Inflammatory signaling in human tuberculosis granulomas is spatially organized

Mohlopheni J. Marakalala, Ravikiran M. Raju, Kirti Sharma, Yanjia J. Zhang, Eliseo Eugenin, Brendan Prideaux, Isaac B. Daudelin, Pei Yu Chen, Matthew G. Booty, Jin Hee Kim, Seok Yong Eum, Laura E. Via, Samuel M. Behar, Clifton E. Barry, Matthias Mann, Véronique Dartois, Eric J. Rubin

Research output: Contribution to journalArticle

78 Citations (Scopus)

Abstract

Granulomas are the pathological hallmark of tuberculosis (TB). However, their function and mechanisms of formation remain poorly understood. To understand the role of granulomas in TB, we analyzed the proteomes of granulomas from subjects with tuberculosis in an unbiased manner. Using laser-capture microdissection, mass spectrometry and confocal microscopy, we generated detailed molecular maps of human granulomas. We found that the centers of granulomas have a pro-inflammatory environment that is characterized by the presence of antimicrobial peptides, reactive oxygen species and pro-inflammatory eicosanoids. Conversely, the tissue surrounding the caseum has a comparatively anti-inflammatory signature. These findings are consistent across a set of six human subjects and in rabbits. Although the balance between systemic pro- and anti-inflammatory signals is crucial to TB disease outcome, here we find that these signals are physically segregated within each granuloma. From the protein and lipid snapshots of human and rabbit lesions analyzed here, we hypothesize that the pathologic response to TB is shaped by the precise anatomical localization of these inflammatory pathways during the development of the granuloma.

Original languageEnglish (US)
Pages (from-to)531-538
Number of pages8
JournalNature Medicine
Volume22
Issue number5
DOIs
StatePublished - May 1 2016
Externally publishedYes

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Granuloma
Tuberculosis
Microdissection
Anti-Inflammatory Agents
Eicosanoids
Confocal microscopy
Proteome
Mass spectrometry
Reactive Oxygen Species
Tissue
Lipids
Peptides
Lasers
Proteins
Laser Capture Microdissection
Rabbits
Confocal Microscopy
Mass Spectrometry

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Marakalala, M. J., Raju, R. M., Sharma, K., Zhang, Y. J., Eugenin, E., Prideaux, B., ... Rubin, E. J. (2016). Inflammatory signaling in human tuberculosis granulomas is spatially organized. Nature Medicine, 22(5), 531-538. https://doi.org/10.1038/nm.4073

Inflammatory signaling in human tuberculosis granulomas is spatially organized. / Marakalala, Mohlopheni J.; Raju, Ravikiran M.; Sharma, Kirti; Zhang, Yanjia J.; Eugenin, Eliseo; Prideaux, Brendan; Daudelin, Isaac B.; Chen, Pei Yu; Booty, Matthew G.; Kim, Jin Hee; Eum, Seok Yong; Via, Laura E.; Behar, Samuel M.; Barry, Clifton E.; Mann, Matthias; Dartois, Véronique; Rubin, Eric J.

In: Nature Medicine, Vol. 22, No. 5, 01.05.2016, p. 531-538.

Research output: Contribution to journalArticle

Marakalala, MJ, Raju, RM, Sharma, K, Zhang, YJ, Eugenin, E, Prideaux, B, Daudelin, IB, Chen, PY, Booty, MG, Kim, JH, Eum, SY, Via, LE, Behar, SM, Barry, CE, Mann, M, Dartois, V & Rubin, EJ 2016, 'Inflammatory signaling in human tuberculosis granulomas is spatially organized', Nature Medicine, vol. 22, no. 5, pp. 531-538. https://doi.org/10.1038/nm.4073
Marakalala, Mohlopheni J. ; Raju, Ravikiran M. ; Sharma, Kirti ; Zhang, Yanjia J. ; Eugenin, Eliseo ; Prideaux, Brendan ; Daudelin, Isaac B. ; Chen, Pei Yu ; Booty, Matthew G. ; Kim, Jin Hee ; Eum, Seok Yong ; Via, Laura E. ; Behar, Samuel M. ; Barry, Clifton E. ; Mann, Matthias ; Dartois, Véronique ; Rubin, Eric J. / Inflammatory signaling in human tuberculosis granulomas is spatially organized. In: Nature Medicine. 2016 ; Vol. 22, No. 5. pp. 531-538.
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