{"gene":"SIGLEC1","run_date":"2026-06-10T07:46:32","timeline":{"discoveries":[{"year":2001,"finding":"CD43 (and CD162/PSGL-1) was identified as a T cell counterreceptor for sialoadhesin (Siglec-1). Sialoadhesin-Fc fusion proteins precipitated CD43 and PSGL-1 from T cell lines in a sialic acid-dependent manner; mutation of R97A in the sialic acid-binding site of sialoadhesin abolished binding. CD43 expressed in COS cells supported increased binding to immobilized sialoadhesin.","method":"Sialoadhesin-Fc pulldown, active-site mutagenesis (R97A), COS cell expression, CHO cell glycoform analysis","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro binding assay with active-site mutagenesis (R97A), multiple cell systems, multiple orthogonal methods in a single study","pmids":["11238599"],"is_preprint":false},{"year":2012,"finding":"Siglec-1 (CD169) on mature dendritic cells specifically binds HIV-1 and vesicles carrying sialyllactose-containing gangliosides (GM3) in a glycoprotein-independent manner, and is essential for DC-mediated trans-infection of CD4+ T cells. This identifies a ganglioside-recognition pathway distinct from DC-SIGN.","method":"Siglec-1 expression on mature DCs, binding assays with HIV-1 and ganglioside-containing vesicles, siRNA knockdown of Siglec-1, trans-infection assays","journal":"PLoS biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — knockdown, rescue by exogenous expression, binding assays, and trans-infection functional readout; independently replicated in multiple subsequent studies","pmids":["23271952"],"is_preprint":false},{"year":2013,"finding":"Siglec-1/CD169 is required for capture of B cell-derived exosomes in spleen (marginal zone) and lymph node (subcapsular sinus) via recognition of α2,3-linked sialic acids on exosome surfaces. CD169−/− mice showed altered exosome distribution and enhanced immune responses to exosomal antigen.","method":"In vitro binding assays on lymphoid tissue sections, CD169−/− knockout mice, flow cytometry-based exosome distribution analysis","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic knockout mice with functional readout, in vitro binding assays, and mechanistic specificity (α2,3-sialic acid dependence) confirmed","pmids":["24255917"],"is_preprint":false},{"year":2013,"finding":"IFNα-activated Siglec-1/CD169 on DCs captures HIV-1 in a GM3 ganglioside-dependent manner; selective CD169 downregulation or GSL depletion from virions abolished DC-mediated HIV capture and trans-infection; exogenous CD169 expression in naive cells rescued GSL-dependent capture. HIV-1 particles co-localized with CD169 at the DC surface and within non-lysosomal compartments that redistributed to DC–T cell infectious synapses.","method":"siRNA knockdown, exogenous CD169 expression rescue, GSL depletion from virions, co-localization microscopy, trans-infection functional assay","journal":"PLoS pathogens","confidence":"High","confidence_rationale":"Tier 2 / Strong — loss-of-function siRNA, gain-of-function rescue, and multiple orthogonal assays; independently replicated across labs","pmids":["23593001"],"is_preprint":false},{"year":2015,"finding":"Siglec-1 associates with DAP12 to recruit and activate SHP2; SHP2 then recruits E3 ubiquitin ligase TRIM27, which induces K48-linked ubiquitination and degradation of TBK1 at Lys251 and Lys372, thereby suppressing viral infection-triggered type I IFN production in macrophages. Expression of Siglec-1 is induced by the IFN/JAK/STAT1 pathway during viral infection, creating a negative feedback loop.","method":"Co-immunoprecipitation, ubiquitination assays, mutagenesis of TBK1 ubiquitination sites (K251, K372), siRNA knockdown, overexpression studies","journal":"Cell research","confidence":"High","confidence_rationale":"Tier 1 / Moderate — reconstitution of signaling complex by Co-IP, site-directed mutagenesis of ubiquitination sites, and multiple orthogonal methods in a single study","pmids":["26358190"],"is_preprint":false},{"year":2015,"finding":"CD169/Siglec-1 on sinus-lining macrophages captures murine leukemia virus (MLV) and HIV via ganglioside recognition; MLV-laden macrophages form long-lived synaptic contacts with B-1 cells to mediate trans-infection; CD169 was required for robust infection in lymph nodes and spleen in vivo.","method":"Intravital microscopy in living mice, CD169 knockout mice, retroviral infection models (MLV and HIV)","journal":"Science","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo imaging plus genetic knockout with clear functional readout; two independent retroviruses tested","pmids":["26429886"],"is_preprint":false},{"year":2015,"finding":"Siglec-1 mediates trans-infection of surface-bound murine leukemia virus (MLV) to B cells in a sialic acid N-acyl side chain-dependent manner. The N-acyl modification of sialic acid in viral membrane gangliosides is a critical determinant for Siglec-1/MLV interaction; N-butanoyl, N-isobutanoyl, N-glycolyl, and N-pentanoyl modifications reduced capture by up to 92%.","method":"Primary macrophage trans-infection assay, biosynthetic sialic acid analog engineering, molecular modeling, co-localization of Gag with Siglec-1","journal":"Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro biochemical reconstitution with systematically modified sialic acid analogs and molecular modeling validation","pmids":["26370074"],"is_preprint":false},{"year":2015,"finding":"Siglec-1 on macrophages initiates formation of the virus-containing compartment (VCC) by capturing ganglioside-bearing viral particles from the extracellular space. Siglec-1 depletion or ganglioside depletion from particles prevented VCC formation and reduced Siglec-1-mediated trans-infection of autologous T cells.","method":"Siglec-1 knockdown in macrophages, exogenous addition of VLPs and virions, ganglioside depletion, VCC volume quantification, trans-infection assay","journal":"PLoS pathogens","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal perturbations (receptor knockdown, ligand depletion) with compartment formation and functional trans-infection readouts","pmids":["28129379"],"is_preprint":false},{"year":2015,"finding":"CD169-mediated trafficking of HIV-1 into plasma membrane invaginations (VCCs) in dendritic cells protects virus from neutralization by broadly neutralizing anti-gp120 antibodies (VRC01, NIH45-46 G54W). The cytoplasmic tail of CD169 is dispensable for HIV-1 trafficking and retention within VCCs, but introduction of a di-aromatic endocytic motif into the cytoplasmic tail suppressed trans-infection.","method":"Super-resolution microscopy, cytoplasmic tail mutagenesis of CD169, neutralization assays with bNAbs, VCC formation assays","journal":"PLoS pathogens","confidence":"High","confidence_rationale":"Tier 1 / Moderate — structure-function mutagenesis of cytoplasmic tail, super-resolution microscopy, and functional neutralization assays","pmids":["25760631"],"is_preprint":false},{"year":2014,"finding":"GM3-CD169 interaction drives gp120-independent HIV-1 sequestration into non-lysosomal tetraspanin-positive compartments in dendritic cells. Artificial virus nanoparticles (AVNs) containing GM3 in a defined membrane composition recapitulated CD169-dependent HIV-1 uptake and compartment sequestration.","method":"Artificial virus nanoparticle reconstitution, CD169-expressing HeLa cells and mature DCs, co-localization microscopy, liposome binding","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Moderate — reconstitution with compositionally defined nanoparticles, mechanistic identification of GM3-CD169 binding as sufficient signal","pmids":["24947940"],"is_preprint":false},{"year":2011,"finding":"Porcine sialoadhesin (CD169) functions as an endocytic receptor; antibody-triggered internalization is clathrin- and Eps15-dependent and delivers cargo to early endosomes but not lysosomes. Demonstrated in primary porcine macrophages and cells expressing recombinant porcine sialoadhesin using chemical inhibitors, double immunofluorescence, and dominant-negative constructs.","method":"Clathrin pathway inhibitors, dominant-negative Eps15 constructs, double immunofluorescence, immunotoxin conjugates","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 1 / Moderate — reconstitution with recombinant receptor, multiple pathway inhibitors, dominant-negative constructs, and subcellular localization readout","pmids":["21359217"],"is_preprint":false},{"year":2016,"finding":"Siglec-1 promotes TGF-β1 production in endotoxin-tolerant macrophages by associating with adaptor protein DAP12 and transducing a signal to Syk kinase. Siglec-1 knockdown in RAW264.7 cells inhibited TGF-β1 production via ubiquitin-dependent degradation of Syk; this was attenuated by Syk inhibitor.","method":"Co-immunoprecipitation of Siglec-1 and DAP12/Syk, siRNA knockdown, Syk inhibitor, ubiquitination assay, TNF-α tolerance assay","journal":"Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — Co-IP establishing complex, ubiquitination assay, kinase inhibitor, and siRNA with defined molecular readout","pmids":["27129263"],"is_preprint":false},{"year":2015,"finding":"miR-27a directly targets Siglec-1 (and TRIM27); IFN/JAK/STAT1/RUNX1-mediated downregulation of miR-27a during viral infection de-represses Siglec-1 and TRIM27, inhibiting type I IFN production. In miR-27a-sponge transgenic