provider: falcon
model: Edison Scientific Literature
cached: false
start_time: '2026-01-30T10:15:37.181742'
end_time: '2026-01-30T10:24:41.960621'
duration_seconds: 544.78
template_file: templates/gene_research_go_focused.md
template_variables:
organism: ANOGA
gene_id: TEP1
gene_symbol: TEP1
uniprot_accession: C9XI63
protein_description: 'RecName: Full=Thioester-containing protein 1 allele S3 {ECO:0000303|PubMed:19797663};
Short=TEP1s {ECO:0000303|PubMed:15006349}; AltName: Full=TEP1-F {ECO:0000303|PubMed:19286136};
Contains: RecName: Full=Thioester-containing protein 1 N-terminal {ECO:0000303|PubMed:19286136};
Short=TEP1-N {ECO:0000303|PubMed:19286136}; Contains: RecName: Full=Thioester-containing
protein 1 C-terminal; Short=TEP1-C {ECO:0000303|PubMed:19286136}; Flags: Precursor;'
gene_info: Name=TEP1 {ECO:0000303|PubMed:19797663};
organism_full: Anopheles gambiae (African malaria mosquito).
protein_family: Not specified in UniProt
protein_domains: A-macroglobulin_rcpt-bd. (IPR009048); A-macroglobulin_rcpt-bd_sf.
(IPR036595); A2M/Complement_sys. (IPR050473); A2M_N_BRD. (IPR011625); A2M_TED.
(IPR041813)
provider_config:
timeout: 600
max_retries: 3
parameters:
allowed_domains: []
temperature: 0.1
citation_count: 29

Question

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

BEFORE YOU BEGIN RESEARCH: You MUST verify you are researching the CORRECT gene/protein. Gene symbols can be ambiguous, especially for less well-characterized genes from non-model organisms.

Target Gene/Protein Identity (from UniProt):

• UniProt Accession: C9XI63
• Protein Description: RecName: Full=Thioester-containing protein 1 allele S3 {ECO:0000303|PubMed:19797663}; Short=TEP1s {ECO:0000303|PubMed:15006349}; AltName: Full=TEP1-F {ECO:0000303|PubMed:19286136}; Contains: RecName: Full=Thioester-containing protein 1 N-terminal {ECO:0000303|PubMed:19286136}; Short=TEP1-N {ECO:0000303|PubMed:19286136}; Contains: RecName: Full=Thioester-containing protein 1 C-terminal; Short=TEP1-C {ECO:0000303|PubMed:19286136}; Flags: Precursor;
• Gene Information: Name=TEP1 {ECO:0000303|PubMed:19797663};
• Organism (full): Anopheles gambiae (African malaria mosquito).
• Protein Family: Not specified in UniProt
• Key Domains: A-macroglobulin_rcpt-bd. (IPR009048); A-macroglobulin_rcpt-bd_sf. (IPR036595); A2M/Complement_sys. (IPR050473); A2M_N_BRD. (IPR011625); A2M_TED. (IPR041813)

MANDATORY VERIFICATION STEPS:

1. Check if the gene symbol "TEP1" matches the protein description above
2. Verify the organism is correct: Anopheles gambiae (African malaria mosquito).
3. Check if protein family/domains align with what you find in literature
4. If you find literature for a DIFFERENT gene with the same or similar symbol, STOP

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

DO NOT PROCEED WITH RESEARCH ON A DIFFERENT GENE. Instead:
- State clearly: "The gene symbol 'TEP1' is ambiguous or literature is limited for this specific protein"
- Explain what you found (e.g., "Found extensive literature on a different gene with the same symbol in a different organism")
- Describe the protein based ONLY on the UniProt information provided above
- Suggest that the protein function can be inferred from domain/family information

Research Target:

Please provide a comprehensive research report on the gene TEP1 (gene ID: TEP1, UniProt: C9XI63) in ANOGA.

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.

We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.

Output

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on:
1. Key concepts and definitions with current understanding
2. Recent developments and latest research (prioritize 2023-2024 sources)
3. Current applications and real-world implementations
4. Expert opinions and analysis from authoritative sources
5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available.
Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

BEFORE YOU BEGIN RESEARCH: You MUST verify you are researching the CORRECT gene/protein. Gene symbols can be ambiguous, especially for less well-characterized genes from non-model organisms.

