version":"4.5.0"},"reference-count":89,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,1,30]],"date-time":"2025-01-30T00:00:00Z","timestamp":1738195200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>Tuberculosis (TB), caused by <jats:italic>Mycobacterium tuberculosis<\/jats:italic> (Mtb), remains a leading cause of mortality worldwide. A crucial factor in <jats:italic>Mtb's<\/jats:italic> 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 <jats:italic>Mtb<\/jats:italic> pathogenesis require further investigation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We explored the roles of PE18 and PPE26 using recombinant <jats:italic>Mycobacterium smegmatis<\/jats:italic> (<jats:italic>Msmeg<\/jats:italic>) 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 <jats:italic>in vitro<\/jats:italic> cytokine production and antigen presentation studies, were performed using TLR2\/Myd88 knockout and wild-type macrophages. <jats:italic>In vivo<\/jats:italic> 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.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Our 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 <jats:italic>in vivo<\/jats:italic> 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 <jats:italic>Msmeg<\/jats:italic> expressing PE18, PPE26, or their combination exhibited enhanced intracellular survival by disrupting endosome-phagosome maturation, likely through interference with actin cytoskeletal organization.<\/jats:p><\/jats:sec><jats:sec><jats:title>Discussion<\/jats:title><jats:p>Our findings elucidate the pivotal roles of PE18 and PPE26 in <jats:italic>Mtb<\/jats:italic> 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 <jats:italic>Mtb<\/jats:italic> 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.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2025.1517822","type":"journal-article","created":{"date-parts":[[2025,1,30]],"date-time":"2025-01-30T06:26:34Z","timestamp":1738218394000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":15,"title":["Deciphering the functional roles of PE18 and PPE26 proteins in modulating Mycobacterium tuberculosis pathogenesis and immune 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