Plasma Levels of a Cleaved Form of Galectin-9 Are the Most Sensitive Biomarkers of Acquired Immune Deficiency Syndrome and Tuberculosis Coinfection

Padilla, Shirley T.; Niki, Toshiro; Furushima, Daisuke; Bai, Gaowa; Chagan-Yasutan, Haorile; Telan, Elizabeth Freda O.; Tactacan-Abrenica, Rosario Jessica; Maeda, Yosuke; Solante, Rontgene; Hattori, Toshio

doi:10.3390/biom10111495

Cited by 15 publications

(21 citation statements)

References 32 publications

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“…This might be related to their hyperimmune activation status or infection-associated indirect cell damage. Gal-9 is reported to be degraded swiftly by proteinases (47). This might be a protective mechanism to prevent off-target effects of this immunomodulatory protein.…”

Section: Discussionmentioning

confidence: 99%

“…For instance, it has been reported that the fulllength Gal-9 (F-Gal-9) levels were extremely elevated in dengue fever (38). However, the cleaved/truncated from of Gal-9 (T-Gal-9) was considered a more sensitive biomarker to distinguish HIV-infected individuals from those coinfected with tuberculosis (47). Therefore, it would be worth examining F-Gal-9 versus T-Gal-9 levels in COVID-19 patients since the R&D Systems ELISA kit quantifies both forms of Gal-9.…”

Section: Discussionmentioning

confidence: 99%

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Galectin-9, a Player in Cytokine Release Syndrome and a Surrogate Diagnostic Biomarker in SARS-CoV-2 Infection

Bozorgmehr

Mashhouri

Rosero

et al. 2021

mBio

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The outbreak of SARS-CoV-2 infection has enormously impacted our lives. Clinical evidence has implicated the emergence of cytokine release syndrome as the prominent cause of mortality in COVID-19 patients. In this study, we observed massive elevation of plasma Galectin-9 (Gal-9) in COVID-19 patients compared to healthy controls (HCs). By using the receiver operating characteristic (ROC) curve, we found that a baseline of 2,042 pg/ml plasma Gal-9 can differentiate SARS-CoV-2-infected from noninfected individuals with high specificity/sensitivity (95%). Analysis of 30 cytokines and chemokines detected a positive correlation of the plasma Gal-9 with C-reactive protein (CRP) and proinflammatory cytokines/chemokines such as interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-α), IP-10, MIP-1α, and MCP-1 but an inverse correlation with transforming growth factor β (TGF-β) in COVID-19 patients. In agreement, we found enhanced production of IL-6 and TNF-α by monocytes and NK cells of COVID-19 patients once treated with the recombinant human Gal-9 in vitro. Also, we observed that although the cell-membrane expression of Gal-9 on monocytes does not change in COVID-19 patients, those with higher Gal-9 expression exhibit an activated phenotype. Furthermore, we noted significant downregulation of surface Gal-9 in neutrophils from COVID-19 patients compared to HCs. Our further investigations indicated that immune activation following SARS-CoV-2 infection results in Gal-9 shedding from neutrophils. The strong correlation of Gal-9 with proinflammatory mediators suggests that inhibition of Gal-9 may severe as a therapeutic approach in COVID-19 infection. Besides, the plasma Gal-9 measurement may be used as a surrogate diagnostic biomarker in COVID-19 patients. IMPORTANCE The outbreak of SARS-CoV-2 infection has enormously impacted our lives. Clinical evidence has implicated the emergence of cytokine release syndrome as the prominent cause of mortality in COVID-19 patients. We observed substantial elevation of the plasma Galectin-9 (Gal-9) in COVID-19 patients compared to healthy controls. Gal-9 is an abundant protein in many immune and nonimmune cells. We found that Gal-9 detection assay can differentiate SARS-CoV-2-infected from noninfected individuals with a specificity/sensitivity of 95%. Importantly, we found a positive correlation of the plasma Gal-9 with a wide range of proinflammatory biomarkers in COVID-19 patients. In agreement, we found enhanced expression and production of such proinflammatory molecules by immune cells of COVID-19 patients once treated with Gal-9 in vitro. Our results propose Gal-9 as an important contributing factor in cytokine release syndrome; therefore, Gal-9 inhibition may serve as a beneficial therapeutic approach by suppressing the hyperimmune activation in COVID-19 patients.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Galectin-9, a Player in Cytokine Release Syndrome and a Surrogate Diagnostic Biomarker in SARS-CoV-2 Infection

Bozorgmehr

Mashhouri

Rosero

et al. 2021

mBio

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“…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 ].…”