mice, Siglec-1 and TRIM27 were elevated and type I IFN production was inhibited in vivo.","method":"miR-27a sponge transgenic mice, luciferase reporter assays for miR-27a targeting of Siglec-1, qPCR, VSV infection model","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — transgenic mouse model plus reporter assays, single lab with multiple methods confirming miR-27a → Siglec-1 axis","pmids":["26700765"],"is_preprint":false},{"year":2018,"finding":"CD169 sialic acid-binding capacity is required for antigen transfer from CD169+ macrophages to BATF3-dependent CD8α+ dendritic cells (DCs) in the spleen, enabling cross-priming of CD8+ T cells. CD169 preferentially binds CD8α+ DCs and the sialic acid-binding function mediates the macrophage–DC interaction.","method":"CD169 blocking antibodies and sialic acid-binding mutants, DC subset depletion (BATF3 KO), DNGR-1 blocking, in vivo antigen targeting, modified vaccinia Ankara infection model","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — loss-of-function genetics (BATF3 KO), functional CD169 neutralization, and sialic acid-binding mutants with defined T cell activation readout","pmids":["29425504"],"is_preprint":false},{"year":2019,"finding":"Siglec-1 recognizes sialylated gangliosides on Ebola virus membranes, mediating viral uptake into activated dendritic cells; blockade with anti-Siglec-1 monoclonal antibodies halted Ebola virus uptake and cytoplasmic entry, and provided cross-protection against HIV-1.","method":"Anti-Siglec-1 monoclonal antibody blockade, viral uptake assays in activated DCs, cytoplasmic entry quantification, cross-virus comparison","journal":"Nature microbiology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — receptor blockade with defined antibody, quantitative uptake assays, mechanistic cross-protection data","pmids":["31160823"],"is_preprint":false},{"year":2019,"finding":"Siglec-1-expressing subcapsular sinus macrophages provide anchorage to hypersialylated pioneer metastatic melanoma cells, and Siglec-1 interaction drives proliferation of cancer cells. Knockout of St3gal3 sialyltransferase in tumor cells reduced α2,3-linked sialylation and compromised metastatic efficiency in lymph nodes.","method":"In vitro co-culture of cancer cells with Siglec-1+ macrophages, transcriptome profiling, St3gal3 knockout, GFP-melanoma implantation model","journal":"eLife","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic knockout of sialylation enzyme with functional metastasis readout, in vitro co-culture; single lab","pmids":["31872800"],"is_preprint":false},{"year":2020,"finding":"Siglec-1 on macrophages localizes predominantly to microtubule-containing tunneling nanotubes (TNTs) in a TB-associated IFN-I-dependent manner. Siglec-1 depletion decreases TNT length, diminishes HIV-1 capture and cell-to-cell transfer via TNTs, and abrogates TB-induced exacerbation of HIV-1 infection.","method":"Siglec-1 siRNA depletion, transcriptomic analysis, TNT length measurement, HIV-1 capture and transfer assays in macrophages, non-human primate co-infection model with immunohistochemistry","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Strong — siRNA depletion with defined TNT and viral transfer readouts, NHP co-infection model, multiple orthogonal methods","pmids":["32223897"],"is_preprint":false},{"year":2022,"finding":"CD169 facilitates ACE2-independent SARS-CoV-2 fusion and entry into macrophages. CD169-mediated entry results in expression of viral genomic and subgenomic RNAs with minimal viral protein and no infectious particle release (post-entry replication block), and this restricted viral RNA expression triggers RIG-I/MDA-5/MAVS-dependent pro-inflammatory cytokine production (TNFα, IL-6, IL-1β).","method":"CD169 blocking, exogenous ACE2 rescue expression, viral RNA quantification, innate immune pathway knockout (RIG-I/MDA-5/MAVS), remdesivir treatment","journal":"PLoS pathogens","confidence":"High","confidence_rationale":"Tier 2 / Strong — gain-of-function rescue (exogenous ACE2), pathway KO (RIG-I/MDA-5/MAVS), pharmacological inhibition, multiple orthogonal methods","pmids":["36279285"],"is_preprint":false},{"year":2023,"finding":"Siglec-1 nanoclustering at the plasma membrane of activated DCs is regulated by Rho-ROCK activation and formin-dependent actin polymerization. Ganglioside binding (HIV-1 or ganglioside liposomes) triggers enhanced Siglec-1 nanoclustering and global actin rearrangements (drop in RhoA activity) that facilitate accumulation of viral particles into a single sac-like VCC.","method":"Super-resolution microscopy (STORM/PALM), single-particle tracking, biochemical perturbations (ROCK inhibitor, formin inhibitor), liposomes with varying ganglioside concentrations, RhoA activity assays","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1 / Moderate — super-resolution structural data combined with single-particle tracking and targeted biochemical perturbations in a single rigorous study","pmids":["36940134"],"is_preprint":false},{"year":2021,"finding":"Siglec-1 is required to induce antigen presentation through uptake of extracellular vesicles (EVs) from Mycobacterium tuberculosis. A SIGLEC1 null variant (Glu88Ter) is associated with extrapulmonary dissemination of Mtb; Siglec-1 knockout mice showed more extensive lung lesions. Siglec-1 limits early local spread of mycobacteria by facilitating antigen exchange via EVs.","method":"SIGLEC1 null variant genotyping in clinical cohorts, Siglec-1 knockout mice Mtb infection model, EV uptake and antigen presentation assays","journal":"Journal of extracellular vesicles","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — knockout mouse model with bacterial infection readout, human genetic cohort, EV functional assay; single lab","pmids":["33489013"],"is_preprint":false},{"year":2016,"finding":"CD169+ macrophage differentiation in lymph nodes and spleen requires dual signaling through RANK and LTβR; loss of either receptor perturbs differentiation. Splenic marginal zone stromal cells were identified as a source of RANKL via a RANKL reporter mouse. Loss of marginal metallophilic macrophages (MMMs) compromised viral capture and CD8+ T cell expansion.","method":"Conditional receptor ablation (RANK and LTβR KO), RANKL reporter mouse, flow cytometry, viral capture assays, CD8+ T cell functional readout","journal":"Proceedings of the National Academy of Sciences","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional genetic ablation of two receptors with defined macrophage differentiation and immune function readouts","pmids":["35031565"],"is_preprint":false},{"year":2019,"finding":"Cervical DCs expressing Siglec-1 capture HIV-1 and mediate trans-infection; a type-I IFN environment enhanced viral capture and trans-infection via Siglec-1; antibodies against Siglec-1 effectively prevented HIV-1 transfer via cervical DCs.","method":"Ex vivo cervical biopsy analysis, anti-Siglec-1 antibody blockade, IFN treatment, viral capture and trans-infection assays","journal":"Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ex vivo human tissue plus antibody blockade and IFN stimulation; single lab","pmids":["31114569"],"is_preprint":false},{"year":2016,"finding":"Siglec-1 on alveolar macrophages mediates phagocytosis of non-typeable Haemophilus influenzae (NTHi); blocking Siglec-1 with an anti-Siglec-1 antibody decreased phagocytosis of NTHi by human alveolar macrophages. Siglec-1 expression was significantly decreased on alveolar macrophages in COPD patients.","method":"Anti-Siglec-1 blocking antibody in phagocytosis assay, flow cytometry of human alveolar macrophages, correlation with lung function","journal":"Respiratory research","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — receptor blocking antibody with phagocytosis functional readout; single lab, single method for mechanism","pmids":["31992280"],"is_preprint":false},{"year":2019,"finding":"Pre-DC blood dendritic cell precursors constitutively express Siglec-1 and are specifically susceptible to HIV-1 infection in a Siglec-1-dependent manner (both CCR5- and CXCR4-tropic strains). Siglec-1 promotes viral attachment and fusion, and HIV-1-infected pre-DCs accumulate virus in intracellular compartments resembling the VCC. Siglec-1 remains functional in antiviral TLR-activated pre-DCs for replication-independent HIV-1 transfer to T cells.","method":"Siglec-1-dependent infection assay in pre-DCs vs. other DC subsets, Vpx restriction factor analysis, HIV-1 fusion assay, T cell trans-infection assay","journal":"Proceedings of the National Academy of Sciences","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple cell types compared, Siglec-1-dependency demonstrated with blocking, and virus entry/fusion mechanistic assays","pmids":["31591213"],"is_preprint":false},{"year":2017,"finding":"IFNα-induced CD169 expression on macrophages and DCs attenuates the antiviral effects of type I IFN by enhancing HIV-1 entry in a CD169-dependent manner (cis infection) and by rescuing HIV-1 infection of CD4+ T cells in trans via DC–T cell co-culture. In SIV/RT-SHIV-infected macaques, CD169 expression was enhanced in lymph nodes and showed extensive co-localization with p27gag.","method":"CD169-dependent HIV-1 entry assay in IFNα-treated THP-1 and primary MDMs, DC–T cell co-culture trans-infection, immunohistochemistry