• Lin Chen, Wanliang Shi, Hui Li, Xiuli Sun, Xionglin Fan, Gene Lesage, Yi Li, Yi Zhang, Xiumei Zhang, Ying Zhang, and Deling Yin.
• Department of Internal Medicine, College of Medicine, East Tennessee State University, Johnson City, Tennessee, United States of America.
• Plos One. 2010 Jan 1;5(2):e9205.

BackgroundAlthough it is established that opioid and Mycobacterium tuberculosis are both public health problems, the mechanisms by which they affect lung functions remain elusive.Methodology/Principal FindingsWe report here that mice subjected to chronic morphine administration and M. tuberculosis infection exhibited significant apoptosis in the lung in wild type mice as demonstrated by the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling assay. Morphine and M. tuberculosis significantly induced the expression of Toll-like receptor 9 (TLR9), a key mediator of innate immunity and inflammation. Interestingly, deficiency in TLR9 significantly inhibited the morphine and M. tuberculosis induced apoptosis in the lung. In addition, chronic morphine treatment and M. tuberculosis infection enhanced the levels of cytokines (TNF-alpha, IL-1beta, and IL-6) in wild type mice, but not in TLR9 knockout (KO) mice. The bacterial load was much lower in TLR9 KO mice compared with that in wild type mice following morphine and M. tuberculosis treatment. Morphine alone did not alter the bacterial load in either wild type or TLR9 KO mice. Moreover, administration of morphine and M. tuberculosis decreased the levels of phosphorylation of Akt and GSK3beta in the wild type mice, but not in TLR9 KO mice, suggesting an involvement of Akt/GSK3beta in morphine and M. tuberculosis-mediated TLR9 signaling. Furthermore, administration of morphine and M. tuberculosis caused a dramatic decrease in Bcl-2 level but increase in Bax level in wild type mice, but not in TLR9 KO mice, indicating a role of Bcl-2 family in TLR9-mediated apoptosis in the lung following morphine and M. tuberculosis administration.Conclusions/SignificanceThese data reveal a role for TLR9 in the immune response to opioids during M. tuberculosis infection.

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