Section: Galectin-9 In a Variety Of Infectious Diseasesmentioning

confidence: 99%

“…Furthermore, it was demonstrated that the exposure to lipoarabinomannan (LAM), a lipid virulence factor secreted by M. tuberculosis , of monocytes during differentiation toward macrophages downregulates their Gal-9 expression, consequently leading to the development of monocyte-derived macrophages (MDM) with a reduced capacity to respond to inflammatory stimuli and restrict M. tuberculosis growth [ 132 ]. Recent study indicated that the plasma levels of Gal-9 in TB patients was significantly higher compared with healthy control subjects ( Table 1 ) and proposed Gal-9 as a biomarker for TB [ 53 ].…”

Section: Galectin-9 In a Variety Of Infectious Diseasesmentioning

confidence: 99%

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

et al. 2021

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Galectin-9 (Gal-9) is a β-galactoside-binding lectin capable of promoting or suppressing the progression of infectious diseases. This protein is susceptible to cleavage of its linker-peptides by several proteases, and the resulting cleaved forms, N-terminal carbohydrate recognition domain (CRD) and C-terminal CRD, bind to various glycans. It has been suggested that full-length (FL)-Gal-9 and the truncated (Tr)-Gal-9s could exert different functions from one another via their different glycan-binding activities. We propose that FL-Gal-9 regulates the pathogenesis of infectious diseases, including human immunodeficiency virus (HIV) infection, HIV co-infected with opportunistic infection (HIV/OI), dengue, malaria, leptospirosis, and tuberculosis (TB). We also suggest that the blood levels of FL-Gal-9 reflect the severity of dengue, malaria, and HIV/OI, and those of Tr-Gal-9 markedly reflect the severity of HIV/OI. Recently, matrix metallopeptidase-9 (MMP-9) was suggested to be an indicator of respiratory failure from coronavirus disease 2019 (COVID-19) as well as useful for differentiating pulmonary from extrapulmonary TB. The protease cleavage of FL-Gal-9 may lead to uncontrolled hyper-immune activation, including a cytokine storm. In summary, Gal-9 has potential to reflect the disease severity for the acute and chronic infectious diseases.

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“…We previously reported that analysis by enzyme-linked immunosorbent assay (ELISA) differentiated between the levels of the cleaved form of OPN (undefined (Ud)-OPN) and FL-OPN [ 27 ]. Recently, we established the ELISA system which can differentiate the truncated form of Gal-9 (Tr-Gal9) and FL-Gal9 [ 34 ], and reported that plasma levels of Tr-Gal9 reflected inflammation and the severity of disease in acquired immunodeficiency syndrome (AIDS) and AIDS associated with tuberculosis (AIDS/TB) patients [ 35 ].…”

Section: Introductionmentioning

confidence: 99%

High Levels of the Cleaved Form of Galectin-9 and Osteopontin in the Plasma Are Associated with Inflammatory Markers That Reflect the Severity of COVID-19 Pneumonia

Bai

Furushima

Niki

et al. 2021

IJMS

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Numbers of patients with coronavirus disease 2019 (COVID-19) have increased rapidly worldwide. Plasma levels of full-length galectin-9 (FL-Gal9) and osteopontin (FL-OPN) as well as their truncated forms (Tr-Gal9, Ud-OPN, respectively), are representative inflammatory biomarkers. Here, we measured FL-Gal9, FL-OPN, Tr-Gal9, and Ud-OPN in 94 plasma samples obtained from 23 COVID-19-infected patients with mild clinical symptoms (CV), 25 COVID-19 patients associated with pneumonia (CP), and 14 patients with bacterial infection (ID). The four proteins were significantly elevated in the CP group when compared with healthy individuals. ROC analysis between the CV and CP groups showed that C-reactive protein had the highest ability to differentiate, followed by Tr-Gal9 and ferritin. Spearman’s correlation analysis showed that Tr-Gal9 and Ud-OPN but not FL-Gal9 and FL-OPN, had a significant association with laboratory markers for lung function, inflammation, coagulopathy, and kidney function in CP patients. CP patients treated with tocilizumab had reduced levels of FL-Gal9, Tr-Gal9, and Ud-OPN. It was suggested that OPN is cleaved by interleukin-6-dependent proteases. These findings suggest that the cleaved forms of OPN and galectin-9 can be used to monitor the severity of pathological inflammation and the therapeutic effects of tocilizumab in CP patients.

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Plasma Levels of a Cleaved Form of Galectin-9 Are the Most Sensitive Biomarkers of Acquired Immune Deficiency Syndrome and Tuberculosis Coinfection

Cited by 15 publications

References 32 publications

Galectin-9, a Player in Cytokine Release Syndrome and a Surrogate Diagnostic Biomarker in SARS-CoV-2 Infection

Galectin-9, a Player in Cytokine Release Syndrome and a Surrogate Diagnostic Biomarker in SARS-CoV-2 Infection

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

High Levels of the Cleaved Form of Galectin-9 and Osteopontin in the Plasma Are Associated with Inflammatory Markers That Reflect the Severity of COVID-19 Pneumonia

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