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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
Induction of ER stress in macrophages of tuberculosis granulomas
PLoS ONE, Volume 5, No. 9, Article e12772, Year 2010
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Description
Background: The endoplasmic reticulum (ER) stress pathway known as the Unfolded Protein Response (UPR) is an adaptive survival pathway that protects cells from the buildup of misfolded proteins, but under certain circumstances it can lead to apoptosis. ER stress has been causally associated with macrophage apoptosis in advanced atherosclerosis of mice and humans. Because atherosclerosis shares certain features with tuberculosis (TB) with regard to lesional macrophage accumulation, foam cell formation, and apoptosis, we investigated if the ER stress pathway is activated during TB infection. Principal Findings: Here we show that ER stress markers such as C/EBP homologous protein (CHOP; also known as GADD153), phosphorylated inositol-requiring enzyme 1 alpha (Ire1α) and eukaryotic initiation factor 2 alpha (eIF2α), and activating transcription factor 3 (ATF3) are expressed in macrophage-rich areas of granulomas in lungs of mice infected with virulent Mycobacterium tuberculosis (Mtb). These areas were also positive for numerous apoptotic cells as assayed by TUNEL. Microarray analysis of human caseous TB granulomas isolated by laser capture microdissection reveal that 73% of genes involved in the UPR are upregulated at the mRNA transcript level. The expression of two ER stress markers, ATF3 and CHOP, were also increased in macrophages of human TB granulomas when assayed by immunohistochemistry. CHOP has been causally associated with ER stress-induced macrophage apoptosis. We found that apoptosis was more abundant in granulomas as compared to non-granulomatous tissue isolated from patients with pulmonary TB, and apoptosis correlated with CHOP expression in areas surrounding the centralized areas of caseation. Conclusions: In summary, ER stress is induced in macrophages of TB granulomas in areas where apoptotic cells accumulate in mice and humans. Although macrophage apoptosis is generally thought to be beneficial in initially protecting the host from Mtb infection, death of infected macrophages in advanced granulomas might favor dissemination of the bacteria. Therefore future work is needed to determine if ER-stress is causative for apoptosis and plays a role in the host response to infection. © 2010 Seimon et al.
Authors & Co-Authors
Seimon, Tracie A.
United States, New York
Columbia University
Kim, Mi Jeong
United States, Ithaca
Cornell University
Blumenthal, Antje
United States, New York
Weill Cornell Medicine
Australia, Brisbane
The University of Queensland
Koo, Jovanka
United States, New York
Weill Cornell Medicine
Ehrt, Sabine
United States, New York
Weill Cornell Medicine
Wainwright, Helen Cecilia
South Africa, Cape Town
Faculty of Health Sciences
Bekker, Linda-Gail Gail
South Africa, Cape Town
University of Cape Town
Kaplan, Gilla
United States, Newark
Public Health Research Institute
Nathan, Carl F.
United States, New York
Weill Cornell Medicine
Tabas, Ira
United States, New York
Columbia University
Russell, David G.
United States, Ithaca
Cornell University
Statistics
Citations: 124
Authors: 11
Affiliations: 7
Identifiers
Doi:
10.1371/journal.pone.0012772
e-ISSN:
19326203
Research Areas
Cancer
Infectious Diseases