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Fibroblasts emerge as major drivers in active TB granuloma and TB-diseased lung tissue, especially the MMP1+CXCL5+ myofibroblast-like fibroblast subset associated with severe disease and higher bacterial burden in nonhuman primate granulomas. Network analyses reveal cross talk between MMP1+CXCL5+ fibroblasts and SPP1+ macrophages in the granuloma cuff, supporting roles in TB immunopathology and informing targets for novel TB therapies.",{"@graph":69,"@context":123},[70,84,106],{"@type":71,"itemListElement":72},"BreadcrumbList",[73,77,79,82],{"item":74,"name":75,"@type":76,"position":8},"https://docshare.wps.com","Home","ListItem",{"item":78,"name":9,"@type":76,"position":14},"https://docshare.wps.com/document/",{"item":80,"name":35,"@type":76,"position":81},"https://docshare.wps.com/document/healthcare/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/single-cell-and-spatial-profiling-highlights-tb-induced-myofibroblasts-as-drivers-of-lung-pathology-introduction/439775/",{"url":83,"name":65,"@type":85,"image":86,"author":91,"headline":65,"publisher":94,"fileFormat":97,"inLanguage":63,"description":67,"dateModified":98,"datePublished":99,"encodingFormat":97,"isAccessibleForFree":100,"interactionStatistic":101},"DigitalDocument",{"url":87,"@type":88,"width":89,"height":90},"https://docshare.wps.com/thumbnails/single-cell-and-spatial-profiling-highlights-tb-induced-myofibroblasts-as-drivers-of-lung-pathology-introduction/439775.png","ImageObject",300,407,{"name":92,"@type":93},"Cart","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-10-31","2026-09-29",true,{"@type":102,"interactionType":103,"userInteractionCount":105},"InteractionCounter",{"@type":104},"ViewAction",14,{"@type":107,"mainEntity":108},"FAQPage",[109,115,119],{"name":110,"@type":111,"acceptedAnswer":112},"What datasets and methods were used to study TB-driven lung pathology?","Question",{"text":113,"@type":114},"Single-cell RNA sequencing and spatial transcriptomics were performed on lung tissues from TB-infected and TB-negative individuals, with findings corroborated by immunohistochemistry, flow cytometry, and independent human datasets.","Answer",{"name":116,"@type":111,"acceptedAnswer":117},"Which cell type is highlighted as a major driver in TB granulomas?",{"text":118,"@type":114},"Fibroblasts are identified as major drivers in both active TB granuloma and TB-diseased lung tissue.",{"name":120,"@type":111,"acceptedAnswer":121},"What specific fibroblast subset is associated with severe TB and higher bacterial burden?",{"text":122,"@type":114},"The MMP1+CXCL5+ fibroblast subset, expressing a myofibroblast-like gene signature, correlates with severe disease and higher bacterial burden in nonhuman primate granulomas.","https://schema.org",{"og:url":83,"og:type":125,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":127,"canonical":83},"index,follow",{"doc_id":129,"site_id":62},439775,1790726781,{"code":4,"msg":5,"data":132},{"doc_id":129,"user_id":133,"nickname":92,"user_avatar":134,"doc_module":4,"category_id":34,"category_name":35,"doc_title":65,"doc_description":67,"doc_content":135,"file_id":136,"file_url":137,"file_type":138,"file_size":139,"view_count":105,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":140,"language":141,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":142,"faqs":143,"seo_title":144,"seo_description":67,"update_tm":145,"read_time":146,"preview_page_count":4},18829141979164,"https://eur-avatar.wpscdn.com/davatar_6f874abed73319feea01a86fa6f0fab8","TECHNICAL ADVANCES AND RESOURCES  \nSingle-cell and spatial profiling highlights TB-induced myofibroblasts as drivers of lung pathology  \nIan M. Mbano1,2*􀀁, Nuo Liu3,4,5,11*􀀁, Marc H. Wadsworth II3,4,5􀀁, Mark J. Chambers1,2􀀁, Thabo Mpotje1,2􀀁, Osaretin E. Asowata1,2􀀁,  \nSarah K. Nyquist3,4,6,7􀀁, Kievershen Nargan1􀀁, Duran Ramsuran1􀀁, Farina Karim1,2􀀁, Travis K. Hughes4,5,8,9􀀁, Joshua D. Bromley3,4,5,10􀀁, Robert Krause1,2􀀁, Threnesan Naidoo1,2􀀁, Liku B. Tezera11,13􀀁, Michaela T. Reichmann11,12􀀁, Sharie Keanne Ganchua17􀀁, Henrik N. Kløverpris1,2,14􀀁, Kaylesh J. Dullabh2􀀁, Rajhmun Madansein2􀀁, Sergio Triana3,4,5􀀁, Adrie J.C. Steyn1,2,15􀀁, Bonnie Berger8,16􀀁, Mohlopheni J. Marakalala1,2,13􀀁, Gabriele Pollara13􀀁, Sarah M. Fortune4,19􀀁, JoAnne L. Flynn17,18􀀁, Paul T. Elkington11,12**􀀁, Alex