As introduced in last years report we have been investigating the use of heme oxygenase-1 and related molecules produced in response to tissue damage as disease biomarkers in human tuberculosis. M. tuberculosis triggers free radical production in infected macrophages which leads to oxidative burst and lipid peroxidation. Excessive oxidative stress is seen in patients with pulmonary TB and is associated with tissue necrosis and cavitary disease. The host produces a variety of anti-oxidant mediators to circumvent the detrimental effects of oxidative stress. In the lungs, the transcription factor NRF-2 is highly expressed and is thought to be a major regulator of the anti-oxidant responses. One of the most important NRF-2 products is the enzyme heme oxygenase-1 (HO-1) that induces cytoprotection by metabolizing free heme, a highly toxic molecule released as a consequence of tissue damage. As introduced previously and published this year (see Scientific Advance below), we measured the enzyme in plasma samples in Indian TB patients and found that concentrations of HO-1 are increased during pulmonary TB and are highest in those patients with bilateral lung lesions and smear positive M. tuberculosis. Moreover, statistical analysis demonstrated that HO-1 levels can be used to discriminate active from latent TB and importantly that the elevations in plasma HO-1 levels seen in TB patients were completely reversed after successful anti-TB therapy. The association of HO-1 levels and active TB was later confirmed in a second study population in Salvador Brazil by our collaborator Theolis Barbosa Bessa. In work performed during this report period we compared HO-1 levels with those of other systemically expressed products of oxidative stress and tissue damage and asked whether combined measurement of these mediators with HO-1 can increase the accuracy and sensitivity of the HO-1 based assay. We found that plasma concentrations of several metalloproteinases (MMP), such as MMP-1, MMP-8 and MMP-9, are increased in active TB patients compared to those with latent infection. Intriguingly, systemic concentrations of these three MMPs are inversely correlated with HO-1 values, such that patients exhibiting high levels of HO-1 display relatively low levels of MMPs and vice versa. While testing combinations of different MMPs and HO-1 to increase accuracy in detecting active disease in our Indian cohort, we observed that the diagnosis performance achieves maximum levels when values of HO-1 and MMP-1 are considered, rather than each biomarker alone. The intriguing observation of a dichotomy in active TB patients with regard to plasma concentrations of HO-1 and MMPs led us to examine the cellular basis of this phenomenon . To do so we employed in vitro models using M. tuberculosis infection of human monocyte-differentiated macrophages and verified that macrophages upregulate production of HO-1 and preferentially MMP-1 (amongst other MMPs). Moreover, MMP-1 induction is reduced in conditions in which HO-1 is overexpressed as a result of pharmacological treatment. We have also demonstrated that both production of reactive oxygen species (ROS) and viable mycobacteria are required for proper induction of HO-1, but not MMP-1, upon M. tuberculosis infection. These findings argue that in macrophages M. tuberculosis induces HO-1 and MMP-1 expression via distinct signals and pathways that may cross regulate each other. In another study, based on results generated in the mouse model of tuberculosis, we investigated the relationship of IL-1 family members, lipid mediators and interferons in TB patients. In two separate study sites, India and China, respectively, we found that the IL-1 response was dampened with pulmonary TB disease status compared to healthy controls or latently infected individuals. Moreover, profiling lipid mediators, such as prostaglandins and lipoxins in combination with IL-1 and interferons, allowed for faithful discrimination of and stratification of disease severity among active TB patients, suggesting that these pathways are uniquely associated with the spectra of pulmonary pathology observed in TB patients.

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Kubler, Andre; Larsson, Christer; Luna, Brian et al. (2016) Cathepsin K Contributes to Cavitation and Collagen Turnover in Pulmonary Tuberculosis. J Infect Dis 213:618-27
Kübler, André; Luna, Brian; Larsson, Christer et al. (2015) Mycobacterium tuberculosis dysregulates MMP/TIMP balance to drive rapid cavitation and unrestrained bacterial proliferation. J Pathol 235:431-44
Mayer-Barber, Katrin D; Sher, Alan (2015) Cytokine and lipid mediator networks in tuberculosis. Immunol Rev 264:264-75
Andrade, Bruno B; Pavan Kumar, Nathella; Amaral, Eduardo P et al. (2015) Heme Oxygenase-1 Regulation of Matrix Metalloproteinase-1 Expression Underlies Distinct Disease Profiles in Tuberculosis. J Immunol 195:2763-73
Andrade, Bruno B; Singh, Amrit; Narendran, Gopalan et al. (2014) Mycobacterial antigen driven activation of CD14++CD16- monocytes is a predictor of tuberculosis-associated immune reconstitution inflammatory syndrome. PLoS Pathog 10:e1004433
Andrade, Bruno B; Pavan Kumar, Nathella; Sridhar, Rathinam et al. (2014) Heightened plasma levels of heme oxygenase-1 and tissue inhibitor of metalloproteinase-4 as well as elevated peripheral neutrophil counts are associated with TB-diabetes comorbidity. Chest 145:1244-54
Barber, Daniel L; Andrade, Bruno B; McBerry, Cortez et al. (2014) Role of IL-6 in Mycobacterium avium--associated immune reconstitution inflammatory syndrome. J Immunol 192:676-82
Narendran, Gopalan; Andrade, Bruno B; Porter, Brian O et al. (2013) Paradoxical tuberculosis immune reconstitution inflammatory syndrome (TB-IRIS) in HIV patients with culture confirmed pulmonary tuberculosis in India and the potential role of IL-6 in prediction. PLoS One 8:e63541
Andrade, Bruno B; Pavan Kumar, Nathella; Mayer-Barber, Katrin D et al. (2013) Plasma heme oxygenase-1 levels distinguish latent or successfully treated human tuberculosis from active disease. PLoS One 8:e62618
Andrade, Bruno Bezerril; Hullsiek, Katherine Huppler; Boulware, David R et al. (2013) Biomarkers of inflammation and coagulation are associated with mortality and hepatitis flares in persons coinfected with HIV and hepatitis viruses. J Infect Dis 207:1379-88

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