Transcriptional reprogramming in nonhuman primate (Rhesus Macaque) tuberculosis granulomas

Smriti Mehra, Bapi Pahar, Noton Dutta, Cecily N. Conerly, Kathrine Philippi-Falkenstein, Xavier Alvarez, Deepak Kaushal

Research output: Contribution to journalArticle

Abstract

Background: In response to Mtb infection, the host remodels the infection foci into a dense mass of cells known as the granuloma. The key objective of the granuloma is to contain the spread of Mtb into uninfected regions of the lung. However, it appears that Mtb has evolved mechanisms to resist killing in the granuloma. Profiling granuloma transcriptome will identify key immune signaling pathways active during TB infection. Such studies are not possible in human granulomas, due to various confounding factors. Nonhuman Primates (NHPs) infected with Mtb accurately reflect human TB in clinical and pathological contexts. Methodology/Principal Findings: We studied transcriptomics of granuloma lesions in the lungs of NHPs exhibiting active TB, during early and late stages of infection. Early TB lesions were characterized by a highly pro-inflammatory environment, expressing high levels of immune signaling pathways involving IFNγ, TNFα, JAK, STAT and C-C/C-X-C chemokines. Late TB lesions, while morphologically similar to the early ones, exhibited an overwhelming silencing of the inflammatory response. Reprogramming of the granuloma transcriptome was highly significant. The expression of ~ two-thirds of all genes induced in early lesions was later repressed. Conclusions/Significance: The transcriptional characteristics of TB granulomas undergo drastic changes during the course of infection. The overwhelming reprogramming of the initial pro-inflammatory surge in late lesions may be a host strategy to limit immunopathology. We propose that these host profiles can predict changes in bacterial replication and physiology, perhaps serving as markers for latency and reactivation.

Original languageEnglish (US)
Article numbere12266
JournalPLoS One
Volume5
Issue number8
DOIs
StatePublished - 2010
Externally publishedYes

Fingerprint

granuloma
Macaca mulatta
Granuloma
tuberculosis
Primates
Tuberculosis
CXC Chemokines
lesions (animal)
Physiology
Genes
Infection
infection
transcriptome
Bacterial Physiological Phenomena
lungs
immunopathology
Lung
Gene Expression Profiling
transcriptomics
Transcriptome

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Mehra, S., Pahar, B., Dutta, N., Conerly, C. N., Philippi-Falkenstein, K., Alvarez, X., & Kaushal, D. (2010). Transcriptional reprogramming in nonhuman primate (Rhesus Macaque) tuberculosis granulomas. PLoS One, 5(8), [e12266]. https://doi.org/10.1371/journal.pone.0012266

Transcriptional reprogramming in nonhuman primate (Rhesus Macaque) tuberculosis granulomas. / Mehra, Smriti; Pahar, Bapi; Dutta, Noton; Conerly, Cecily N.; Philippi-Falkenstein, Kathrine; Alvarez, Xavier; Kaushal, Deepak.

In: PLoS One, Vol. 5, No. 8, e12266, 2010.

Research output: Contribution to journalArticle

Mehra, S, Pahar, B, Dutta, N, Conerly, CN, Philippi-Falkenstein, K, Alvarez, X & Kaushal, D 2010, 'Transcriptional reprogramming in nonhuman primate (Rhesus Macaque) tuberculosis granulomas', PLoS One, vol. 5, no. 8, e12266. https://doi.org/10.1371/journal.pone.0012266
Mehra, Smriti ; Pahar, Bapi ; Dutta, Noton ; Conerly, Cecily N. ; Philippi-Falkenstein, Kathrine ; Alvarez, Xavier ; Kaushal, Deepak. / Transcriptional reprogramming in nonhuman primate (Rhesus Macaque) tuberculosis granulomas. In: PLoS One. 2010 ; Vol. 5, No. 8.
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