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.

Circulating full-length osteopontin (FL-OPN) is elevated in plasma from patients with various infectious diseases, such as adult T-cell leukemia, Mycobacterium tuberculosis (TB), hepatitis virus infection, leptospirosis, acquired immune deficiency syndrome (AIDS), AIDS/TB, and coronavirus disease 2019 (COVID-19). Proteolysis of OPN by thrombin, matrix metalloproteases, caspase 8/3, cathepsin D, plasmin, and enterokinase generates various cleaved OPNs with a variety of bioactivities by binding to different target cells. Moreover, OPN is susceptible to gradual proteolysis. During inflammation, one of the cleaved fragments, N-terminal thrombin-cleaved OPN (trOPN or OPN-Arg¹⁶⁸ [OPN-R]), induces dendritic cell (DC) adhesion. Further cleavage by carboxypeptidase B2 or carboxypeptidase N removes Arg¹⁶⁸ from OPN-R to OPN-Leu¹⁶⁷ (OPN-L). Consequently, OPN-L decreases DC adhesion. In particular, the differences in plasma level over time are observed between FL-OPN and its cleaved OPNs during inflammation. We found that the undefined OPN levels (mixture of FL-OPN and cleaved OPN) were elevated in plasma and reflected the pathology of TB and COVID-19 rather than FL-OPN. These infections are associated with elevated levels of various proteases. Inhibition of the cleavage or the activities of cleaved products may improve the outcome of the therapy. Research on the metabolism of OPN is expected to create new therapies against infectious diseases.

Galectin-9 (Gal-9) is known to contribute to antiviral responses in coronavirus disease 2019 (COVID-19). Increased circulating Gal-9 in COVID-19 is associated with COVID-19 severity. In a while, the linker-peptide of Gal-9 is susceptible to proteolysis that can cause the change or loss of Gal-9 activity. Here, we measured plasma levels of N-cleaved-Gal9, which is Gal9 carbohydrate-recognition domain at the N-terminus (NCRD) with attached truncated linker peptide that differs in length depending on the type of proteases, in COVID-19. We also investigated the time course of plasma N-cleaved-Gal9 levels in severe COVID-19 treated with tocilizumab (TCZ). As a result, we observed an increase in plasma N-cleaved-Gal9 levels in COVID-19 and its higher levels in COVID-19 with pneumonia compared to the mild cases (healthy: 326.1 pg/mL, mild: 698.0 pg/mL, and with pneumonia: 1570 pg/mL). N-cleaved-Gal9 levels were associated with lymphocyte counts, C-reactive protein (CRP), soluble interleukin-2 receptor (sIL-2R), D-dimer, and ferritin levels, and ratio of percutaneous oxygen saturation to fraction of inspiratory oxygen (S/F ratio) in COVID-19 with pneumonia and discriminated different severity groups with high accuracy (area under the curve (AUC): 0.9076). Both N-cleaved-Gal9 and sIL-2R levels were associated with plasma matrix metalloprotease (MMP)-9 levels in COVID-19 with pneumonia. Furthermore, a decrease in N-cleaved-Gal9 levels was associated with a decrease of sIL-2R levels during TCZ treatment. N-cleaved-Gal9 levels showed a moderate accuracy (AUC: 0.8438) for discriminating the period before TCZ from the recovery phase. These data illustrate that plasma N-cleaved-Gal9 is a potential surrogate marker for assessing COVID-19 severity and the therapeutic effects of TCZ.

