Review
Flavivirus Entry Receptors: An Update
1 INSERM U944, CNRS 7212, Laboratoire de
Pathologie et Virologie Moléculaire, Hôpital Saint-Louis, 1 Avenue Claude
Vellefaux, Paris 75010, France2 Institut Universitaire d'Hématologie, Hôpital Saint-Louis, 1
Avenue Claude Vellefaux, Paris 75010, France3 Université Paris Diderot, Sorbonne Paris
Cité, Hôpital St. Louis, 1 Avenue Claude Vellefaux, Paris 75475, France
* Author to
whom correspondence should be addressed.
Received: 8 October 2013 / Revised: 12 December 2013 / Accepted: 12
December 2013 / Published: 30 December 2013
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.
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.
Keywords: flavivirus; West Nile virus; dengue virus; viral entry; C-type lectin receptor; phosphatidylserine receptors
This is an open
access article distributed under the Creative Commons Attribution License (CC BY) which permits unrestricted use, distribution, and reproduction in
any medium, provided the original work is properly cited.
View Full Text: http://www.mdpi.com/1999-4915/6/1/69/htm
Review
Flavivirus Entry Receptors: An Update
1 INSERM U944, CNRS 7212, Laboratoire de
Pathologie et Virologie Moléculaire, Hôpital Saint-Louis, 1 Avenue Claude
Vellefaux, Paris 75010, France2 Institut Universitaire d'Hématologie, Hôpital Saint-Louis, 1
Avenue Claude Vellefaux, Paris 75010, France3 Université Paris Diderot, Sorbonne Paris
Cité, Hôpital St. Louis, 1 Avenue Claude Vellefaux, Paris 75475, France
* Author to
whom correspondence should be addressed.
Received: 8 October 2013 / Revised: 12 December 2013 / Accepted: 12
December 2013 / Published: 30 December 2013
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.
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.
Keywords: flavivirus; West Nile virus; dengue virus; viral entry; C-type lectin receptor; phosphatidylserine receptors
This is an open
access article distributed under the Creative Commons Attribution License (CC BY) which permits unrestricted use, distribution, and reproduction in
any medium, provided the original work is properly cited.
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