in pigtailed macaque lymph nodes","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple cell types and in vivo NHP colocalization data; single lab","pmids":["28794041"],"is_preprint":false},{"year":2018,"finding":"Siglec-1 on RSV-infected adult monocytes inhibits IFN-γ production by adult CD4+ T cells, and this inhibition is mediated by Siglec-1 binding to its ligand CD43, which is highly expressed on adult but not newborn CD4+ T cells.","method":"In vitro co-culture of monocytes and T cells, anti-Siglec-1 blocking, CD43 expression analysis by flow cytometry, RSV infection model","journal":"European journal of immunology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — functional blockade assay with CD43 ligand identification; single lab, limited mechanistic depth","pmids":["29266251"],"is_preprint":false},{"year":2013,"finding":"Porcine, murine, and human sialoadhesin (Siglec-1) can each promote PRRSV infection of CD163-expressing cells; intact sialic acid-binding domains are crucial, as non-sialic acid-binding mutants of all three species' Siglec-1 failed to promote infection.","method":"Recombinant expression of species-specific Siglec-1 and sialic acid-binding mutants in CD163+ cells, PRRSV infection assay","journal":"Journal of general virology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — active-site mutagenesis abolishing function, reconstitution in defined cell system, three orthologous proteins tested","pmids":["23740482"],"is_preprint":false}],"current_model":"SIGLEC1/CD169 is a macrophage- and DC-restricted sialic acid-binding I-type lectin that functions as an endocytic pattern-recognition receptor: it captures sialylated ligands (including ganglioside GM3 on enveloped viruses, exosomes, apoptotic vesicles, and sialomucins such as CD43 on T cells) via its membrane-distal Ig-like domain; upon ligand binding it signals through DAP12/SHP2/TRIM27 to promote K48-linked ubiquitination and degradation of TBK1 (suppressing type I IFN), through DAP12/Syk to promote TGF-β1 production in tolerant macrophages, and through Rho-ROCK/formin-actin machinery to form nanoclusters that traffic captured cargo into non-lysosomal virus-containing compartments for trans-infection of lymphocytes; its differentiation in lymphoid organs requires dual RANK and LTβR signals, and its expression is transcriptionally induced by the IFN/JAK/STAT1 pathway, creating a negative feedback circuit on antiviral innate immunity."},"narrative":{"mechanistic_narrative":"SIGLEC1 (CD169/sialoadhesin) is a macrophage- and dendritic cell-restricted sialic acid-binding I-type lectin that functions as an endocytic pattern-recognition receptor coupling sialylated-ligand capture to immune surveillance, antigen handling, and modulation of innate immune signaling [PMID:23271952, PMID:26358190]. Through its sialic acid-binding site it recognizes α2,3-linked sialic acids and sialyllactose-containing gangliosides (GM3), with the N-acyl side chain of sialic acid acting as a key specificity determinant, enabling glycoprotein-independent capture of enveloped viruses, exosomes, and sialylated counterreceptors such as CD43 on T cells [PMID:11238599, PMID:26370074, PMID:24947940]. CD169 captures HIV-1, MLV, Ebola, and SARS-CoV-2 via ganglioside recognition and traffics cargo into non-lysosomal virus-containing compartments (VCCs) that shield virions from neutralizing antibodies and are delivered to lymphocytes for trans-infection [PMID:23593001, PMID:26429886, PMID:31160823, PMID:25760631]; ganglioside engagement drives Rho-ROCK- and formin-actin-dependent nanoclustering that concentrates particles into a single sac-like VCC, and the receptor also localizes to tunneling nanotubes to mediate cell-to-cell viral transfer [PMID:36940134, PMID:32223897]. Beyond pathogen capture, CD169 transduces intracellular signals through DAP12: it recruits SHP2 and the E3 ligase TRIM27 to drive K48-linked ubiquitination and degradation of TBK1, suppressing type I IFN, while a DAP12/Syk arm promotes TGF-β1 production in tolerant macrophages [PMID:26358190, PMID:27129263]. Because SIGLEC1 is transcriptionally induced by the IFN/JAK/STAT1 axis, this establishes a negative-feedback circuit on antiviral immunity [PMID:26358190]. CD169+ macrophages also mediate antigen transfer to cross-priming CD8α+ dendritic cells and uptake of bacterial extracellular vesicles, and their differentiation in lymphoid organs requires dual RANK and LTβR signaling [PMID:29425504, PMID:33489013, PMID:35031565]. A SIGLEC1 null variant (Glu88Ter) is associated with extrapulmonary dissemination of Mycobacterium tuberculosis [PMID:33489013].","teleology":[{"year":2001,"claim":"Establishing what natural ligands sialoadhesin engages was needed to define its receptor function; identification of T cell CD43/PSGL-1 as sialic acid-dependent counterreceptors gave it a defined cellular target.","evidence":"Sialoadhesin-Fc pulldown with active-site (R97A) mutagenesis and COS cell expression","pmids":["11238599"],"confidence":"High","gaps":["Functional consequence of CD43 engagement for T cells not established here","Did not address viral or vesicle ligands"]},{"year":2011,"claim":"Whether CD169 is an internalizing receptor and where cargo is delivered was unclear; demonstrating clathrin/Eps15-dependent endocytosis to early endosomes but not lysosomes defined it as an endocytic receptor sparing cargo from degradation.","evidence":"Clathrin inhibitors, dominant-negative Eps15, immunofluorescence and immunotoxin in porcine macrophages","pmids":["21359217"],"confidence":"High","gaps":["Studied in porcine system","Did not connect endocytic route to viral trans-infection"]},{"year":2012,"claim":"The molecular basis of DC-mediated HIV-1 trans-infection was unresolved; showing Siglec-1 binds HIV-1 and GM3-bearing vesicles glycoprotein-independently and is essential for trans-infection defined a ganglioside-recognition capture pathway distinct from DC-SIGN.","evidence":"Siglec-1 knockdown, ganglioside-vesicle binding, and trans-infection assays in mature DCs","pmids":["23271952"],"confidence":"High","gaps":["Intracellular trafficking route not yet defined","Signaling consequences of capture not addressed"]},{"year":2013,"claim":"Whether GM3 recognition was sufficient and where captured virus is stored was unknown; rescue and reconstitution showed GM3-CD169 binding alone sequesters HIV-1 into non-lysosomal tetraspanin-positive compartments that traffic to the infectious synapse.","evidence":"siRNA/rescue, GSL depletion, artificial virus nanoparticle reconstitution, co-localization microscopy (multiple studies)","pmids":["23593001","24947940"],"confidence":"High","gaps":["Cytoskeletal machinery forming the compartment not yet identified","In vivo relevance not established here"]},{"year":2013,"claim":"The physiological role of CD169 in lymphoid organs was unclear; showing it captures B cell-derived exosomes via α2,3-sialic acids and shapes antigen distribution extended its function to endogenous sialylated vesicles.","evidence":"CD169−/− mice, tissue-section binding assays, exosome distribution analysis","pmids":["24255917"],"confidence":"High","gaps":["Downstream antigen-presentation pathway not detailed","Signaling not addressed"]},{"year":2015,"claim":"How CD169 modulates innate signaling was unknown; identifying the DAP12/SHP2/TRIM27 axis that ubiquitinates and degrades TBK1, together with IFN/STAT1 induction of SIGLEC1, defined a negative-feedback brake on type I IFN.","evidence":"Co-IP, ubiquitination assays, TBK1 K251/K372 mutagenesis, knockdown/overexpression","pmids":["26358190"],"confidence":"High","gaps":["In vivo significance of IFN suppression incompletely defined here","Ligand triggering the signal not specified"]},{"year":2015,"claim":"Whether trans-infection occurs in vivo and the chemical determinants of capture were open; intravital imaging in CD169 KO mice and systematic sialic acid N-acyl engineering established in vivo synaptic trans-infection and the N-acyl side chain as a specificity determinant.","evidence":"Intravital microscopy, CD169 KO mice, MLV/HIV models, biosynthetic sialic acid analogs and modeling","pmids":["26429886","26370074"],"confidence":"High","gaps":["Quantitative contribution relative to other capture routes unclear","Human in vivo data lacking"]},{"year":2015,"claim":"How the protective virus-containing compartment forms and what determines retention was unknown; cytoplasmic-tail mutagenesis and VCC quantification showed CD169 initiates VCC formation, the cytoplasmic tail is dispensable for retention, and VCCs shield virus from broadly neutralizing antibodies.","evidence":"Super-resolution microscopy, CD169 cytoplasmic-tail mutagenesis, bNAb neutralization and VCC formation assays","pmids":["25760631","28129379"],"confidence":"High","gaps":["Actin/Rho machinery driving compartment formation not yet identified","Endocytic motif effect mechanistically unresolved"]},{"year":2015,"claim":"Whether the lectin function is conserved and broadly co-opted by viruses was unclear; showing porcine, murine, and human Siglec-1 each promote PRRSV infection in a sialic acid-binding-dependent manner via active-site mutants generalized the capture mechanism across orthologs and pathogens.","evidence":"Recombinant species-specific Siglec-1 and binding-site mutants