A 75-year-old female with a history of stomach cancer and depression was referred to our hospital for left cervical lymphadenopathy. The biopsy of her left cervical lymph node revealed noncaseating granulomas with multinucleated giant cells. The positron emission tomography/computed tomography (PET/CT) indicated general lymphadenopathy (left supraclavicular left axillary, hepatic lymph nodes), except for the hilar lymph node. Both histology by transbronchial lung biopsy (TBLB) and analysis of broncho alveolar lavage fluid (BALF) were indicative of sarcoidosis. C-reactive protein (CRP) and soluble interleukin-2 receptor (sIL-2R) were increased in the sera. An alternative cause of granulomatous disease was ruled out, and on follow-up, she was diagnosed with sarcoidosis. Two years later, she was hospitalized for fever, anorexia, lymph node tenderness, and erythema nodosum with significant increases in CRP and sIL-2R. After admission, the repetitive axillary lymph biopsy showed the same histological findings as before, but the G-band staining showed clonal abnormalities. Bone marrow biopsy revealed abnormal lymphocytes with petal-like nuclei. Finally, she was diagnosed with malignant lymphoma infiltrating the bone marrow. After CHOP-based chemotherapy, her laboratory data, lymphadenopathy, and clinical findings improved, and she was discharged from the hospital on the 90th day. Careful medical treatment, including genetic analysis of the lymph node, is necessary in patients with sarcoidosis if lymphadenopathy is predominant.

Background and Clinical Significance: COVID-19 may worsen in patients receiving immunosuppressants. Furthermore, drug–drug interactions and concomitant use of anti-inflammatory drugs complicate treatment. We report the clinical course of severe COVID-19 pneumonia in a 74-year-old Japanese male kidney transplant recipient. Case Presentation: The patient had been taking tacrolimus (TAC) (2.5 mg/day), mycophenolate mofetil (1000 mg/day), and prednisone (5 mg/day) since his kidney transplant 7 years earlier. Twenty days before admission, he tested positive for SARS-CoV-2 antigen and was administered molnupiravir for 5 days. At admission, real-time PCR testing of a nasopharyngeal specimen revealed high viral loads, with Ct values of 22.2 and 27.9 for the E and N2 genes, respectively. An oxygen flow rate of 15 L/min was required to maintain arterial oxygen saturation above 90%. TAC was continued, and antibiotics, steroids, anti-interleukin-6 receptor antibodies, intravenous immunoglobulin, and ensitrelvir (ESV) were administered. With invasive positive-pressure ventilation, positive end-expiratory pressure (PEEP), and prone positioning, the arterial oxygen tension/inspired oxygen tension (P/F) improved from 61.3 to 386 within 7 h. The patient was extubated 30 h after admission. The TAC dose was adjusted from 2.5 mg/day to 1 mg/day to achieve the target trough level. The patient was discharged on hospital day 8. PCR testing at discharge showed a decrease in viral load. Conclusions: This study provides insights into the treatment of COVID-19 in patients receiving immunosuppressants. Combination therapy of ESV and TAC was feasible in kidney transplant recipients with dose adjustment. The use of other anti-inflammatory drugs should also be considered.

A COVID-19 patient (53-year-old woman from Japan) was admitted to our hospital. She had a high fever (38.3 °C), cough, fatigue, and loss of appetite. She was a smoker and took migraine medication. A thoracic computed tomography (CT) scan showed no evidence of pneumonia. She was treated with antibiotics, protease inhibitors, inhalant corticosteroids, and antivirals. Anti-interleukin-6 receptor antibody tocilizumab (TCZ 400 mg) was added on day 2. On day 4, her temperature decreased, but her vital signs suddenly worsened, with an SpO₂ of 70% in ambient air, a blood pressure of 70 mmHg (systolic), loss of consciousness, and tachypnea. Her CT showed bilateral lung consolidation and no pulmonary embolism. She was connected to the ventilator. On day 11, her respiratory condition improved (PaO₂/FIO₂ 400), and she was able to withdraw from the ventilator. Her laboratory data (white cell count, ferritin, d-Dimer, C-reactive protein, and β₂-microglobulin) did not increase even at the time of exacerbation, except for Galectin-9 (Gal-9). The plasma Gal-9 levels increased 2.3 times from before the administration of TCZ, followed by a swift decrease associated with improvements in respiratory status. She was discharged on day 16. Patients with TCZ-treated COVID-19 require careful observation.