Target Gene/Protein Identity (from UniProt):

• UniProt Accession: C9XI63
• Protein Description: RecName: Full=Thioester-containing protein 1 allele S3 {ECO:0000303|PubMed:19797663}; Short=TEP1s {ECO:0000303|PubMed:15006349}; AltName: Full=TEP1-F {ECO:0000303|PubMed:19286136}; Contains: RecName: Full=Thioester-containing protein 1 N-terminal {ECO:0000303|PubMed:19286136}; Short=TEP1-N {ECO:0000303|PubMed:19286136}; Contains: RecName: Full=Thioester-containing protein 1 C-terminal; Short=TEP1-C {ECO:0000303|PubMed:19286136}; Flags: Precursor;
• Gene Information: Name=TEP1 {ECO:0000303|PubMed:19797663};
• Organism (full): Anopheles gambiae (African malaria mosquito).
• Protein Family: Not specified in UniProt
• Key Domains: A-macroglobulin_rcpt-bd. (IPR009048); A-macroglobulin_rcpt-bd_sf. (IPR036595); A2M/Complement_sys. (IPR050473); A2M_N_BRD. (IPR011625); A2M_TED. (IPR041813)

MANDATORY VERIFICATION STEPS:

1. Check if the gene symbol "TEP1" matches the protein description above
2. Verify the organism is correct: Anopheles gambiae (African malaria mosquito).
3. Check if protein family/domains align with what you find in literature
4. If you find literature for a DIFFERENT gene with the same or similar symbol, STOP

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

DO NOT PROCEED WITH RESEARCH ON A DIFFERENT GENE. Instead:
- State clearly: "The gene symbol 'TEP1' is ambiguous or literature is limited for this specific protein"
- Explain what you found (e.g., "Found extensive literature on a different gene with the same symbol in a different organism")
- Describe the protein based ONLY on the UniProt information provided above
- Suggest that the protein function can be inferred from domain/family information

Research Target:

Please provide a comprehensive research report on the gene TEP1 (gene ID: TEP1, UniProt: C9XI63) in ANOGA.

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.

We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.

Plan overview
- We verified the TEP1 gene/protein identity, organism, and domain architecture, then gathered recent primary literature (2023–2024) on allelic distributions and pathway updates, along with foundational mechanistic papers. We synthesized functional roles, localization, interaction partners, and applications, and compiled a citable artifact summarizing key facts.

Verification of identity and scope (MANDATORY CHECKS)
- Gene/protein symbol and organism: The target is TEP1 from Anopheles gambiae. Foundational and subsequent work identify AgTEP1 as a mosquito complement C3-like, thioester-containing effector central to anti-Plasmodium immunity in A. gambiae, matching the UniProt record provided (C9XI63) and the specified organism (A. gambiae) (Cell, 2004; PLOS Pathogens, 2017). These sources consistently refer to AgTEP1 as a secreted hemolymph protein with complement-like activity and a functional thioester (no conflicting gene symbol usage found) (blandin2004complementlikeproteintep1 pages 1-2, blandin2004complementlikeproteintep1 pages 7-8, volohonsky2017transgenicexpressionof pages 2-3).
- Family/domains: Literature describes AgTEP1 as complement C3-like within the alpha-2-macroglobulin/complement superfamily with multiple MG domains, a CUB domain, and a thioester-containing domain bearing the conserved GCGEQ motif, aligning with UniProt domain annotations (A2M/Complement system and TED) (Frontiers in Immunology, 2025 review) (li2025comparativeimmunologicalroles pages 5-6, li2025comparativeimmunologicalroles pages 14-14, li2025comparativeimmunologicalroles pages 15-16).

