Pathway Human Homo sapiens

Dengue Virus Attachment and Entry

R-HSA-9918485 in Reactome release 97: under Dengue Virus Infection, with 44 genes placed in it by the mapping files and 0 child pathways in the hierarchy.

The same number in the other species

Reactome writes the mouse and rat events it infers from a human pathway under the human number with the species token. A door opens only where that species' own list in this release holds the id; neither of the other two lists holds it. Whether the event was inferred from this one is what the record says.

The record
The genes
Parents and children

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01The record

Reactome's own record of this pathway

What this tells you

The pathway list, the hierarchy and the genes on this page are read from the files Reactome publishes for Reactome release 97, built into this site on 2026-09-09: the pathway list, the hierarchy relationship file and the two gene mapping files. The record card is the one live read, Reactome's own record of this pathway.

Reactome's download page describes the mapping files: Mapping files link the source database identifier to the lowest level pathway diagram or subset of the pathway, all levels of the pathway hierarchy or database identifier to all reactions. [R13] The gene list here is the all-levels mapping of NCBI Gene ids, filled from the all-levels mapping of Ensembl ids where the NCBI file has no row for a gene; each row names which file it came from by the shape of its source id. Each row carries the evidence codes the file writes for it, as written and unranked, and both where the file writes both; no page of Reactome's documentation the survey read defines the codes, so this page does not expand them. A gene id the identity files do not name is kept as the source's own id with no door rather than turned into a symbol.

On citing what a search finds, Reactome says: It should be remembered that while we strive to contain the most current and accurate data, Reactome should not be used in citations where other primary sources of information are available. [R12] The record card prints the literature Reactome attaches to a curated pathway for that reason. The data are public domain: All data in the Reactome database and files derived from that data are licensed under the Creative Commons Public Domain Dedication (CC0). User may copy, modify, and distribute these data, even for commercial purposes, without asking for permission. Attribution is encouraged but not required. [R10] The pathway illustrations are licensed apart, under CC BY 4.0, and none is shown here.

A gene on this list is one Reactome places in this pathway in this release, and that is all the row says: it does not say the gene is expressed in a tissue or associated with a disease, which are the other two explorers' questions, read from other sources. Reactome's papers of record are [R01] [R02].

[R01] Ragueneau E, Gong C, Sinquin P, Sevilla C, Beavers D, Grentner A, et al. (2026). The Reactome Knowledgebase 2026. Nucleic Acids Research 54:D673-D681. PMID 41251150, doi 10.1093/nar/gkaf1223.
[R02] Milacic M, Beavers D, Conley P, Gong C, Gillespie M, Griss J, et al. (2024). The Reactome Pathway Knowledgebase 2024. Nucleic Acids Research 52:D672-D678. PMID 37941124, doi 10.1093/nar/gkad1025.
[R10] Reactome, reactome.org. License Agreement. https://reactome.org/license, read 2026-09-09.
[R12] Reactome, reactome.org. Citing us. https://reactome.org/cite, read 2026-09-09.
[R13] Reactome, reactome.org. Download. https://reactome.org/download-data, read 2026-09-09.

Stable id: R-HSA-9918485.1
Class: Pathway
Species: Homo sapiens (human)
Inferred: no: a curated human pathway
Disease pathway: yes, as Reactome flags it
Released: 2025-12-08
Events inside: 10, counted from the record

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.

Literature Reactome attaches

The TIM and TAM families of phosphatidylserine receptors mediate dengue virus entryCell Host Microbe, 2012, vol. 12, p. 544-57PubMed 23084921
Viral apoptotic mimicryNat Rev Microbiol, 2015, vol. 13, p. 461-9PubMed 26052667
A variant in the CD209 promoter is associated with severity of dengue diseaseNat Genet, 2005, vol. 37, p. 507-13PubMed 15838506
DC-SIGN (CD209) mediates dengue virus infection of human dendritic cellsJ Exp Med, 2003, vol. 197, p. 823-9PubMed 12682107
Host genetics and dengue feverInfect Genet Evol, 2017, vol. 56, p. 99-110PubMed 29133029
Receptors and routes of dengue virus entry into the host cellsFEMS Microbiol Rev, 2015, vol. 39, p. 155-70PubMed 25725010
The mannose receptor mediates dengue virus infection of macrophagesPLoS Pathog, 2008, vol. 4, p. e17PubMed 18266465