in CD163+ cells, PRRSV infection","pmids":["23740482"],"confidence":"High","gaps":["Did not address trafficking in this context","Trans-infection not tested"]},{"year":2016,"claim":"Whether CD169 signals beyond IFN suppression was unknown; identifying a DAP12/Syk arm that promotes TGF-β1 in endotoxin-tolerant macrophages broadened its signaling output toward immune tolerance.","evidence":"Co-IP of Siglec-1/DAP12/Syk, siRNA, Syk inhibitor, ubiquitination and tolerance assays in RAW264.7","pmids":["27129263"],"confidence":"High","gaps":["Ligand initiating tolerant-macrophage signaling not defined","In vivo relevance not tested"]},{"year":2016,"claim":"What controls CD169+ macrophage development in lymphoid organs was unknown; conditional RANK and LTβR ablation with a RANKL reporter showed dual signaling is required for differentiation and downstream viral capture and CD8+ T cell expansion.","evidence":"Conditional RANK/LTβR knockout, RANKL reporter mouse, viral capture and T cell assays","pmids":["35031565"],"confidence":"High","gaps":["Transcriptional program downstream of RANK/LTβR not detailed","Human relevance not addressed"]},{"year":2018,"claim":"Whether CD169 contributes to adaptive priming was open; sialic acid-binding mutants and BATF3 KO showed CD169 mediates antigen transfer to cross-priming CD8α+ DCs, linking lectin capture to CD8 T cell activation.","evidence":"CD169 blocking/binding mutants, BATF3 KO, DNGR-1 blocking, in vivo MVA model","pmids":["29425504"],"confidence":"High","gaps":["Molecular form of transferred antigen not defined","Signaling in macrophage during transfer unclear"]},{"year":2019,"claim":"The breadth of viral substrates and translational potential of blockade were unclear; anti-Siglec-1 antibodies blocking Ebola uptake with cross-protection against HIV-1, plus pre-DC and cervical DC capture data, generalized CD169 as a pan-enveloped-virus capture receptor and therapeutic target.","evidence":"Anti-Siglec-1 mAb blockade, viral uptake/fusion assays, pre-DC infection and ex vivo cervical DC models","pmids":["31160823","31591213","31114569"],"confidence":"High","gaps":["In vivo efficacy of blockade not established","Cervical DC data single-lab, medium confidence"]},{"year":2019,"claim":"Whether CD169 acts in cancer was unknown; sinus-lining macrophage CD169 anchoring hypersialylated melanoma cells and driving proliferation, with St3gal3 KO compromising metastasis, extended the lectin role to lymph node metastatic niches.","evidence":"Co-culture, transcriptomics, St3gal3 KO, GFP-melanoma implantation","pmids":["31872800"],"confidence":"Medium","gaps":["Single lab","Direct CD169-ligand on tumor cells not molecularly resolved"]},{"year":2020,"claim":"How captured virus moves between cells beyond synapses was unclear; showing IFN-I-dependent Siglec-1 enrichment on tunneling nanotubes that mediate HIV transfer, exacerbated in TB co-infection, added a cytoskeletal conduit to its trafficking repertoire.","evidence":"siRNA depletion, TNT length measurement, HIV capture/transfer assays, NHP co-infection model","pmids":["32223897"],"confidence":"High","gaps":["Molecular link between Siglec-1 and TNT formation incomplete","Generalizability to other viruses untested here"]},{"year":2021,"claim":"Whether SIGLEC1 has a protective antibacterial role and a human genetic phenotype was unknown; KO mice and a Glu88Ter null variant linked CD169-dependent EV uptake to control of early Mtb dissemination.","evidence":"SIGLEC1 null-variant genotyping, KO mouse Mtb infection, EV uptake/antigen presentation assays","pmids":["33489013"],"confidence":"Medium","gaps":["Single lab","Causality of Glu88Ter variant not functionally proven","Mechanism of EV-driven protection partial"]},{"year":2022,"claim":"Whether CD169 supports a productive or abortive viral fate was unresolved for SARS-CoV-2; showing ACE2-independent fusion/entry with a post-entry replication block triggering RIG-I/MDA-5/MAVS inflammation revealed CD169 entry can drive inflammation without productive infection.","evidence":"CD169 blocking, exogenous ACE2 rescue, viral RNA quantification, RIG-I/MDA-5/MAVS KO, remdesivir","pmids":["36279285"],"confidence":"High","gaps":["In vivo contribution to COVID-19 inflammation not established","Determinant of the replication block undefined"]},{"year":2023,"claim":"The biophysical mechanism forming the single VCC was unknown; super-resolution and single-particle tracking with Rho-ROCK and formin perturbations showed ganglioside binding triggers Siglec-1 nanoclustering and actin rearrangement to concentrate virions into one sac-like compartment.","evidence":"STORM/PALM, single-particle tracking, ROCK/formin inhibitors, RhoA activity assays, ganglioside liposomes","pmids":["36940134"],"confidence":"High","gaps":["Link between nanoclustering and DAP12 signaling not connected","Whether mechanism applies to non-viral cargo untested"]},{"year":null,"claim":"How ligand engagement is mechanistically partitioned between endocytic/trans-infection trafficking and the DAP12/SHP2 and DAP12/Syk signaling outputs, and how these are integrated in vivo, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model linking nanoclustering, VCC formation, and DAP12 signaling","Ligand-specific signaling outcomes undefined","Therapeutic blockade efficacy in vivo unestablished"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0001618","term_label":"virus receptor activity","supporting_discovery_ids":[1,3,5,14,17,26]},{"term_id":"GO:0038024","term_label":"cargo receptor activity","supporting_discovery_ids":[2,7,13,19]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[4,11]},{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[0,25]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[3,8,18]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[9,10]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[10]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[16,18]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[4,13,20]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[3,14,17,19]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[7,10]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[4,11]}],"complexes":[],"partners":["DAP12","SHP2","TRIM27","SYK","CD43","PSGL-1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9BZZ2","full_name":"Sialoadhesin","aliases":["Sialic acid-binding Ig-like lectin 1","Siglec-1"],"length_aa":1709,"mass_kda":182.6,"function":"Macrophage-restricted adhesion molecule that mediates sialic-acid dependent binding to lymphocytes, including granulocytes, monocytes, natural killer cells, B-cells and CD8 T-cells. Plays a crucial role in limiting bacterial dissemination by engaging sialylated bacteria to promote effective phagocytosis and antigen presentation for the adaptive immune response (PubMed:12940982, PubMed:33489013). Mediates the uptake of various enveloped viruses via sialic acid recognition and subsequently induces the formation of intracellular compartments filled with virions (VCCs) (PubMed:28129379). In turn, enhances macrophage-to-T-cell transmission of several viruses including HIV-1 or SARS-CoV-2 (PubMed:28129379, PubMed:34782760). Acts as an endocytic receptor mediating clathrin dependent endocytosis. Preferentially binds to alpha-2,3-linked sialic acid (PubMed:12940982). Binds to SPN/CD43 on T-cells (By similarity). May play a role in hemopoiesis. Plays a role in the inhibition of antiviral innate immune by promoting TBK1 degradation via TYROBP and TRIM27-mediated ubiquitination (PubMed:26358190) (Microbial infection) Facilitates viral cytoplasmic entry into activated dendritic cells via recognition of sialylated gangliosides pesent on viral membrane","subcellular_location":"Secreted","url":"https://www.uniprot.org/uniprotkb/Q9BZZ2/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SIGLEC1","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/SIGLEC1","total_profiled":1310},"omim":[{"mim_id":"613381","title":"CYSTATHIONINE BETA-SYNTHASE; CBS","url":"https://www.omim.org/entry/613381"},{"mim_id":"606094","title":"SIALIC ACID-BINDING IMMUNOGLOBULIN-LIKE LECTIN 12; SIGLEC12","url":"https://www.omim.org/entry/606094"},{"mim_id":"600751","title":"SIALIC ACID-BINDING IMMUNOGLOBULIN-LIKE LECTIN 1; SIGLEC1","url":"https://www.omim.org/entry/600751"},{"mim_id":"182160","title":"SIALOPHORIN; SPN","url":"https://www.omim.org/entry/182160"},{"mim_id":"107266","title":"CD22 ANTIGEN; CD22","url":"https://www.omim.org/entry/107266"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in many","driving_tissues":[],"url":"https://www.proteinatlas.org/search/SIGLEC1"},"hgnc":{"alias_symbol":["SIGLEC-1","CD169","FLJ00051","FLJ00055","FLJ00073","FLJ32150","dJ1009E24.1"],"prev_symbol":["SN"]},"alphafold":{"accession":"Q9BZZ2","domains":[{"cath_id":"2.60.40.10","chopping":"23-215","consensus_level":"medium","plddt":85.6568,"start":23,"end":215},{"cath_id":"2.60.40.10","chopping":"240-322","consensus_level":"high","plddt":85.5081,"start":240,"end":322},{"cath_id":"2.60.40.10","chopping":"338-407","consensus_level":"medium","plddt":79.2916,"start":338,"end":407},{"cath_id":"2.60.40.10","chopping":"410-508_924-975","consensus_level":"medium","plddt":77.6404,"start":410,"end":975},{"cath_id":"2.60.40.10","chopping":"512-596","consensus_level":"medium","plddt":79.7429,"start":512,"end":596},{"cath_id":"2.60.40.10","chopping":"719-732_741-786","consensus_level":"high","plddt":78.452,"start":719,"end":786},{"cath_id":"2.60.40.10","chopping":"794-892","consensus_level":"medium","plddt":76.4071,"start":794,"end":892},{"cath_id":"2.60.40.10","chopping":"1171-1260","consensus_level":"medium","plddt":73.6606,"start":1171,"end":1260},{"cath_id":"2.60.40.10","chopping":"1269-1337","consensus_level":"medium","plddt":78.7371,"start":1269,"end":1337},{"cath_id":"2.60.40.10","chopping":"1347-1390_1399-1531","consensus_level":"medium","plddt":73.8628,"start":1347,"end":1531},{"cath_id":"2.60.40.10","chopping":"1538-1634","consensus_level":"high","plddt":75.5265,"start":1538,"end":1634}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9BZZ2","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9BZZ2-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9BZZ2-F1-predicted_aligned_error_v6.png","plddt_mean":76.62},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SIGLEC1","jax_strain_url":"https://www.jax.org/strain/search?query=SIGLEC1"},"sequence":{"accession":"Q9BZZ2","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9BZZ2.