Abstract
Tuberculosis (TB) caused by Mycobacterium tuberculosis (Mtb) is a global health problem. At present, prior exposure to Mtb can be determined by blood-based interferon-gamma release assay (IGRA), but active TB is not always detectable by blood tests such as CRP and ESR. This study was undertaken to investigate whether leucine-rich alpha-2 glycoprotein (LRG), a new inflammatory biomarker, could be used to assess active disease of TB. Cynomolgus macaques pretreated with or without Bacille Calmette-Guerin (BCG) vaccination were inoculated with Mtb to induce active TB. Blood was collected over time from these animals and levels of LRG as well as CRP and ESR were quantified. In the macaques without BCG vaccination, Mtb inoculation caused extensive TB and significantly increased plasma CRP and LRG levels, but not ESR. In the macaques with BCG vaccination, whereas Mtb challenge caused pulmonary TB, only LRG levels were significantly elevated. By immunohistochemical analysis of the lung, LRG was visualized in epithelioid cells and giant cells of the granulation tissue. In humans, serum LRG levels in TB patients were significantly higher than those in healthy controls and declined one month after anti-tubercular therapy. These findings suggest that LRG is a promising biomarker when performed following IGRA for the detection of active TB.
Highlights
Tuberculosis (TB) caused by Mycobacterium tuberculosis (Mtb) is a global health problem
When the optimal cutoff values were determined by receiver operating characteristic (ROC) curve analysis of all macaques (Fig. 3C), the sensitivity, specificity, positive predictive value and negative predictive value for leucine-rich alpha-2 glycoprotein (LRG) in discriminating macaque TB were 100%, 100%, 100% and 100%, respectively, which were superior to those for erythrocyte sedimentation rate (ESR) (55.0%, 90.0%, 84.6% and 66.7%, respectively) or those for C-reactive protein (CRP) (50.0%, 95.0%, 90.9% and 65.5%, respectively). These results suggest that LRG is a better marker than ESR or CRP in detecting active TB, for those that received Bacille CalmetteGuerin (BCG) vaccination
Like humans, acute phase reactants including LRG and CRP are elevated in non-human primate (NHP) during inflammation
Summary
Tuberculosis (TB) caused by Mycobacterium tuberculosis (Mtb) is a global health problem. Prior exposure to Mtb can be determined by blood-based interferon-gamma release assay (IGRA), but active TB is not always detectable by blood tests such as CRP and ESR. In the macaques without BCG vaccination, Mtb inoculation caused extensive TB and significantly increased plasma CRP and LRG levels, but not ESR. Serum LRG levels in TB patients were significantly higher than those in healthy controls and declined one month after anti-tubercular therapy. These findings suggest that LRG is a promising biomarker when performed following IGRA for the detection of active TB. Given that there has been no report about the utilization of LRG in detecting active TB, here we examined LRG levels in a non-human primate (NPH) model of TB and in human TB patients
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