Key concepts and definitions with current understanding
- Molecular identity: AgTEP1 is a secreted ~165 kDa complement C3-like thioester-containing protein that circulates in mosquito hemolymph and covalently attaches to pathogen surfaces via its reactive thioester (GCGEQ) (Frontiers in Immunology, 2025; PLOS Pathogens, 2017) (li2025comparativeimmunologicalroles pages 5-6, volohonsky2017transgenicexpressionof pages 2-3).
- Processed forms: Two principal forms exist: full-length TEP1 (TEP1-F) and a proteolytically cleaved, activated form (TEP1cut). TEP1cut remains disulfide-linked and is the thioester-exposed, opsonic form found in hemolymph complexes (PLOS Pathogens, 2017) (volohonsky2017transgenicexpressionof pages 2-3).
- Core partners and pathway components: The LRIM1/APL1C leucine-rich repeat heterodimer binds/stabilizes TEP1cut, preventing its precipitation and enabling delivery to targets; the CLIP-domain serine protease homolog SPCLIP1 is required for accumulation/recruitment of TEP1 to microbial/parasite surfaces, indicating a complement-convertase-like cascade in mosquitoes (PLoS Pathogens, 2011; 2013; PLOS Pathogens, 2017) (li2025comparativeimmunologicalroles pages 14-14, volohonsky2017transgenicexpressionof pages 2-3).
- Mechanism of action: AgTEP1 binds Plasmodium ookinetes at the midgut basal lamina. Binding leads to parasite killing via lysis and/or triggers melanization depending on the genetic background; TEP1 knockdown increases oocyst numbers in susceptible lines and abolishes melanization in refractory lines, demonstrating TEP1’s determinant role in vectorial capacity (Cell, 2004; PLOS Pathogens, 2017) (blandin2004complementlikeproteintep1 pages 1-2, blandin2004complementlikeproteintep1 pages 7-8, volohonsky2017transgenicexpressionof pages 2-3).
- Localization: The fat body is the main site of TEP1 expression; TEP1 is secreted into the hemolymph and binds to ookinetes at the midgut basal lamina; it can be taken up by hemocytes during immune challenge (PLOS Pathogens, 2017; Cell, 2004) (volohonsky2017transgenicexpressionof pages 2-3, blandin2004complementlikeproteintep1 pages 1-2).

Recent developments and latest research (emphasis 2023–2024)
- Population genetics across transmission gradients (The Gambia, 2023): A Malaria Journal study analyzed >1,000 archived A. gambiae complex mosquitoes (2009–2019) from eastern (higher) and western (lower) Gambia. Eight common TEP1 variants were identified. Overall, there was no significant disproportionate distribution of TEP1 alleles by transmission setting, and temporal distributions were consistent. The susceptible allele TEP1s was most frequent (East 21.4–68.4%; West 23.5–67.2%). In An. arabiensis, wild-type TEP1 and TEP1s were significantly higher in the low-transmission setting (TEP1 Z = −4.831, P < 0.0001; TEP1s Z = −2.073, P = 0.038). Heterozygosity and recombination events were common, and resistant alleles (TEP1rA/rB) generally remained at lower frequencies (Malaria Journal, Mar 2023; https://doi.org/10.1186/s12936-023-04518-1) (hamidadiamoh2023distributionofanopheles pages 1-2, hamidadiamoh2023distributionofanopheles pages 7-8, hamidadiamoh2023distributionofanopheles pages 5-7, hamidadiamoh2023distributionofanopheles pages 4-5, hamidadiamoh2023distributionofanopheles pages 8-8).
- Allele frequencies and infection phenotypes (Ethiopia, 2024): A PLOS ONE study genotyped 330 An. gambiae s.l. collected in 2019–2020 from southwest Ethiopia. Two alleles were detected: TEP1S1 at 82% and TEP1R1 at 18%, with genotypes S1/S1 65.15%, R1/R1 2.12%, and S1/R1 32.73%. Functional feeding assays with P. falciparum and P. vivax reported that mosquitoes with TEP1*RR were classified as susceptible yet yielded fewer oocysts than SR and SS, suggesting complex genotype–phenotype relationships and highlighting the need for further investigation (PLOS ONE, Oct 9, 2024; https://doi.org/10.1371/journal.pone.0311783) (tsegaye2024genotypedistributionand pages 1-2).
- Late sporogonic stages and melanization (2024): New experimental evidence shows that late-stage oocysts and sporozoites can be melanized in A. gambiae when negative regulators of melanization (CLIPA14 and CLIPA2) are co-silenced. Critically, melanization of late-stage oocysts under these conditions requires TEP1 and the cSPH module (TEP1 or CLIPA28 knockdown dramatically reduces melanized oocysts), expanding the recognized window of TEP1-associated effector activity beyond ookinetes (Frontiers in Cellular and Infection Microbiology, Aug 2024; https://doi.org/10.3389/fcimb.2024.1438019) (zeineddine2024latesporogonicstages pages 4-6, zeineddine2024latesporogonicstages pages 13-13).

