Tuberculosis : An international study conducted by the teams of Drs. Isabelle Maridonneau-Parini and Olivier Neyrolles at the Institute of Pharmacology and Structural Biology reports the identification and characterization of an anti-inflammatory human monocyte population, shaped by the infectious microenvironment, which favors the resilience of Mycobacterium tuberculosis and is deleterious to the host immune response against this intracellular pathogen. The results of this study are published in the international peer-reviewed journal Cell Research.
Tuberculosis is a widespread, infectious disease caused by different strains of mycobacteria, but most commonly by Mycobacterium tuberculosis. In 2013, there were 9 million cases of tuberculosis, accounting for an estimated total of 1.5 million deaths in the world, ultimately ranking this disease as the second most deadly one due to a single infectious agent (WHO, 2014). Without doubt, better diagnostic tools and correct treatment to complement existing technologies would make most tuberculosis cases curable. At the heart of this issue is the role played by fundamental science to better characterize the interface between M. tuberculosis and the human host. In humans, there are two types of monocyte populations distinguished by the extra-cellular surface expression of the CD16 receptor, which are either negative or positive. In healthy subjects, there is a range between 5-10% of circulating CD16+monocytes; in tuberculosis patients, this monocyte population increases even up 70%! The origin and consequences for this expansion of CD16+monocytes remain unknown in tuberculosis.
Thanks to an international collaboration between multiple research teams, we have become a step closer to better understand the expansion of CD16+ monocytes in tuberculosis. First, the expansion of CD16+monocytes appears to be part of a differentiation program towards anti-inflammatory macrophages that are characterized by cell-surface receptor repertory, including CD163 and MerTK. Indeed, this differentiation program, including the shedding of the CD163 receptor into a soluble form, is heavily accentuated according to disease severity, as correlated in both tuberculosis patients and in a non-human primate model of M. tuberculosis infection. Second, the CD16+ monocyte expansion is accompanied by a functional program distinguished by an increase capacity to migrate in dense environments (mimicking tissues such as lungs), a decreased ability to control the bacillus’ intracellular growth, and immuno-modulatory activity that includes a diminished activation of T lymphocytes, and thus reflecting a probable deleterious role in the immune response against M. tuberculosis. Finally, at the molecular level, the origin of the CD16+ monocyte expansion along with the phenotypic and functional program is due to activation of the transcription factor STAT3 by the proposed secretion of the cytokine IL-10, an anti-inflammatory signaling molecule that is secreted by infected macrophages and that is known to be elevated in the serum of patients with active tuberculosis.
Altogether, this study promotes novel therapeutic applications. On the one hand, the activation of STAT3 along with the phenotypic profile (CD16, CD163 and MerTK) form part of a biological signature that is directly correlated according to the severity of tuberculosis disease. In particular, the detection of the soluble form of CD163 in the serum may serve as an important diagnostic tool to better diagnose and monitor disease severity, and to follow anti-tuberculosis treatment and the risk of relapse. On the other hand, the proposed pharmacological inhibition of the IL-10/STAT3 axis could represent a novel therapeutic approach to complement existing antibiotic treatments and to restore the immune response efficiency against tuberculosis.
This study was performed in collaboration with the research teams of Drs. M.C. Sasiain (National Academy of Medicine, Buenos Aires, Argentina), V. Rasolofo (Pasteur Institute of Madagascar) and F.A.W. Verreck (Biomedical Primate Research Centre, Rijswijk, Pays-Bas)
Anti-inflammatory macrophages (green), expressed STAT3 (red) in the cell nucleus (blue), in the context of non-human primate pulmonary tuberculous granuloma. © Shanti Souriant - IPBS (CNRS/UPS)
Claire Lastrucci, Alan Bénard, Luciana Balboa, Karine Pingris, Shanti Souriant, Renaud Poincloux, Talal Al Saati, Voahangy Rasolofo, Pablo González-Montaner, Sandra Inwentarz, Eduardo Jose Moraña, Ivanela Kondova, Frank A.W. Verreck, Maria del Carmen Sasiain, Olivier Neyrolles, Isabelle Maridonneau-Parini, Geanncarlo Lugo-Villarino, Céline Cougoule. Tuberculosis is associated with expansion of a motile, permissive and immunomodulatory CD16+ monocyte population via the IL-10/STAT3 axis. Cell Research 20 October 2015 Read the article...
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Olivier Neyrolles l T 05 61 17 54 75 l Olivier.Neyrolles@ipbs.fr
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