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9BZZ2/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9BZZ2"}},"corpus_meta":[{"pmid":"21282381","id":"PMC_21282381","title":"Bone 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Sialoadhesin-Fc fusion proteins precipitated CD43 and PSGL-1 from T cell lines in a sialic acid-dependent manner; mutation of R97A in the sialic acid-binding site of sialoadhesin abolished binding. CD43 expressed in COS cells supported increased binding to immobilized sialoadhesin.\",\n      \"method\": \"Sialoadhesin-Fc pulldown, active-site mutagenesis (R97A), COS cell expression, CHO cell glycoform analysis\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro binding assay with active-site mutagenesis (R97A), multiple cell systems, multiple orthogonal methods in a single study\",\n      \"pmids\": [\"11238599\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Siglec-1 (CD169) on mature dendritic cells specifically binds HIV-1 and vesicles carrying sialyllactose-containing gangliosides (GM3) in a glycoprotein-independent manner, and is essential for DC-mediated trans-infection of CD4+ T cells. This identifies a ganglioside-recognition pathway distinct from DC-SIGN.\",\n      \"method\": \"Siglec-1 expression on mature DCs, binding assays with HIV-1 and ganglioside-containing vesicles, siRNA knockdown of Siglec-1, trans-infection assays\",\n      \"journal\": \"PLoS biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — knockdown, rescue by exogenous expression, binding assays, and trans-infection functional readout; independently replicated in multiple subsequent studies\",\n      \"pmids\": [\"23271952\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Siglec-1/CD169 is required for capture of B cell-derived exosomes in spleen (marginal zone) and lymph node (subcapsular sinus) via recognition of α2,3-linked sialic acids on exosome surfaces. CD169−/− mice showed altered exosome distribution and enhanced immune responses to exosomal antigen.\",\n      \"method\": \"In vitro binding assays on lymphoid tissue sections, CD169−/− knockout mice, flow cytometry-based exosome distribution analysis\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic knockout mice with functional readout, in vitro binding assays, and mechanistic specificity (α2,3-sialic acid dependence) confirmed\",\n      \"pmids\": [\"24255917\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"IFNα-activated Siglec-1/CD169 on DCs captures HIV-1 in a GM3 ganglioside-dependent manner; selective CD169 downregulation or GSL depletion from virions abolished DC-mediated HIV capture and trans-infection; exogenous CD169 expression in naive cells rescued GSL-dependent capture. HIV-1 particles co-localized with CD169 at the DC surface and within non-lysosomal compartments that redistributed to DC–T cell infectious synapses.\",\n      \"method\": \"siRNA knockdown, exogenous CD169 expression rescue, GSL depletion from virions, co-localization microscopy, trans-infection functional assay\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — loss-of-function siRNA, gain-of-function rescue, and multiple orthogonal assays; independently replicated across labs\",\n      \"pmids\": [\"23593001\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Siglec-1 associates with DAP12 to recruit and activate SHP2; SHP2 then recruits E3 ubiquitin ligase TRIM27, which induces K48-linked ubiquitination and degradation of TBK1 at Lys251 and Lys372, thereby suppressing viral infection-triggered type I IFN production in macrophages. Expression of Siglec-1 is induced by the IFN/JAK/STAT1 pathway during viral infection, creating a negative feedback loop.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays, mutagenesis of TBK1 ubiquitination sites (K251, K372), siRNA knockdown, overexpression studies\",\n      \"journal\": \"Cell research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — reconstitution of signaling complex by Co-IP, site-directed mutagenesis of ubiquitination sites, and multiple orthogonal methods in a single study\",\n      \"pmids\": [\"26358190\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"CD169/Siglec-1 on sinus-lining macrophages captures murine leukemia virus (MLV) and HIV via ganglioside recognition; MLV-laden macrophages form long-lived synaptic contacts with B-1 cells to mediate trans-infection; CD169 was required for robust infection in lymph nodes and spleen in vivo.\",\n      \"method\": \"Intravital microscopy in living mice, CD169 knockout mice, retroviral infection models (MLV and HIV)\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo imaging plus genetic knockout with clear functional readout; two independent retroviruses tested\",\n      \"pmids\": [\"26429886\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Siglec-1 mediates trans-infection of surface-bound murine leukemia virus (MLV) to B cells in a sialic acid N-acyl side chain-dependent manner. The N-acyl modification of sialic acid in viral membrane gangliosides is a critical determinant for Siglec-1/MLV interaction; N-butanoyl, N-isobutanoyl, N-glycolyl, and N-pentanoyl modifications reduced capture by up to 92%.\",\n      \"method\": \"Primary macrophage trans-infection assay, biosynthetic sialic acid analog engineering, molecular modeling, co-localization of Gag with Siglec-1\",\n      \"journal\": \"Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro biochemical reconstitution with systematically modified sialic acid analogs and molecular modeling validation\",\n      \"pmids\": [\"26370074\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Siglec-1 on macrophages initiates formation of the virus-containing compartment (VCC) by capturing ganglioside-bearing viral particles from the extracellular space. Siglec-1 depletion or ganglioside depletion from particles prevented VCC formation and reduced Siglec-1-mediated trans-infection of autologous T cells.\",\n      \"method\": \"Siglec-1 knockdown in macrophages, exogenous addition of VLPs and virions, ganglioside depletion, VCC volume quantification, trans-infection assay\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal perturbations (receptor knockdown, ligand depletion) with compartment formation and functional trans-infection readouts\",\n      \"pmids\": [\"28129379\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"CD169-mediated trafficking of HIV-1 into plasma membrane invaginations (VCCs) in dendritic cells protects virus from neutralization by broadly neutralizing anti-gp120 antibodies (VRC01, NIH45-46 G54W). The cytoplasmic tail of CD169 is dispensable for HIV-1 trafficking and retention within VCCs, but introduction of a di-aromatic endocytic motif into the cytoplasmic tail suppressed trans-infection.\",\n      \"method\": \"Super-resolution microscopy, cytoplasmic tail mutagenesis of CD169, neutralization assays with bNAbs, VCC formation assays\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — structure-function mutagenesis of cytoplasmic tail, super-resolution microscopy, and functional neutralization assays\",\n      \"pmids\": [\"25760631\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"GM3-CD169 interaction drives gp120-independent HIV-1 sequestration into non-lysosomal tetraspanin-positive compartments in dendritic cells. Artificial virus nanoparticles (AVNs) containing GM3 in a defined membrane composition recapitulated CD169-dependent HIV-1 uptake and compartment sequestration.\",\n      \"method\": \"Artificial virus nanoparticle reconstitution, CD169-expressing HeLa cells and mature DCs, co-localization microscopy, liposome binding\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — reconstitution with compositionally defined nanoparticles, mechanistic identification of GM3-CD169 binding as sufficient signal\",\n      \"pmids\": [\"24947940\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Porcine sialoadhesin (CD169) functions as an endocytic receptor; antibody-triggered internalization is clathrin- and Eps15-dependent and delivers cargo to early endosomes but not lysosomes. Demonstrated in primary porcine macrophages and cells expressing recombinant porcine sialoadhesin using chemical inhibitors, double immunofluorescence, and dominant-negative constructs.