Discipline of Infectious Diseases and Immunology, University of Sydney, Camperdown, New South Wales, Australia.
Division of Immune Regulation, La Jolla Institute for Allergy and Immunology, La Jolla, California, USA.
J Virol. 2019 Jan 17;93(3). doi: 10.1128/JVI.01746-18. Print 2019 Feb 1.
Human cytomegalovirus (HCMV) is a ubiquitous human herpesvirus. While HCMV infection is generally asymptomatic in the immunocompetent, it can have devastating consequences in those with compromised or underdeveloped immune systems, including transplant recipients and neonates. Galectins are a widely expressed protein family that have been demonstrated to modulate both antiviral immunity and regulate direct host-virus interactions. The potential for galectins to directly modulate HCMV infection has not previously been studied, and our results reveal that galectin-9 (Gal-9) can potently inhibit HCMV infection. Gal-9-mediated inhibition of HCMV was dependent upon its carbohydrate recognition domains and thus dependent on glycan interactions. Temperature shift studies revealed that Gal-9 specific inhibition was mediated primarily at the level of virus-cell fusion and not binding. Additionally, we found that during reactivation of HCMV in hematopoietic stem cell transplant (HSCT) patients soluble Gal-9 is upregulated. This study provides the first evidence for Gal-9 functioning as a potent antiviral defense effector molecule against HCMV infection and identifies it as a potential clinical candidate to restrict HCMV infections. Human cytomegalovirus (HCMV) continues to cause serious and often life-threatening disease in those with impaired or underdeveloped immune systems. This virus is able to infect and replicate in a wide range of human cell types, which enables the virus to spread to other individuals in a number of settings. Current antiviral drugs are associated with a significant toxicity profile, and there is no vaccine; these factors highlight a need to identify additional targets for the development of anti-HCMV therapies. We demonstrate for the first time that secretion of a member of the galectin family of proteins, galectin-9 (Gal-9), is upregulated during natural HCMV-reactivated infection and that this soluble cellular protein possesses a potent capacity to block HCMV infection by inhibiting virus entry into the host cell. Our findings support the possibility of harnessing the antiviral properties of Gal-9 to prevent HCMV infection and disease.
人巨细胞病毒（HCMV）是一种普遍存在的人类疱疹病毒。虽然 HCMV 感染在免疫功能正常的人群中通常无症状，但在免疫功能受损或发育不全的人群中，包括移植受者和新生儿，可能会产生毁灭性的后果。半乳糖凝集素是一种广泛表达的蛋白质家族，已被证明能调节抗病毒免疫和调节宿主-病毒相互作用。半乳糖凝集素直接调节 HCMV 感染的潜力尚未得到研究，我们的研究结果表明，半乳糖凝集素-9（Gal-9）可以有效地抑制 HCMV 感染。Gal-9 介导的 HCMV 抑制依赖于其碳水化合物识别结构域，因此依赖于糖相互作用。温度转移研究表明，Gal-9 的特异性抑制主要发生在病毒-细胞融合水平，而不是结合水平。此外，我们发现，在造血干细胞移植（HSCT）患者的 HCMV 再激活过程中，可溶性 Gal-9 上调。这项研究首次提供了 Gal-9 作为针对 HCMV 感染的有效抗病毒防御效应分子的证据，并将其鉴定为限制 HCMV 感染的潜在临床候选物。人巨细胞病毒（HCMV）继续在免疫功能受损或发育不全的人群中引起严重且常常危及生命的疾病。这种病毒能够感染和复制广泛的人类细胞类型，这使得病毒能够在许多环境中传播给其他人。目前的抗病毒药物与显著的毒性谱相关，并且没有疫苗；这些因素突出表明需要确定针对 HCMV 治疗的其他靶标。我们首次证明，半乳糖凝集素家族蛋白成员之一半乳糖凝集素-9（Gal-9）的分泌在自然 HCMV 再激活感染期间上调，并且这种可溶性细胞蛋白具有通过抑制病毒进入宿主细胞来阻断 HCMV 感染的强大能力。我们的研究结果支持利用 Gal-9 的抗病毒特性来预防 HCMV 感染和疾病的可能性。