Reactome ContentService, this pathway's record · Reactome v97 · read 2026-10-05 ET · Reactome pathway browser"Dengue Virus Attachment and Entry". Reactome, release 97, https://reactome.org/PathwayBrowser/#/R-HSA-9918485 with StableID: R-HSA-9918485.1 (accessed 2026-10-05 ET). Reactome version 97 (CC0).

Reading this pathway's record from Reactome (the pathway record).Still reading. A first read of a pathway can take a while; this page waits up to 35 seconds for it, and its scripts then bring in the panel, or a line saying what did not arrive.

02The genes

Genes Reactome places in this human pathway

The mapping files place 44 genes in this human pathway; showing 1 to 44, in pages of 100, sorted by symbol for reading. The order carries no ranking.

Genes Reactome places in this human pathway, page 1 of 1
Gene	Authority id	Mapping file id	Evidence codes
GeneAGRN	AuthorityHGNC:329	Mapping file id375790 NCBI file	EvidenceTAS
GeneAP2A1	AuthorityHGNC:561	Mapping file id160 NCBI file	EvidenceTAS
GeneAP2A2	AuthorityHGNC:562	Mapping file id161 NCBI file	EvidenceTAS
GeneAP2B1	AuthorityHGNC:563	Mapping file id163 NCBI file	EvidenceTAS
GeneAP2M1	AuthorityHGNC:564	Mapping file id1173 NCBI file	EvidenceTAS
GeneAP2S1	AuthorityHGNC:565	Mapping file id1175 NCBI file	EvidenceTAS
GeneATG7	AuthorityHGNC:16935	Mapping file id10533 NCBI file	EvidenceTAS
GeneAXL	AuthorityHGNC:905	Mapping file id558 NCBI file	EvidenceTAS
GeneCD14	AuthorityHGNC:1628	Mapping file id929 NCBI file	EvidenceTAS
GeneCD209	AuthorityHGNC:1641	Mapping file id30835 NCBI file	EvidenceTAS
GeneCD300A	AuthorityHGNC:19319	Mapping file id11314 NCBI file	EvidenceTAS
GeneCD33	AuthorityHGNC:1659	Mapping file id945 NCBI file	EvidenceTAS
GeneCLDN1	AuthorityHGNC:2032	Mapping file id9076 NCBI file	EvidenceTAS
GeneEMC4	AuthorityHGNC:28032	Mapping file id51234 NCBI file	EvidenceTAS
GeneFURIN	AuthorityHGNC:8568	Mapping file id5045 NCBI file	EvidenceTAS
GeneGAS6	AuthorityHGNC:4168	Mapping file id2621 NCBI file	EvidenceTAS
GeneGPC1	AuthorityHGNC:4449	Mapping file id2817 NCBI file	EvidenceTAS
GeneGPC2	AuthorityHGNC:4450	Mapping file id221914 NCBI file	EvidenceTAS
GeneGPC3	AuthorityHGNC:4451	Mapping file id2719 NCBI file	EvidenceTAS
GeneGPC4	AuthorityHGNC:4452	Mapping file id2239 NCBI file	EvidenceTAS
GeneGPC5	AuthorityHGNC:4453	Mapping file id2262 NCBI file	EvidenceTAS
GeneGPC6	AuthorityHGNC:4454	Mapping file id10082 NCBI file	EvidenceTAS
GeneHAVCR1	AuthorityHGNC:17866	Mapping file id26762 NCBI file	EvidenceTAS
GeneHSPA5	AuthorityHGNC:5238	Mapping file id3309 NCBI file	EvidenceTAS
GeneHSPG2	AuthorityHGNC:5273	Mapping file id3339 NCBI file	EvidenceTAS
GeneLY6E	AuthorityHGNC:6727	Mapping file id4061 NCBI file	EvidenceTAS
GeneMAPRE3	AuthorityHGNC:6892	Mapping file id22924 NCBI file	EvidenceTAS
GeneMERTK	AuthorityHGNC:7027	Mapping file id10461 NCBI file	EvidenceTAS
GeneMRC1	AuthorityHGNC:7228	Mapping file id4360 NCBI file	EvidenceTAS
GenePIK3R1	AuthorityHGNC:8979	Mapping file id5295 NCBI file	EvidenceTAS
GenePROS1	AuthorityHGNC:9456	Mapping file id5627 NCBI file	EvidenceTAS
GeneRNASEK	AuthorityHGNC:33911	Mapping file id440400 NCBI file	EvidenceTAS
GeneRPSA	AuthorityHGNC:6502	Mapping file id3921 NCBI file	EvidenceTAS
GeneSDC1	AuthorityHGNC:10658	Mapping file id6382 NCBI file	EvidenceTAS
GeneSDC2	AuthorityHGNC:10659	Mapping file id6383 NCBI file	EvidenceTAS
GeneSDC3	AuthorityHGNC:10660	Mapping file id9672 NCBI file	EvidenceTAS
GeneSDC4	AuthorityHGNC:10661	Mapping file id6385 NCBI file	EvidenceTAS
GeneTIMD4	AuthorityHGNC:25132	Mapping file id91937 NCBI file	EvidenceTAS
GeneTYRO3	AuthorityHGNC:12446	Mapping file id7301 NCBI file	EvidenceTAS
GeneUBA1	AuthorityHGNC:12469	Mapping file id7317 NCBI file	EvidenceTAS
GeneUBA3	AuthorityHGNC:12470	Mapping file id9039 NCBI file	EvidenceTAS
GeneUBA5	AuthorityHGNC:23230	Mapping file id79876 NCBI file	EvidenceTAS
GeneUBA6	AuthorityHGNC:25581	Mapping file id55236 NCBI file	EvidenceTAS
GeneUBA7	AuthorityHGNC:12471	Mapping file id7318 NCBI file	EvidenceTAS

