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  • Kübler, AndréJohns Hopkins Univ, Sch Med, Ctr TB Res, Baltimore, MD USA (author)

Mycobacterium tuberculosis dysregulates MMP/TIMP balance to drive rapid cavitation and unrestrained bacterial proliferation.

  • Article/chapterEnglish2015

Publisher, publication year, extent ...

  • 2014-10-06
  • Wiley,2015
  • printrdacarrier

Numbers

  • LIBRIS-ID:oai:DiVA.org:umu-93713
  • https://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-93713URI
  • https://doi.org/10.1002/path.4432DOI

Supplementary language notes

  • Language:English
  • Summary in:English

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  • Subject category:ref swepub-contenttype
  • Subject category:art swepub-publicationtype

Notes

  • Active tuberculosis (TB) often presents with advanced pulmonary disease, including irreversible lung damage and cavities. Cavitary pathology contributes to antibiotic failure, transmission, morbidity and mortality. Matrix metalloproteinases (MMPs), in particular MMP-1 are implicated in TB pathogenesis. We explored the mechanisms relating MMP/TIMP imbalance to cavity formation in a modified rabbit model of cavitary TB. Our model results in consistent progression of consolidation to human-like cavities (100% by day 28) with resultant bacillary burdens (>10(7) CFU/g) far greater than those found in matched granulomatous tissue (10(5) CFU/g). Using a novel, breath-hold computerized tomography scanning and image analysis protocol. We show that cavities develop rapidly from areas of densely consolidated tissue. Radiological change correlated with a decrease in functional lung tissue as estimated by changes in lung density during controlled pulmonary expansion (R(2) =0.6356, p < 0.0001). We demonstrated that the expression of interstitial collagenase (MMP-1) is specifically greater in cavitary compared to granulomatous lesions (p < 0.01), and that TIMP-3 significantly decreases at the cavity surface. Our findings demonstrate that an MMP-1/TIMP imbalance, is associated with the progression of consolidated regions to cavities containing very high bacterial burdens. Our model provided mechanistic insight, correlating with human disease at the pathological, microbiological and molecular levels,. It also provides a strategy to investigate therapeutics in the context of complex TB pathology. We used these findings to predict a MMP/TIMP balance in active TB; and confirmed this in human plasma, revealing the potential of MMP/TIMP levels as key components of a diagnostic matrix aimed at distinguishing active from latent TB (PPV=92.9%; 95%CI 66.1-99.8%, NPV=85.6%; 95%CI 77.0-91.9%).

Subject headings and genre

Added entries (persons, corporate bodies, meetings, titles ...)

  • Luna, BrianJohns Hopkins Univ, Sch Med, Ctr TB Res, Baltimore, MD USA (author)
  • Larsson, ChristerUmeå universitet,Institutionen för molekylärbiologi (Teknisk-naturvetenskaplig fakultet)(Swepub:umu)chrlan97 (author)
  • Ammerman, Nicole CKwaZulu Natal Res Inst TB & HIV K RITH, Durban, South Africa (author)
  • Andrade, Bruno BNIAID, Immunobiol Sect, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA (author)
  • Orandle, MarleneNIAID, Infect Dis Pathogenesis Sect, Comparat Med Branch, NIH, Bethesda, MD 20892 USA (author)
  • Bock, Kevin WNIAID, Infect Dis Pathogenesis Sect, Comparat Med Branch, NIH, Bethesda, MD 20892 USA (author)
  • Xu, ZiyueNIH, Bethesda, MD 20892 USA (author)
  • Bagci, UlasNIH, Bethesda, MD 20892 USA (author)
  • Molura, Daniel J (author)
  • Marshall, John (author)
  • Burns, Jay (author)
  • Winglee, Kathryn (author)
  • Ahidjo, Bintou Ahmadou (author)
  • Cheung, Laurene S (author)
  • Klunk, Mariah (author)
  • Jain, Sanjay K (author)
  • Kumar, Nathella Pavan (author)
  • Babu, Subash (author)
  • Sher, Alan (author)
  • Friedland, Jon S (author)
  • Elkington, Paul T G (author)
  • Bishai, William R (author)
  • Johns Hopkins Univ, Sch Med, Ctr TB Res, Baltimore, MD USAInstitutionen för molekylärbiologi (Teknisk-naturvetenskaplig fakultet) (creator_code:org_t)

Related titles

  • In:Journal of Pathology: Wiley235:3, s. 431-4440022-34171096-9896

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