Current applications and real-world implementations
- Genetic control/transmission-blocking strategies: Transgenic overexpression of the refractory TEP1r allele in fat body cells rescued loss-of-function phenotypes but, in the presence of a wild-type susceptible allele, did not further enhance resistance, indicating challenges in leveraging TEP1 overexpression alone to improve parasite resistance. The study also reported moderate in vivo elevation using TALEs and noted that increased TEP1 expression did not translate to increased resistance, underscoring the pathway’s tight regulation and the necessity of co-factors (PLOS Pathogens, Jan 2017; https://doi.org/10.1371/journal.ppat.1006113) (volohonsky2017transgenicexpressionof pages 2-3).
- Surveillance utility: Recent population-genetic surveys provide actionable allele-frequency baselines (e.g., Gambia 2009–2019; Ethiopia 2019–2020) that can inform local vector competence risk assessment and guide targeting of transmission-blocking interventions or gene drive designs considering prevalent TEP1 alleles and recombination patterns (Malaria Journal, 2023; PLOS ONE, 2024) (hamidadiamoh2023distributionofanopheles pages 1-2, hamidadiamoh2023distributionofanopheles pages 5-7, tsegaye2024genotypedistributionand pages 1-2).

Expert opinions and analysis from authoritative sources
- Foundational perspective: TEP1 is a principal determinant of vectorial capacity in A. gambiae. RNAi of TEP1 increases parasite survival in susceptible lines and abrogates melanization in refractory lines, indicating that TEP1-mediated opsonization is upstream of both lysis and melanization pathways and is central to antiplasmodial immunity (Cell, Mar 2004; https://doi.org/10.1016/S0092-8674(04)00173-4) (blandin2004complementlikeproteintep1 pages 1-2, blandin2004complementlikeproteintep1 pages 7-8).
- Mechanistic integration: Reviews and mechanistic studies converge that LRIM1/APL1C stabilization of TEP1cut and SPCLIP1-mediated recruitment are essential for efficient complement-like activation, implying a convertase-like cascade in insects with pathogen-specific nuances (PLoS Pathogens 2011/2013; summarized in 2017/2025 literature) (li2025comparativeimmunologicalroles pages 14-14, volohonsky2017transgenicexpressionof pages 2-3, li2025comparativeimmunologicalroles pages 5-6, li2025comparativeimmunologicalroles pages 15-16).
- Emerging understanding (2024): The requirement for TEP1 in melanization of late oocysts in a sensitized background (dual negative regulator knockdown) suggests broader TEP1 involvement across parasite stages than previously appreciated, with implications for timing and targets of transmission-blocking strategies (Frontiers in Cellular and Infection Microbiology, Aug 2024; https://doi.org/10.3389/fcimb.2024.1438019) (zeineddine2024latesporogonicstages pages 4-6, zeineddine2024latesporogonicstages pages 13-13).

Relevant statistics and data from recent studies
- Allele distributions (The Gambia, 2009–2019): TEP1s allele frequency ranges: East = 21.4–68.4%, West = 23.5–67.2%. In An. arabiensis, TEP1 and TEP1s were higher in low-transmission settings (TEP1: Z = −4.831, P < 0.0001; TEP1s: Z = −2.073, P = 0.038). Temporal increase in TEP1s in An. coluzzii high-transmission east: 0% (2009) → 18.2% (2016) → 59% (2019). Resistant alleles generally remained at low frequency; TEP1rB was rare (e.g., 2019: 1.9% An. arabiensis; 9% An. coluzzii) (Malaria Journal, Mar 2023; https://doi.org/10.1186/s12936-023-04518-1) (hamidadiamoh2023distributionofanopheles pages 1-2, hamidadiamoh2023distributionofanopheles pages 5-7, hamidadiamoh2023distributionofanopheles pages 4-5).
- Allele/genotype frequencies (Ethiopia, 2019–2020 collections; published 2024): TEP1S1 82%, TEP1R1 18%; genotypes S1/S1 65.15%, R1/R1 2.12%, S1/R1 32.73%. Diversity: nucleotide diversity 0.36554–0.46751; haplotype diversity 0.48871–0.63161; positive Tajima’s D and Fu’s Fs across sites. Functional feeding assays reported fewer oocysts in RR than SR/SS despite classifying RR as susceptible, indicating non-linear genotype–phenotype effects (PLOS ONE, Oct 9, 2024; https://doi.org/10.1371/journal.pone.0311783) (tsegaye2024genotypedistributionand pages 1-2).
- Late-stage melanization depends on TEP1 in sensitized backgrounds: Co-silencing CLIPA14 and CLIPA2 elevates melanization of day-14 oocysts/sporozoites; additional silencing of TEP1 or CLIPA28 dramatically reduces melanized oocysts, demonstrating TEP1 dependence. Salivary-gland sporozoites decreased by day 21 in melanization-augmented mosquitoes (Frontiers in Cellular and Infection Microbiology, Aug 2024; https://doi.org/10.3389/fcimb.2024.1438019) (zeineddine2024latesporogonicstages pages 4-6).

