Flavivirus entry receptors: an update

Abstract

Flaviviruses enter host cells by endocytosis initiated when the virus particles interact with cell surface receptors. The current model suggests that flaviviruses use at least two different sets of molecules for infectious entry: attachment factors that concentrate and/or recruit viruses on the cell surface and primary receptor(s) that bind to virions and direct them to the endocytic pathway. Here, we present the currently available knowledge regarding the flavivirus receptors described so far with specific attention to C-type lectin receptors and the phosphatidylserine receptors, T-cell immunoglobulin and mucin domain (TIM) and TYRO3, AXL and MER (TAM). Their role in flavivirus attachment and entry as well as their implication in the virus biology will be discussed in depth.

Figure 1

Attachment of flaviviruses to C-type lectin receptors has different implications in flaviviruses infections. (A) In mammalian cells, DC-SIGN/L-SIGN and the mannose receptor (MR) act as attachment factors that bind virions and facilitate their entry by transferring them to the bona fide receptor(s) involved in endocytosis; (B) In mammalian cells, binding of flaviviruses to CLEC5A triggers DAP12 phosphorylation and downstream signaling pathways that lead to the release of pro-inflammatory cytokines and aggravation of the disease; (C) In mosquitoes, virus entry is facilitated by the binding of virus/mosGCTL-1 complexes to cellular mosPTP-1.

Figure 2

Hypothetical model for flavivirus recognition by TIM and TAM receptors. Phosphatidylserine (PtdSer) is expressed at the viral membrane and its recognition by TIM and TAM receptors occurs through a bimodal mechanism. The MILIBS pocket within the IgV domain of TIM receptors directly interacts with PtdSer. In contrast, the recognition of viral particles by TAM receptors is indirect and requires the presence of a TAM ligand, Gas6 or ProS. These molecules recognize both the virus-associated PtdSer via their Gla domain, and the TAM receptors through their LG domains and, thus, act as bridging factors.

Figure 3

Dual role of TAM receptors during flavivirus infection. During entry, TAM receptors capture virus-Gas6/ProS complexes and enhance virus internalization through still unknown mechanisms. In parallel, virus-Gas6/ProS complexes activate TAM receptors, which recruit interferon receptor (IFNAR) to induce SOCS1/3 expression, thereby inhibiting innate antiviral responses and facilitating flavivirus replication.

Figure 4

Possible mechanisms of PtdSer exposure in flavivirus virions. (A) Flavivirus particles produced in mosquito cells at 28 °C have a closed herringbone smooth conformation that protects the lipid envelope from the external medium. Upon an increase in temperature, particles expand and adopt a “bumpy” conformation that renders virion-associated PtdSer accessible. At 37 °C, the human body temperature, almost all virions present this conformation; (B) Inefficient cleavage of prM by cellular furin leads to the release of immature or partially mature (mosaic) virions in wich the lipid envelope is exposed to the external medium. Virion-associated PtdSer could therefore be accessible to TIM and TAM receptors.