{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T07:22:57Z","timestamp":1792480977904,"version":"4.5.0"},"posted":{"date-parts":[[2026,5,15]]},"group-title":"Molecular Biology","reference-count":60,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,5,15]],"date-time":"2026-05-15T00:00:00Z","timestamp":1778803200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"award":["INV-027276"],"award-info":[{"award-number":["INV-027276"]}],"id":[{"id":"https:\/\/ror.org\/0456r8d26","id-type":"ROR","asserted-by":"publisher"}]},{"award":["INV-012045"],"award-info":[{"award-number":["INV-012045"]}],"id":[{"id":"https:\/\/ror.org\/0456r8d26","id-type":"ROR","asserted-by":"publisher"}]},{"award":["INV-040485"],"award-info":[{"award-number":["INV-040485"]}],"id":[{"id":"https:\/\/ror.org\/0456r8d26","id-type":"ROR","asserted-by":"publisher"}]},{"award":["R01AI50684"],"award-info":[{"award-number":["R01AI50684"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]},{"award":["UM1AI7179669"],"award-info":[{"award-number":["UM1AI7179669"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,5,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Tuberculosis lesions are structurally and physiologically heterogeneous, creating microenvironments that restrict antibiotic penetration and alter bacterial susceptibility. This heterogeneity remains a major impediment to shortening tuberculosis treatment, as it is difficult to predict which regimens will sterilize bacteria in these hard-to-treat lesion niches. Many\n                  <jats:italic>in vitro<\/jats:italic>\n                  systems and commonly used animal models fail to recapitulate the necrotic, caseous lesion pathology associated with treatment failure and relapse. Here, we show that resource-efficient\n                  <jats:italic>in vitro<\/jats:italic>\n                  assays engineered to mimic key lesion microenvironments, including those with lipid-rich, caseum-like matrices with controlled oxygenation and pH, generate drug-response metrics that predict lesion-level treatment responses in a non-human primate model. We stratified individual marmoset lesions by baseline 2-deoxy-2-[18F] fluoro-D-glucose ([18F] FDG) positron emission tomography\/computed tomography (PET\/CT) features, then quantified drug potency and interactions across three lipid-induced dormancy (LIDs) conditions under both equipotent and lesion pharmacokinetic-informed dosing schemes. LIDs-based and pharmacokinetic-informed measurements aligned more closely with treatment responses in severe lesions than conventional\n                  <jats:italic>in vitro<\/jats:italic>\n                  data and recapitulated interaction patterns consistent with known regimen performance. Integrating imaging-derived and\n                  <jats:italic>in vitro<\/jats:italic>\n                  features in multivariate, sequential computational models improved predictive accuracy over baseline imaging alone and identified a subset of informative\n                  <jats:italic>in vitro<\/jats:italic>\n                  metrics. Together, these results establish a scalable framework linking lesion-mimicking assays to lesion-specific outcomes, enabling earlier, more cost-effective prioritization of pre-clinical regimens aimed at sterilizing hard-to-treat tuberculosis lesions and shortening therapy.\n                <\/jats:p>","DOI":"10.64898\/2026.05.13.724664","type":"posted-content","created":{"date-parts":[[2026,5,16]],"date-time":"2026-05-16T04:05:21Z","timestamp":1778904321000},"source":"Crossref","is-referenced-by-count":2,"title":["<i>In vitro<\/i>\n                  dormancy models improve ability to predict treatment response in severe marmoset tuberculosis lesions"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-3358-0391","authenticated-orcid":false,"given":"Joshua J.","family":"Whiteley","sequence":"first","affiliation":[{"name":"Department of Biomedical Engineering, Tufts University School of Engineering; Medford, MA, United States."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Talia","family":"Greenstein","sequence":"additional","affiliation":[{"name":"Tufts University School of Graduate Biomedical Sciences; Boston, MA, United States."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariana Pereira","family":"Moraes","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology and Microbiology, Tufts University School of Medicine; Boston, MA, United States."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maral","family":"Budak","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, University of Michigan Medical School; Ann Arbor, MI, United States."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Danielle M.","family":"Weiner","sequence":"additional","affiliation":[{"name":"Tuberculosis Research Section, Laboratory of Clinical Infectious Diseases, NIAID, NIH; Bethesda, MD, United States."},{"name":"Tuberculosis Imaging Program, Division of Intramural Research, NIAID, NIH; Bethesda, MD, United States."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ayan","family":"Abdi","sequence":"additional","affiliation":[{"name":"Tuberculosis Imaging Program, Division of Intramural Research, NIAID, NIH; Bethesda, MD, United States."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joel D.","family":"Fleegle","sequence":"additional","affiliation":[{"name":"Tuberculosis Imaging Program, Division of Intramural Research, NIAID, NIH; Bethesda, MD, United States."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Felipe","family":"Gomez","sequence":"additional","affiliation":[{"name":"Tuberculosis Imaging Program, Division of Intramural Research, NIAID, NIH; Bethesda, MD, United States."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura E.","family":"Via","sequence":"additional","affiliation":[{"name":"Tuberculosis Research Section, Laboratory of Clinical Infectious Diseases, NIAID, NIH; Bethesda, MD, United States."},{"name":"Tuberculosis Imaging Program, Division of Intramural Research, NIAID, NIH; Bethesda, MD, United States."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"suffix":"III","given":"Clifton E.","family":"Barry","sequence":"additional","affiliation":[{"name":"Tuberculosis Research Section, Laboratory of Clinical Infectious Diseases, NIAID, NIH; Bethesda, MD, United States."},{"name":"Centre for Infectious Disease Research in Africa, Institute of Infectious Disease and Molecular Medicine and Department of Medicine, University of Cape Town, Observatory 7925, Republic of South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jansy","family":"Sarathy","sequence":"additional","affiliation":[{"name":"Center for Discovery and Innovation, Hackensack Meridian Health; Nutley, NJ, United States."},{"name":"Hackensack Meridian School of Medicine, Department of Medical Sciences; Nutley, NJ, United States."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Denise","family":"Kirschner","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, University of Michigan Medical School; Ann Arbor, MI, United States."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Veronique","family":"Dartois","sequence":"additional","affiliation":[{"name":"Center for Discovery and Innovation, Hackensack Meridian Health; Nutley, NJ, United States."},{"name":"Hackensack Meridian School of Medicine, Department of Medical Sciences; Nutley, NJ, United States."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2236-1424","authenticated-orcid":false,"given":"Bree B.","family":"Aldridge","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, Tufts University School of Engineering; Medford, MA, United States."},{"name":"Tufts University School of Graduate Biomedical Sciences; Boston, MA, United States."},{"name":"Department of Molecular Biology and Microbiology, Tufts University School of Medicine; Boston, MA, United States."},{"name":"Stuart B. 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Wang , E. Klein , S. N. Cho , C. E. Barry , J. L. Flynn , PET\/CT imaging reveals a therapeutic response to oxazolidinones in macaques and humans with tuberculosis. Sci. Transl. 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