Mechanistic narrative: function, substrates, and pathway placement
- Substrate/target: TEP1’s reactive thioester covalently binds to pathogen surface moieties; for Plasmodium, TEP1 decorates ookinetes after they traverse the midgut epithelium and associates with degenerate parasites, marking them for clearance (Cell, 2004; PLOS Pathogens, 2017) (blandin2004complementlikeproteintep1 pages 1-2, volohonsky2017transgenicexpressionof pages 2-3).
- Activation and regulation: Proteolytic activation generates TEP1cut. The LRIM1/APL1C complex stabilizes TEP1cut in hemolymph; SPCLIP1 is required for TEP1 accumulation/recruitment on microbial/parasite surfaces. These interactions parallel vertebrate complement convertase logic in an insect context (PLoS Pathogens 2011; 2013; PLOS Pathogens, 2017) (li2025comparativeimmunologicalroles pages 14-14, volohonsky2017transgenicexpressionof pages 2-3).
- Effector outcomes: In susceptible backgrounds, TEP1-mediated opsonization promotes parasite lysis; in refractory backgrounds, it additionally triggers a serine protease cascade that activates melanization (phenoloxidase pathway), encapsulating and killing parasites. RNAi of TEP1 increases oocysts and abolishes melanization in refractory lines (Cell, 2004; PLOS Pathogens, 2017) (blandin2004complementlikeproteintep1 pages 1-2, blandin2004complementlikeproteintep1 pages 7-8, volohonsky2017transgenicexpressionof pages 2-3).
- Stage breadth: New evidence shows TEP1 contribution to melanization of late sporogonic stages in a context where negative regulators are removed, extending TEP1’s functional footprint beyond ookinetes (Frontiers in Cellular and Infection Microbiology, 2024) (zeineddine2024latesporogonicstages pages 4-6).

Allelic variation and vector competence
- Two major classes—TEP1R (resistant) and TEP1S (susceptible)—differ in stability and activity of the thioester domain and in immune outcomes in vivo. R alleles (e.g., R1) are classically associated with strong refractoriness and melanization (e.g., L3-5 strain), whereas S alleles are associated with higher oocyst loads (Cell, 2004; PLOS Pathogens, 2017). Field data show S alleles are common, with resistant alleles at lower frequencies, but distributions vary by species, location, and time (Malaria Journal, 2023; PLOS ONE, 2024) (blandin2004complementlikeproteintep1 pages 7-8, volohonsky2017transgenicexpressionof pages 2-3, hamidadiamoh2023distributionofanopheles pages 1-2, hamidadiamoh2023distributionofanopheles pages 5-7, tsegaye2024genotypedistributionand pages 1-2).