\",\n      \"method\": \"Clathrin pathway inhibitors, dominant-negative Eps15 constructs, double immunofluorescence, immunotoxin conjugates\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — reconstitution with recombinant receptor, multiple pathway inhibitors, dominant-negative constructs, and subcellular localization readout\",\n      \"pmids\": [\"21359217\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Siglec-1 promotes TGF-β1 production in endotoxin-tolerant macrophages by associating with adaptor protein DAP12 and transducing a signal to Syk kinase. Siglec-1 knockdown in RAW264.7 cells inhibited TGF-β1 production via ubiquitin-dependent degradation of Syk; this was attenuated by Syk inhibitor.\",\n      \"method\": \"Co-immunoprecipitation of Siglec-1 and DAP12/Syk, siRNA knockdown, Syk inhibitor, ubiquitination assay, TNF-α tolerance assay\",\n      \"journal\": \"Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — Co-IP establishing complex, ubiquitination assay, kinase inhibitor, and siRNA with defined molecular readout\",\n      \"pmids\": [\"27129263\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"miR-27a directly targets Siglec-1 (and TRIM27); IFN/JAK/STAT1/RUNX1-mediated downregulation of miR-27a during viral infection de-represses Siglec-1 and TRIM27, inhibiting type I IFN production. In miR-27a-sponge transgenic mice, Siglec-1 and TRIM27 were elevated and type I IFN production was inhibited in vivo.\",\n      \"method\": \"miR-27a sponge transgenic mice, luciferase reporter assays for miR-27a targeting of Siglec-1, qPCR, VSV infection model\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — transgenic mouse model plus reporter assays, single lab with multiple methods confirming miR-27a → Siglec-1 axis\",\n      \"pmids\": [\"26700765\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CD169 sialic acid-binding capacity is required for antigen transfer from CD169+ macrophages to BATF3-dependent CD8α+ dendritic cells (DCs) in the spleen, enabling cross-priming of CD8+ T cells. CD169 preferentially binds CD8α+ DCs and the sialic acid-binding function mediates the macrophage–DC interaction.\",\n      \"method\": \"CD169 blocking antibodies and sialic acid-binding mutants, DC subset depletion (BATF3 KO), DNGR-1 blocking, in vivo antigen targeting, modified vaccinia Ankara infection model\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — loss-of-function genetics (BATF3 KO), functional CD169 neutralization, and sialic acid-binding mutants with defined T cell activation readout\",\n      \"pmids\": [\"29425504\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Siglec-1 recognizes sialylated gangliosides on Ebola virus membranes, mediating viral uptake into activated dendritic cells; blockade with anti-Siglec-1 monoclonal antibodies halted Ebola virus uptake and cytoplasmic entry, and provided cross-protection against HIV-1.\",\n      \"method\": \"Anti-Siglec-1 monoclonal antibody blockade, viral uptake assays in activated DCs, cytoplasmic entry quantification, cross-virus comparison\",\n      \"journal\": \"Nature microbiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — receptor blockade with defined antibody, quantitative uptake assays, mechanistic cross-protection data\",\n      \"pmids\": [\"31160823\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Siglec-1-expressing subcapsular sinus macrophages provide anchorage to hypersialylated pioneer metastatic melanoma cells, and Siglec-1 interaction drives proliferation of cancer cells. Knockout of St3gal3 sialyltransferase in tumor cells reduced α2,3-linked sialylation and compromised metastatic efficiency in lymph nodes.\",\n      \"method\": \"In vitro co-culture of cancer cells with Siglec-1+ macrophages, transcriptome profiling, St3gal3 knockout, GFP-melanoma implantation model\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockout of sialylation enzyme with functional metastasis readout, in vitro co-culture; single lab\",\n      \"pmids\": [\"31872800\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Siglec-1 on macrophages localizes predominantly to microtubule-containing tunneling nanotubes (TNTs) in a TB-associated IFN-I-dependent manner. Siglec-1 depletion decreases TNT length, diminishes HIV-1 capture and cell-to-cell transfer via TNTs, and abrogates TB-induced exacerbation of HIV-1 infection.\",\n      \"method\": \"Siglec-1 siRNA depletion, transcriptomic analysis, TNT length measurement, HIV-1 capture and transfer assays in macrophages, non-human primate co-infection model with immunohistochemistry\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — siRNA depletion with defined TNT and viral transfer readouts, NHP co-infection model, multiple orthogonal methods\",\n      \"pmids\": [\"32223897\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CD169 facilitates ACE2-independent SARS-CoV-2 fusion and entry into macrophages. CD169-mediated entry results in expression of viral genomic and subgenomic RNAs with minimal viral protein and no infectious particle release (post-entry replication block), and this restricted viral RNA expression triggers RIG-I/MDA-5/MAVS-dependent pro-inflammatory cytokine production (TNFα, IL-6, IL-1β).\",\n      \"method\": \"CD169 blocking, exogenous ACE2 rescue expression, viral RNA quantification, innate immune pathway knockout (RIG-I/MDA-5/MAVS), remdesivir treatment\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — gain-of-function rescue (exogenous ACE2), pathway KO (RIG-I/MDA-5/MAVS), pharmacological inhibition, multiple orthogonal methods\",\n      \"pmids\": [\"36279285\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Siglec-1 nanoclustering at the plasma membrane of activated DCs is regulated by Rho-ROCK activation and formin-dependent actin polymerization. Ganglioside binding (HIV-1 or ganglioside liposomes) triggers enhanced Siglec-1 nanoclustering and global actin rearrangements (drop in RhoA activity) that facilitate accumulation of viral particles into a single sac-like VCC.\",\n      \"method\": \"Super-resolution microscopy (STORM/PALM), single-particle tracking, biochemical perturbations (ROCK inhibitor, formin inhibitor), liposomes with varying ganglioside concentrations, RhoA activity assays\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — super-resolution structural data combined with single-particle tracking and targeted biochemical perturbations in a single rigorous study\",\n      \"pmids\": [\"36940134\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Siglec-1 is required to induce antigen presentation through uptake of extracellular vesicles (EVs) from Mycobacterium tuberculosis. A SIGLEC1 null variant (Glu88Ter) is associated with extrapulmonary dissemination of Mtb; Siglec-1 knockout mice showed more extensive lung lesions. Siglec-1 limits early local spread of mycobacteria by facilitating antigen exchange via EVs.\",\n      \"method\": \"SIGLEC1 null variant genotyping in clinical cohorts, Siglec-1 knockout mice Mtb infection model, EV uptake and antigen presentation assays\",\n      \"journal\": \"Journal of extracellular vesicles\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — knockout mouse model with bacterial infection readout, human genetic cohort, EV functional assay; single lab\",\n      \"pmids\": [\"33489013\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"CD169+ macrophage differentiation in lymph nodes and spleen requires dual signaling through RANK and LTβR; loss of either receptor perturbs differentiation. Splenic marginal zone stromal cells were identified as a source of RANKL via a RANKL reporter mouse. Loss of marginal metallophilic macrophages (MMMs) compromised viral capture and CD8+ T cell expansion.\",\n      \"method\": \"Conditional receptor ablation (RANK and LTβR KO), RANKL reporter mouse, flow cytometry, viral capture assays, CD8+ T cell functional readout\",\n      \"journal\": \"Proceedings of the National Academy of Sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional genetic ablation of two receptors with defined macrophage differentiation and immune function readouts\",\n      \"pmids\": [\"35031565\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Cervical DCs expressing Siglec-1 capture HIV-1 and mediate trans-infection; a type-I IFN environment enhanced viral capture and trans-infection via Siglec-1; antibodies against Siglec-1 effectively prevented HIV-1 transfer via cervical DCs.\",\n      \"method\": \"Ex vivo cervical biopsy analysis, anti-Siglec-1 antibody blockade, IFN treatment, viral capture and trans-infection assays\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ex vivo human tissue plus antibody blockade and IFN stimulation; single lab\",\n      \"pmids\": [\"31114569\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Siglec-1 on alveolar macrophages mediates phagocytosis of non-typeable Haemophilus influenzae (NTHi); blocking Siglec-1 with an anti-Siglec-1 antibody decreased phagocytosis of NTHi by human alveolar macrophages. Siglec-1 expression was significantly decreased on alveolar macrophages in COPD patients.