Fig. 1.

An immunological equilibrium is needed during viral infections and Siglecs could be a key to this equilibrium. The lack of adequate immune responses to viral infection can result in uncontrolled viral replication and worse disease outcome (left) whereas hyper-activation of immune response can also lead to worse outcome as a side-effect of hyperinflammation (right). Inhibitory Siglecs could regulate the crucial immune equilibrium by various mechanisms; 1) inhibitory Siglec expression, 2) maintaining the Siglec-Sialic acid interactions, 3) and/or by maintaining the balanced sialic acid levels on cell surface. The higher expression of inhibitory Siglecs on immune cells, higher expression of sialyltransferases in target cells, and/or lower activity of sialidases can lead to enhanced Siglec-sialic acid interactions and subsequently inhibit immune responses. On the other hand, the lower expression of inhibitory Siglecs in immune cells, lower expression of sialyltransferases in target cells, and/or higher sialidases activity can lower Siglec-sialic acid interactions and subsequently induce immune inflammation (top). Viruses can evade immune system by engaging the inhibitory Siglecs on immune cells either by the sialic acids present on its surface (such as the case of sialic acid on the surface of HBV that binds to Siglec-3 on myeloid cells) or by increasing the expression of sialic acid on infected cell (such as the case of α 2,3 sialic acid on the surface of HIV-infected cells that binds to Siglec-9 on NK cells). The sialic acids engage the inhibitory Siglecs and suppress the immune response against viral pathogen (left). On the other hand, viruses could induce hyper-inflammation by releasing Siglec dependent inhibition (such as the case of Siglec-9 ligands on neutrophils during COVID-19) (right).