DENV infection starts in skin cells after a bite by an infected mosquito (Duangkhae et al., 2018). The receptor(s) for DENV infection of keratinocytes is unknown (reviewed by Marti et al., 2024). Subsequently, macrophages get infected and spread the virus out of the skin (Schaeffer et al., 2015; reviewed by Santos Souza et al., 2016; Marti et al., 2024). DENV replicates in many cell lines but in vivo, DENV replicates only in few cell types. The most extensively studied organs/tissues where DENV was not only present but also replicated are skin, peripheral blood, spleen, lymph node and liver (reviewed in Begum et al., 2019).
The Dengue virus is enveloped and the envelope is covered with a glycoprotein known as the E protein (envelope protein) (reviewed by Rodenhuis-Zybert et al., 2010). E protein is responsible for mediating the attachment and entry of the virus into host cells (reviewed by Rodenhuis-Zybert et al., 2010). PrM protein (Precursor Membrane Protein) helps stabilize the E protein in the course of virion assembly and is cleaved during virus maturation, leaving the M fragment bound to E (reviewed by Rodenhuis-Zybert et al., 2010).
The Dengue virus can attach to a variety of host cell receptors, depending on the cell type and the serotype of the virus. Some of the known receptors and attachment factors include: CD209 (also known as DC-SIGN, Dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin), or CLEC4L (C-type lectin domain family 4 member L; Tassanetrithep et al., 2003), heparan sulfate (Chen et al., 1997), heat shock proteins HSP70 and HSP90 (Reyes-Del Valle et al., 2005), RPSA (also known as Small ribosomal subunit protein uS2, 67 kDa laminin receptor, 67LR, LAMR1, or LAMBR) (Thepparit et al., 2004), GAS6 (also known as Growth arrest-specific protein 6, AXL receptor tyrosine kinase ligand, or AXLLG) and PROS1 (also known as Vitamin K dependent protein S, PROS) (Meertens et al., 2012; reviewed in Oliveira & Peron, 2019), and the macrophage mannose receptor MRC1 (Miller et al., 2008).
It is generally agreed that CD209 is the main receptor for Dengue virus entry in dendritic cells (DCs). CD209 is a receptor on DCs and macrophages that binds to the E protein of the Dengue virus (Tassanetrithep et al. 2003). Genetic variations in CD209 may influence susceptibility or resistance to dengue virus infection, as well as disease progression and severity (reviewed in Xavier-Carvalho et al. 2017). A promoter polymorphism in the CD209 gene is associated with protection from dengue fever, but not dengue hemorrhagic fever (Sakuntabhai et al. 2005).
GAS6 plays a role in Dengue virus entry by apoptotic mimicry (Meertens et al. 2012). Apoptotic mimicry is a strategy used by some pathogens to evade the host's immune system by mimicking the characteristics of apoptotic cells to enter the host cells without triggering a strong immune response (reviewed in Amara and Mercer 2015). In apoptotic cells, phosphatidylserine (PtdSer) externalization occurs, where PtdSer flips from the inner to the outer leaflet of the plasma membrane (reviewed in Amara and Mercer 2015). External PtdSer serves as a signal that promotes recognition and phagocytosis of dying cells by macrophages and other phagocytes without triggering inflammation (reviewed in Amara and Mercer 2015). The Dengue virus displays PtdSer on its envelope, allowing it to bind to TIM and TAM receptors on phagocytic cells and to enter the phagocytes via a pathway they normally use to engulf apoptotic bodies. TIM receptors TIM1, TIM3, and TIM4 can directly interact with the Dengue virion-associated PtdSer, with TIM1 and TIM4 potentiating the infection most significantly, while TIM3 had a modest effect (Meertens et al. 2012). TAM receptors AXL and TYRO3 interact with the Dengue virion-associated PtdSer indirectly, with the TAM receptor ligands GAS6 and PROS (Protein S) serving as a bridge to bind to the virion PtdSer (Meertens et al. 2012). In neural cells, prohibitin 1/2 (PHB1, PHB2) has been identified as DENV-3 receptor (Sharma et al., 2020).
After attachment, the Dengue virion is typically taken into the cell through a process known as receptor-mediated endocytosis (reviewed in Carro & Cherry, 2020). Inside the endosome, the acidic environment triggers a conformational change in the E protein. This change allows the viral envelope to fuse with the endosomal membrane, releasing the viral RNA into the cytosol of the host cell, where replication and translation can begin. For a review of DENV attachment and entry see Cruz-Oliveira et al., 2015.
