{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,29]],"date-time":"2026-10-29T20:50:01Z","timestamp":1793307001939,"version":"4.5.0"},"reference-count":27,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,9,2]],"date-time":"2025-09-02T00:00:00Z","timestamp":1756771200000},"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. Cell. Infect. Microbiol."],"abstract":"<jats:sec>\n                    <jats:title>Objectives<\/jats:title>\n                    <jats:p>\n                      <jats:italic>Mycobacterium tuberculosis<\/jats:italic>\n                      (Mtb) modulates macrophage polarization to evade host immunity and enhance intracellular survival. Rv3737, a probable conserved transmembrane protein in Mtb, has an unclear biological function. This study investigates the role of Rv3737 in regulating macrophage polarization and Mtb survival within host cells.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      The structure of Rv3737 was predicted using bioinformatics tools. Macrophage polarization markers were assessed by real-time PCR for M1\/M2-associated cytokines, and flow cytometry for CD86\n                      <jats:sup>+<\/jats:sup>\n                      \/CD206\n                      <jats:sup>+<\/jats:sup>\n                      expression. RNA sequencing, along with KEGG and GO analyses, was used to explore underlying regulatory pathways. Western blotting evaluated the phosphorylation status of NF-\u03baB (P65, I\u03baB) and MAPK (ERK, P38, JNK) signaling components. Colony-forming units (CFUs) and inducible nitric oxide synthase (iNOS) levels were examined in H37Rv\u0394Rv3737-infected macrophages pretreated with specific inhibitors (JSH-23, U0126-EtOH, SB203580, SP600125).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Rv3737 is predicted to contain 10 transmembrane segments enriched in aliphatic amino acids. Deletion of Rv3737 in H37Rv (H37Rv\u0394Rv3737) led to upregulation of M1 markers (TNF-\u03b1, IL-1\u03b2, IL-6, iNOS, MCP-1, CD86) and downregulation of M2 markers (Arg-1, IL-10, TGF-\u03b2, CD206). Conversely, overexpression of Rv3737 (MS_Rv3737) promoted M2 polarization. RNA sequencing indicated NF-\u03baB pathway activation in macrophages infected with H37Rv\u0394Rv3737, along with increased phosphorylation of P65, I\u03baB, ERK, and P38. Inhibition of NF-\u03baB (with JSH-23) and P38 MAPK (with SB203580) reduced iNOS levels and partially restored Mtb survival, indicating that Rv3737 deletion enhances the macrophage antimicrobial response.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Rv3737 suppresses M1 macrophage polarization to promote Mtb survival. Its deletion enhances host antimicrobial activity by activating NF-\u03baB and MAPK signaling pathways. Targeting Rv3737 may represent a novel strategy for tuberculosis therapy.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fcimb.2025.1592296","type":"journal-article","created":{"date-parts":[[2025,9,2]],"date-time":"2025-09-02T05:32:21Z","timestamp":1756791141000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":5,"title":["Depletion of Mycobacterium tuberculosis transmembrane protein Rv3737 reduces pathogen survival and induces M1 macrophage polarization against tuberculosis"],"prefix":"10.3389","volume":"15","author":[{"given":"Zhangli","family":"Peng","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chao","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taixian","family":"You","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chengjie","family":"Shu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qing","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nana","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Renzhong","family":"He","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ling","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lin","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,9,2]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"207","DOI":"10.1038\/s41392-023-01452-1","article-title":"Macrophages in immunoregulation and therapeutics","volume":"8","author":"Chen","year":"2023","journal-title":"Signal Transduct Target Ther."},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0164458","article-title":"Mycobacterium tuberculosis Rv2882c Protein Induces Activation of Macrophages through TLR4 and Exhibits Vaccine Potential","volume":"11","author":"Choi","year":"2016","journal-title":"PloS One"},{"key":"B3","doi-asserted-by":"publisher","first-page":"28","DOI":"10.3390\/molecules28052379","article-title":"Macrophage polarization: an important candidate regulator for lung diseases","author":"Deng","year":"2023","journal-title":"Molecules"},{"key":"B4","doi-asserted-by":"publisher","first-page":"7405","DOI":"10.1002\/jcp.v236.11","article-title":"Mycobacterium tuberculosis effector PPE36 attenuates host cytokine storm damage via inhibiting macrophage M1 polarization","volume":"236","author":"Gong","year":"2021","journal-title":"J. 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