Evidence codes on this page: TAS, as the mapping file writes them; a row carrying two was written twice by the file, once under each. The mapping file id says which file placed the gene: an NCBI Gene id from NCBI2Reactome_All_Levels.txt, an Ensembl gene id from Ensembl2Reactome_All_Levels.txt. The two files can disagree about a code, so a row's codes are the one file's view. Measured by this site's build over this release on 2026-09-09: of the 138,908 human pathway-gene pairs both files place, 207 (0.149 per cent, over 47 genes) carry TAS in the Ensembl file where the NCBI rows carry IEA alone.

Reactome mapping files, the human rows for this pathway · Reactome release 97 · read 2026-09-09 · Reactome downloads"NCBI2Reactome_All_Levels.txt" and "Ensembl2Reactome_All_Levels.txt", Reactome, release 97, https://reactome.org/download-data/ (date of access 2026-09-09). Data CC0; attribution encouraged.

03The hierarchy

Parents and children in this release's hierarchy

Parents

Dengue Virus InfectionR-HSA-9839923404 genes

Children

None: no pathway of this release's list names this one as a parent.

Reactome's hierarchy is a graph rather than a tree: a pathway can sit under more than one parent, and the gene counts are each pathway's own placements at every level under it, so a parent's count is not the sum of its children's.

Reactome, the human pathway list and hierarchy relationship file · Reactome release 97 · read 2026-09-09 · Reactome downloads"ReactomePathways.txt" and "ReactomePathwaysRelation.txt", Reactome, release 97, https://reactome.org/download-data/ (date of access 2026-09-09). Data CC0; attribution encouraged.