Elevated Levels of Galectin-9 but Not Osteopontin in HIV and Tuberculosis Infections Indicate Their Roles in Detecting MTB Infection in HIV Infected Individuals

Abstract

Galectin-9 (Gal-9) and osteopontin (OPN) play immunomodulatory roles in tuberculosis and HIV infections. Evaluation of their levels as well as their interplay with different pro-inflammatory cytokines is critical to understand their role in immunopathogenesis of HIV/tuberculosis co-infection considering the complexity of the disease. Plasma levels of these proteins were measured by ELISAs in HIV-negative individuals with pulmonary (n = 21), extrapulmonary (n = 33), and latent tuberculosis (n = 22) and in HIV infected patients with pulmonary (n = 14), latent tuberculosis (n = 17), and without tuberculosis (n = 41). Levels of pro-inflammatory cytokines were estimated by Luminex assay. Receiver operated characteristic curve analysis was performed to evaluate discriminatory roles of these proteins. Spearman's correlation analysis was performed with the markers of HIV and tuberculosis disease progression to evaluate their immunopathogenic roles. Gal-9 and OPN levels were higher in HIV uninfected patients with active tuberculosis than with latent tuberculosis. Gal-9 but not OPN levels were higher in HIV infected patients with active tuberculosis than with latent tuberculosis. Area under curve for Galectin-9 was >0.9 in HIV/tuberculosis coinfection and extrapulmonary tuberculosis. OPN and IL-6 levels were higher in patients with severe chest X-ray grade indicating its association with severity of the disease and positively correlated with each other. Stronger positive and negative correlations of Gal-9 levels, respectively, with viral loads and CD4 cell counts in HIV infected patients were observed than OPN levels indicating their association with HIV disease progression. Thus, significantly elevated Gal-9 levels were reported for the first time in HIV/tuberculosis co-infection and extrapulmonary tuberculosis in our study than single infections with HIV and tuberculosis. The study indicated a need for further evaluation of monitoring role of Gal-9 for detection of developing tuberculosis in HIV infected individuals. The findings also indicated differential roles of Gal-9 and OPN in the pathogenesis of tuberculosis and HIV infections.

Blood Levels of Galectin-9, an Immuno-Regulating Molecule, Reflect the Severity for the Acute and Chronic Infectious Diseases

“…Recently, an assay to measure the cleaved form of Gal-9 was developed [ 50 ]. A biomarker analysis conducted in patients with HIV/OI revealed that levels of Tr-Gal-9 markedly reflect the disease severity of the co-infected individuals [ 53 , 96 ]. The Tr-Gal-9 may be generated via cleavage by MMP-9, which has also been proposed to be a non-sputum-based biomarker for differentiating pulmonary TB and extrapulmonary TB [ 97 ].…”

Both Full-Length and Protease-Cleaved Products of Osteopontin Are Elevated in Infectious Diseases

“…Ud-OPN and IL-6 levels were higher in patients with severe chest X-ray grade, indicating their association with disease severity, and were positively correlated with each other [114]. The plasma levels of Ud-OPN were significantly higher in patients with severe PTB in which lesions involved four or more zones without cavities or more than three zones with cavities, as compared with those with non-severe PTB (Table 2).…”

“…Ud-OPN levels were also significantly higher in patients with AIDS/TB and TB [105,106,114]. Although the OPN levels were significantly higher in human immunodeficiency virus (HIV)-negative pulmonary TB (PTB) patients than in those with latent TB, the same trend was not observed in HIV-infected patients, indicating its limitation in detecting TB development in HIV infection [114]. The levels decreased significantly after successful TB treatment, as indicated by clinical improvement or sputum smear conversion, suggesting its potential to monitor the effect of treatment [104,121].…”

“…Higher levels were found in acquired immune deficiency syndrome (AIDS) associated with TB (AIDS/TB) [106]. Ud-OPN levels were also significantly higher in patients with AIDS/TB and TB [105,106,114]. Although the OPN levels were significantly higher in human immunodeficiency virus (HIV)-negative pulmonary TB (PTB) patients than in those with latent TB, the same trend was not observed in HIV-infected patients, indicating its limitation in detecting TB development in HIV infection [114].…”

“…Detailed analysis of brain tissues and CSF showed elevated levels of OPN in HIVassociated dementia, and it was implicated that OPN stimulates HIV-1 replication in the brain [94]. Recently it was shown that OPN levels showed significant negative correlation with CD4 counts (r = −0.345) and showed significant positive correlation with viral loads (r = 0.334) of the HIV-infected patients, indicating that systemic replication might also be enhanced by OPN [114].…”