\",\n      \"method\": \"Anti-Siglec-1 blocking antibody in phagocytosis assay, flow cytometry of human alveolar macrophages, correlation with lung function\",\n      \"journal\": \"Respiratory research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — receptor blocking antibody with phagocytosis functional readout; single lab, single method for mechanism\",\n      \"pmids\": [\"31992280\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Pre-DC blood dendritic cell precursors constitutively express Siglec-1 and are specifically susceptible to HIV-1 infection in a Siglec-1-dependent manner (both CCR5- and CXCR4-tropic strains). Siglec-1 promotes viral attachment and fusion, and HIV-1-infected pre-DCs accumulate virus in intracellular compartments resembling the VCC. Siglec-1 remains functional in antiviral TLR-activated pre-DCs for replication-independent HIV-1 transfer to T cells.\",\n      \"method\": \"Siglec-1-dependent infection assay in pre-DCs vs. other DC subsets, Vpx restriction factor analysis, HIV-1 fusion assay, T cell trans-infection assay\",\n      \"journal\": \"Proceedings of the National Academy of Sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple cell types compared, Siglec-1-dependency demonstrated with blocking, and virus entry/fusion mechanistic assays\",\n      \"pmids\": [\"31591213\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"IFNα-induced CD169 expression on macrophages and DCs attenuates the antiviral effects of type I IFN by enhancing HIV-1 entry in a CD169-dependent manner (cis infection) and by rescuing HIV-1 infection of CD4+ T cells in trans via DC–T cell co-culture. In SIV/RT-SHIV-infected macaques, CD169 expression was enhanced in lymph nodes and showed extensive co-localization with p27gag.\",\n      \"method\": \"CD169-dependent HIV-1 entry assay in IFNα-treated THP-1 and primary MDMs, DC–T cell co-culture trans-infection, immunohistochemistry in pigtailed macaque lymph nodes\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple cell types and in vivo NHP colocalization data; single lab\",\n      \"pmids\": [\"28794041\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Siglec-1 on RSV-infected adult monocytes inhibits IFN-γ production by adult CD4+ T cells, and this inhibition is mediated by Siglec-1 binding to its ligand CD43, which is highly expressed on adult but not newborn CD4+ T cells.\",\n      \"method\": \"In vitro co-culture of monocytes and T cells, anti-Siglec-1 blocking, CD43 expression analysis by flow cytometry, RSV infection model\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — functional blockade assay with CD43 ligand identification; single lab, limited mechanistic depth\",\n      \"pmids\": [\"29266251\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Porcine, murine, and human sialoadhesin (Siglec-1) can each promote PRRSV infection of CD163-expressing cells; intact sialic acid-binding domains are crucial, as non-sialic acid-binding mutants of all three species' Siglec-1 failed to promote infection.\",\n      \"method\": \"Recombinant expression of species-specific Siglec-1 and sialic acid-binding mutants in CD163+ cells, PRRSV infection assay\",\n      \"journal\": \"Journal of general virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — active-site mutagenesis abolishing function, reconstitution in defined cell system, three orthologous proteins tested\",\n      \"pmids\": [\"23740482\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SIGLEC1/CD169 is a macrophage- and DC-restricted sialic acid-binding I-type lectin that functions as an endocytic pattern-recognition receptor: it captures sialylated ligands (including ganglioside GM3 on enveloped viruses, exosomes, apoptotic vesicles, and sialomucins such as CD43 on T cells) via its membrane-distal Ig-like domain; upon ligand binding it signals through DAP12/SHP2/TRIM27 to promote K48-linked ubiquitination and degradation of TBK1 (suppressing type I IFN), through DAP12/Syk to promote TGF-β1 production in tolerant macrophages, and through Rho-ROCK/formin-actin machinery to form nanoclusters that traffic captured cargo into non-lysosomal virus-containing compartments for trans-infection of lymphocytes; its differentiation in lymphoid organs requires dual RANK and LTβR signals, and its expression is transcriptionally induced by the IFN/JAK/STAT1 pathway, creating a negative feedback circuit on antiviral innate immunity.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SIGLEC1 (CD169/sialoadhesin) is a macrophage- and dendritic cell-restricted sialic acid-binding I-type lectin that functions as an endocytic pattern-recognition receptor coupling sialylated-ligand capture to immune surveillance, antigen handling, and modulation of innate immune signaling [#1, #4]. Through its sialic acid-binding site it recognizes α2,3-linked sialic acids and sialyllactose-containing gangliosides (GM3), with the N-acyl side chain of sialic acid acting as a key specificity determinant, enabling glycoprotein-independent capture of enveloped viruses, exosomes, and sialylated counterreceptors such as CD43 on T cells [#0, #6, #9]. CD169 captures HIV-1, MLV, Ebola, and SARS-CoV-2 via ganglioside recognition and traffics cargo into non-lysosomal virus-containing compartments (VCCs) that shield virions from neutralizing antibodies and are delivered to lymphocytes for trans-infection [#3, #5, #14, #8]; ganglioside engagement drives Rho-ROCK- and formin-actin-dependent nanoclustering that concentrates particles into a single sac-like VCC, and the receptor also localizes to tunneling nanotubes to mediate cell-to-cell viral transfer [#18, #16]. Beyond pathogen capture, CD169 transduces intracellular signals through DAP12: it recruits SHP2 and the E3 ligase TRIM27 to drive K48-linked ubiquitination and degradation of TBK1, suppressing type I IFN, while a DAP12/Syk arm promotes TGF-β1 production in tolerant macrophages [#4, #11]. Because SIGLEC1 is transcriptionally induced by the IFN/JAK/STAT1 axis, this establishes a negative-feedback circuit on antiviral immunity [#4]. CD169+ macrophages also mediate antigen transfer to cross-priming CD8α+ dendritic cells and uptake of bacterial extracellular vesicles, and their differentiation in lymphoid organs requires dual RANK and LTβR signaling [#13, #19, #20]. A SIGLEC1 null variant (Glu88Ter) is associated with extrapulmonary dissemination of Mycobacterium tuberculosis [#19].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Establishing what natural ligands sialoadhesin engages was needed to define its receptor function; identification of T cell CD43/PSGL-1 as sialic acid-dependent counterreceptors gave it a defined cellular target.\",\n      \"evidence\": \"Sialoadhesin-Fc pulldown with active-site (R97A) mutagenesis and COS cell expression\",\n      \"pmids\": [\"11238599\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of CD43 engagement for T cells not established here\", \"Did not address viral or vesicle ligands\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Whether CD169 is an internalizing receptor and where cargo is delivered was unclear; demonstrating clathrin/Eps15-dependent endocytosis to early endosomes but not lysosomes defined it as an endocytic receptor sparing cargo from degradation.\",\n      \"evidence\": \"Clathrin inhibitors, dominant-negative Eps15, immunofluorescence and immunotoxin in porcine macrophages\",\n      \"pmids\": [\"21359217\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Studied in porcine system\", \"Did not connect endocytic route to viral trans-infection\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"The molecular basis of DC-mediated HIV-1 trans-infection was unresolved; showing Siglec-1 binds HIV-1 and GM3-bearing vesicles glycoprotein-independently and is essential for trans-infection defined a ganglioside-recognition capture pathway distinct from DC-SIGN.\",\n      \"evidence\": \"Siglec-1 knockdown, ganglioside-vesicle binding, and trans-infection assays in mature DCs\",\n      \"pmids\": [\"23271952\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Intracellular trafficking route not yet defined\", \"Signaling consequences of capture not addressed\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Whether GM3 recognition was sufficient and where captured virus is stored was unknown; rescue and reconstitution showed GM3-CD169 binding alone sequesters HIV-1 into non-lysosomal tetraspanin-positive compartments that traffic to the infectious synapse.\",\n      \"evidence\": \"siRNA/rescue, GSL depletion, artificial virus nanoparticle reconstitution, co-localization microscopy (multiple studies)\",\n      \"pmids\": [\"23593001\", \"24947940\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cytoskeletal machinery forming the compartment not yet identified\", \"In vivo relevance not established here\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"The physiological role of CD169 in lymphoid organs was unclear; showing it captures B cell-derived exosomes via α2,3-sialic acids and shapes antigen distribution extended its function to endogenous sialylated vesicles.\",\n      \"evidence\": \"CD169−/− mice, tissue-section binding assays, exosome distribution analysis\",\n      \"pmids\": [\"24255917\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream antigen-presentation pathway not detailed\", \"Signaling not addressed\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"How CD169 modulates innate signaling was unknown; identifying the DAP12/SHP2/TRIM27 axis that ubiquitinates and degrades TBK1, together with IFN/STAT1 induction of SIGLEC1, defined a negative-feedback brake on type I IFN.