Different viruses employ various spread mechanisms both systemically and within the site of infection, including cell–cell fusion, transmigration and neuroinvasion. Viruses often take advantage of components of the innate immune system to target the cell type of interest at distant locations. Glycans play an important role in these mechanisms (Figure 2, bottom left panel). In the deadly Hendra virus the globular head region of glycoprotein G is important for binding to the entry receptors Ephrin B2/B3. Mutation of N-glycosylation sites in the globular head of glycoprotein G increased cell–cell fusion, whereas removal of a glycosite in the stalk region of Hendra glycoprotein G abolished cell–cell fusion (Bradel-Tretheway et al. 2015). In case of O-glycans, however, removal of distinct O-glycosites within a cluster in the stalk region resulted in both hypo- and hyperfusogenic phenotypes (Stone et al. 2016), and neither N- nor O-glycosite mutants exhibited impaired receptor binding (Bradel-Tretheway et al. 2015; Stone et al. 2016). This suggests that glycans influence other aspects of membrane fusion; possibly by affecting the thermodynamics of conformational changes. The impact of N-glycans in viral spread has also been demonstrated in in vivo models. Interestingly, the glycosylation status of West Nile virus glycoproteins has been associated with neuroinvasiveness, where abolishment of glycosites led to attenuation (Whiteman et al. 2010). Similarly, loss of a N-glycosite on Ross River virus glycoprotein E1 was associated with milder pathogenesis and increased virus clearance in a disease mouse model (Nelson et al. 2016). Finally, specific N-glycosylation patterns on both HA and NA on avian influenza A virus are required for efficient transmission in mammalian models (Park et al. 2016). A more direct role of glycans emerges from the viral exploitation of innate immune receptors as a helping hand during establishing the viral infection. Such innate immune receptors and other secreted glycan binding proteins present on infected host cells or antigen presenting cells are naturally the first line of defense against invading pathogens. For instance, secreted C-type lectins, ficolin-2 and mannose-binding lectin, inhibit HCV entry into hepatocytes (Brown et al. 2010; Zhao et al. 2014). However, these carbohydrate binding proteins can convey both protective and deleterious effects during viral infection, which are exploited by viruses to enter host cells. For example, secreted galectin-1 promotes entry of Nipah virus into endothelial cells by bridging viral and cellular glycans, when the glycan binding proteins are present during initial phases of infection. In contrast, galectin-1 inhibits viral spread, when added postinfection (Garner et al. 2015). Galectin-1 has also been shown to promote HIV-1 infection by crosslinking the viral particles and cell entry receptors, whereas influenza virus infection was inhibited (St-Pierre et al. 2011; Yang et al. 2011). As already mentioned, several viruses specifically use C-type lectin receptors for entry or transmission. Ebola virus utilizes an array of different C-type lectins, such as L-SIGN, DC-SIGN and LSECtin, for entry into various cell types (Lennemann et al. 2014). HIV-1 uses DC-SIGN on dendritic cells for migration to T cells (Hong et al. 2002). Although it is not entirely clear how the balance between antigen presentation and transmission is maintained, it has been proposed that homogeneous high-mannose type N-glycans enhance antigen presentation and virus degradation compared to intrinsically heterogeneous gp120 N-glycosylation (van Montfort et al. 2011). Interestingly, HIV-1 has also been shown to exploit sialic-acid binding lectin Siglec-1 for more efficient entry into macrophages, likewise promoting the existence of complex-type N-glycans on viral particles (Zou et al. 2011). In a similar context, we have demonstrated, that very early chemokine-mediated immune response to HSV-2 infection of the vaginal mucosa in mice relies on the presence of elongated O-linked glycans on the viral particles (Iversen et al. 2016). Although truncation of O-glycans might benefit the virus in escaping the early recognition by the host, elongated O-glycans are essential for viral replication (Bagdonaite et al. 2015; Iversen et al. 2016). Various carbohydrate structures from many bacteria and parastic worms are known to elicit robust innate immune responses via toll-like and other receptors (Rabinovich and Toscano 2009; Prasanphanich et al. 2013). It is only conceivable that analogous carbohydrate-mediated mechanisms could exist for early detection of viral infections, but have not been described in detail.