K. Shalek3,4,5**􀀁, and Alasdair Leslie1,2,13**􀀁  \nTuberculosis (TB) typically causes lung destruction and fibrosis, leading to ∼1.3 million deaths annually. The cellular drivers of human TB immunopathology remain poorly defined. We performed single-cell RNA sequencing and spatial transcriptomics on lung tissues from TB-infected and TB-negative individuals, identifying 30 distinct immune, parenchymal, and stromal cell subsets. Several were linked to TB pathology and corroborated through immunohistochemistry, flow cytometry, and independent human datasets. Fibroblasts were identified as major drivers in both active TB granuloma and TB-diseased lung tissue. In particular, theMMP1+CXCL5+ fibroblast subset, expressing a myofibroblast-like gene signature, was associated with severe disease and higher bacterial burden in nonhuman primate granulomas. Network analyses revealed cross talk between MMP1+CXCL5+ fibroblasts andSPP1+ macrophages within the granuloma cuff, which has been reported in other disease contexts, and may play an important role in TB immunopathology. Our findings highlight previously unappreciated cell populations and potential targets for novel TB therapies.  \nIntroduction  \nTuberculosis (TB), caused by infection with Myco∼bacterium tu  \nberculosis (M.tb), remains a global epidemic, with 10.6 million new cases and 1.3 million deaths annually (Carranza et al., 2020, World Health Organization, 2023). The development of highly effective anti-TB drugs∼ and programmatic improvements led  \nto global cure rates of 85% in drug-susceptible TB from 1995 to 2015, as well as reduced mortality rates (World Health Organization, 2020). Unfortunately, however, mortality remains persistently high (Pai et al., 2022), highlighting the need for improved interventions.  \nM.tb infection occurs primarily in the lung, where interactions between host cells and the pathogen typically result in the formation of a granuloma—an aggregation of infected myeloid cells, usually surrounded by an inner ring of macrophages and an outer cuff of lymphoid cells. This specialized immunological niche is highly heterogeneous in its overall cellular makeup, with the composition of each lesion independently influencing bacterial growth and disease progression (Davis and Ramakrishnan, 2009; McCaffrey et al., 2022) . In progressive TB, extensive lung extracellular matrix (ECM) remodeling via  \n1Africa Health Research Institute, Durban, South Africa; 2School of Laboratory Medicine and Medical Sciences, College of Health Sciences, University of KwaZulu-Natal, Durban, South Africa; 3Institute for Medical Engineering & Science, Department of Chemistry, and Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA; 4Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA, USA; 5Broad Institute of MIT and Harvard, Cambridge, MA, USA; 6Program in Computational & Systems Biology, Massachusetts Institute of Technology, Cambridge, MA, USA; 7Computer Science & Artificial Intelligence Lab, Massachusetts Institute of Technology, Cambridge, MA, USA; 8Program in Health Sciences & Technology, Harvard Medical School and Massachusetts Institute of Tech","cbCaijoIMKIuySLG","https://ap.wps.com/l/cbCaijoIMKIuySLG","pdf",13005591,37,"English","# Introduction\n## Cellular drivers of TB immunopathology\n## Granuloma as a heterogeneous immune niche\n## ECM remodeling and disease progression","[{\"question\":\"What datasets and methods were used to study TB-driven lung pathology?\",\"answer\":\"Single-cell RNA sequencing and spatial transcriptomics were performed on lung tissues from TB-infected and TB-negative individuals, with findings corroborated by immunohistochemistry, flow cytometry, and independent human datasets.\"},{\"question\":\"Which cell type is highlighted as a major driver in TB granulomas?\",\"answer\":\"Fibroblasts are identified as major drivers in both active TB granuloma and TB-diseased lung tissue.\"},{\"question\":\"What specific fibroblast subset is associated with severe TB and higher bacterial burden?\",\"answer\":\"The MMP1+CXCL5+ fibroblast subset, expressing a myofibroblast-like gene signature, correlates with severe disease and higher bacterial burden in nonhuman primate granulomas.\"}]","Single-cell and spatial profiling highlights TB-induced myofibroblasts as drivers of lung pathology - Introduction | PDF",1790690161,93]