\",\n      \"evidence\": \"Co-IP, ubiquitination assays, TBK1 K251/K372 mutagenesis, knockdown/overexpression\",\n      \"pmids\": [\"26358190\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo significance of IFN suppression incompletely defined here\", \"Ligand triggering the signal not specified\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Whether trans-infection occurs in vivo and the chemical determinants of capture were open; intravital imaging in CD169 KO mice and systematic sialic acid N-acyl engineering established in vivo synaptic trans-infection and the N-acyl side chain as a specificity determinant.\",\n      \"evidence\": \"Intravital microscopy, CD169 KO mice, MLV/HIV models, biosynthetic sialic acid analogs and modeling\",\n      \"pmids\": [\"26429886\", \"26370074\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Quantitative contribution relative to other capture routes unclear\", \"Human in vivo data lacking\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"How the protective virus-containing compartment forms and what determines retention was unknown; cytoplasmic-tail mutagenesis and VCC quantification showed CD169 initiates VCC formation, the cytoplasmic tail is dispensable for retention, and VCCs shield virus from broadly neutralizing antibodies.\",\n      \"evidence\": \"Super-resolution microscopy, CD169 cytoplasmic-tail mutagenesis, bNAb neutralization and VCC formation assays\",\n      \"pmids\": [\"25760631\", \"28129379\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Actin/Rho machinery driving compartment formation not yet identified\", \"Endocytic motif effect mechanistically unresolved\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Whether the lectin function is conserved and broadly co-opted by viruses was unclear; showing porcine, murine, and human Siglec-1 each promote PRRSV infection in a sialic acid-binding-dependent manner via active-site mutants generalized the capture mechanism across orthologs and pathogens.\",\n      \"evidence\": \"Recombinant species-specific Siglec-1 and binding-site mutants in CD163+ cells, PRRSV infection\",\n      \"pmids\": [\"23740482\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not address trafficking in this context\", \"Trans-infection not tested\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Whether CD169 signals beyond IFN suppression was unknown; identifying a DAP12/Syk arm that promotes TGF-β1 in endotoxin-tolerant macrophages broadened its signaling output toward immune tolerance.\",\n      \"evidence\": \"Co-IP of Siglec-1/DAP12/Syk, siRNA, Syk inhibitor, ubiquitination and tolerance assays in RAW264.7\",\n      \"pmids\": [\"27129263\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Ligand initiating tolerant-macrophage signaling not defined\", \"In vivo relevance not tested\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"What controls CD169+ macrophage development in lymphoid organs was unknown; conditional RANK and LTβR ablation with a RANKL reporter showed dual signaling is required for differentiation and downstream viral capture and CD8+ T cell expansion.\",\n      \"evidence\": \"Conditional RANK/LTβR knockout, RANKL reporter mouse, viral capture and T cell assays\",\n      \"pmids\": [\"35031565\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Transcriptional program downstream of RANK/LTβR not detailed\", \"Human relevance not addressed\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Whether CD169 contributes to adaptive priming was open; sialic acid-binding mutants and BATF3 KO showed CD169 mediates antigen transfer to cross-priming CD8α+ DCs, linking lectin capture to CD8 T cell activation.\",\n      \"evidence\": \"CD169 blocking/binding mutants, BATF3 KO, DNGR-1 blocking, in vivo MVA model\",\n      \"pmids\": [\"29425504\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular form of transferred antigen not defined\", \"Signaling in macrophage during transfer unclear\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"The breadth of viral substrates and translational potential of blockade were unclear; anti-Siglec-1 antibodies blocking Ebola uptake with cross-protection against HIV-1, plus pre-DC and cervical DC capture data, generalized CD169 as a pan-enveloped-virus capture receptor and therapeutic target.\",\n      \"evidence\": \"Anti-Siglec-1 mAb blockade, viral uptake/fusion assays, pre-DC infection and ex vivo cervical DC models\",\n      \"pmids\": [\"31160823\", \"31591213\", \"31114569\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo efficacy of blockade not established\", \"Cervical DC data single-lab, medium confidence\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Whether CD169 acts in cancer was unknown; sinus-lining macrophage CD169 anchoring hypersialylated melanoma cells and driving proliferation, with St3gal3 KO compromising metastasis, extended the lectin role to lymph node metastatic niches.\",\n      \"evidence\": \"Co-culture, transcriptomics, St3gal3 KO, GFP-melanoma implantation\",\n      \"pmids\": [\"31872800\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Direct CD169-ligand on tumor cells not molecularly resolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"How captured virus moves between cells beyond synapses was unclear; showing IFN-I-dependent Siglec-1 enrichment on tunneling nanotubes that mediate HIV transfer, exacerbated in TB co-infection, added a cytoskeletal conduit to its trafficking repertoire.\",\n      \"evidence\": \"siRNA depletion, TNT length measurement, HIV capture/transfer assays, NHP co-infection model\",\n      \"pmids\": [\"32223897\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular link between Siglec-1 and TNT formation incomplete\", \"Generalizability to other viruses untested here\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Whether SIGLEC1 has a protective antibacterial role and a human genetic phenotype was unknown; KO mice and a Glu88Ter null variant linked CD169-dependent EV uptake to control of early Mtb dissemination.\",\n      \"evidence\": \"SIGLEC1 null-variant genotyping, KO mouse Mtb infection, EV uptake/antigen presentation assays\",\n      \"pmids\": [\"33489013\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Causality of Glu88Ter variant not functionally proven\", \"Mechanism of EV-driven protection partial\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Whether CD169 supports a productive or abortive viral fate was unresolved for SARS-CoV-2; showing ACE2-independent fusion/entry with a post-entry replication block triggering RIG-I/MDA-5/MAVS inflammation revealed CD169 entry can drive inflammation without productive infection.\",\n      \"evidence\": \"CD169 blocking, exogenous ACE2 rescue, viral RNA quantification, RIG-I/MDA-5/MAVS KO, remdesivir\",\n      \"pmids\": [\"36279285\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo contribution to COVID-19 inflammation not established\", \"Determinant of the replication block undefined\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"The biophysical mechanism forming the single VCC was unknown; super-resolution and single-particle tracking with Rho-ROCK and formin perturbations showed ganglioside binding triggers Siglec-1 nanoclustering and actin rearrangement to concentrate virions into one sac-like compartment.\",\n      \"evidence\": \"STORM/PALM, single-particle tracking, ROCK/formin inhibitors, RhoA activity assays, ganglioside liposomes\",\n      \"pmids\": [\"36940134\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Link between nanoclustering and DAP12 signaling not connected\", \"Whether mechanism applies to non-viral cargo untested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How ligand engagement is mechanistically partitioned between endocytic/trans-infection trafficking and the DAP12/SHP2 and DAP12/Syk signaling outputs, and how these are integrated in vivo, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model linking nanoclustering, VCC formation, and DAP12 signaling\", \"Ligand-specific signaling outcomes undefined\", \"Therapeutic blockade efficacy in vivo unestablished\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0001618\", \"supporting_discovery_ids\": [1, 3, 5, 14, 17, 26]},\n      {\"term_id\": \"GO:0038024\", \"supporting_discovery_ids\": [2, 7, 13, 19]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [4, 11]},\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [0, 25]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [3, 8, 18]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [9, 10]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [10]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [16, 18]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [4, 13, 20]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [3, 14, 17, 19]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [7, 10]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [4, 11]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"DAP12\", \"SHP2\", \"TRIM27\", \"SYK\", \"CD43\", \"PSGL-1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}