Embedded quick-reference artifact
| Topic | Key finding (1–2 sentences) | Year | Source (authors/journal) | URL/DOI | Context ID to cite |
|---|---|---:|---|---|---|
| Identity & domains | AgTEP1 is a ~165 kDa secreted glycoprotein containing multiple macroglobulin (MG) domains, a CUB domain and a thioester-containing domain (TED) with the conserved GCGEQ motif; the TED thioester mediates covalent attachment to targets. | 2025 | Li et al., Frontiers in Immunology | https://doi.org/10.3389/fimmu.2025.1629262 | (li2025comparativeimmunologicalroles pages 5-6) |
| Processing forms (TEP1-F, TEP1cut) | TEP1 is present as full-length TEP1-F and a proteolytically processed activated form (TEP1cut); TEP1cut circulates in hemolymph and is the active, thioester-exposed form involved in target binding. | 2017 | Volohonsky et al., PLOS Pathogens | https://doi.org/10.1371/journal.ppat.1006113 | (volohonsky2017transgenicexpressionof pages 2-3) |
| Core partners (LRIM1/APL1C, SPCLIP1) | The LRIM1/APL1C heterodimer binds and stabilizes cleaved TEP1 in solution preventing aggregation, while the CLIP-domain homolog SPCLIP1 regulates recruitment/accumulation of TEP1 on microbial/plasmodial surfaces. | 2011–2017 | Povelones et al. (PLoS Pathogens 2011/2013); Volohonsky et al. (PLOS Pathogens 2017) | Povelones et al. (2011) https://doi.org/10.1371/journal.ppat.1002023; Volohonsky et al. (2017) https://doi.org/10.1371/journal.ppat.1006113 | (li2025comparativeimmunologicalroles pages 14-14, volohonsky2017transgenicexpressionof pages 2-3) |
| Primary functions (opsonization, killing, melanization) | TEP1 opsonizes Plasmodium ookinetes via thioester-mediated binding, leading to parasite lysis or triggering melanization depending on genetic background; TEP1 knockdown increases oocyst numbers and abolishes melanization in refractory strains. | 2004, 2017 | Blandin et al., Cell (2004); Volohonsky et al., PLOS Pathogens (2017) | https://doi.org/10.1016/S0092-8674(04)00173-4; https://doi.org/10.1371/journal.ppat.1006113 | (blandin2004complementlikeproteintep1 pages 1-2, volohonsky2017transgenicexpressionof pages 2-3) |
| Localization (tissue / subcellular) | TEP1 is produced mainly by the fat body, secreted into the hemolymph, and binds invading ookinetes at the midgut basal lamina; it is taken up by hemocytes upon immune challenge. | 2004, 2017 | Blandin et al., Cell (2004); Volohonsky et al., PLOS Pathogens (2017) | https://doi.org/10.1016/S0092-8674(04)00173-4; https://doi.org/10.1371/journal.ppat.1006113 | (blandin2004complementlikeproteintep1 pages 1-2, volohonsky2017transgenicexpressionof pages 2-3) |
| Allelic classes (R vs S) and phenotypes | Two major allele classes, TEP1S (susceptible) and TEP1R (resistant), exist: R alleles (e.g., R1) confer strong refractoriness with parasite melanization, while S alleles associate with higher parasite survival. | 2004–2017 | Blandin et al., Cell (2004); Volohonsky et al., PLOS Pathogens (2017) | https://doi.org/10.1016/S0092-8674(04)00173-4; https://doi.org/10.1371/journal.ppat.1006113 | (blandin2004complementlikeproteintep1 pages 7-8, volohonsky2017transgenicexpressionof pages 2-3) |
| Recent population-genetics (2023–2024) | Field studies report predominant susceptible alleles (e.g., TEP1*S1 ~80–82%) with resistant alleles at ~18–20%; 2024 PLOS ONE genotyping (n=330) found S1 82%, R1 18% with genotype frequencies S1/S1 65.15%, R1/R1 2.12%, S1/R1 32.73%. | 2022–2024 | Onyango et al., Malaria Journal (2022); Tsegaye et al., PLOS ONE (2024) | Onyango et al. 2022 https://doi.org/10.1186/s12936-022-04256-w; Tsegaye et al. 2024 https://doi.org/10.1371/journal.pone.0311783 | (onyango2022molecularcharacterizationand pages 1-2, tsegaye2024genotypedistributionand pages 1-2) |

Table: Concise, citable summary of AgTEP1 (UniProt C9XI63) covering identity, processing, partners, functions, localization, allelic phenotypes, and 2022–2024 population-genetics evidence; useful for quick reference and citation in a comprehensive report.

Limitations and open questions
- While TEP1 is essential for early-stage parasite killing and can contribute to late-stage melanization in sensitized conditions, how often late-stage melanization occurs in natural populations and how allele-specific differences modulate these outcomes remain open questions raised by 2023–2024 population studies and the 2024 mechanistic report (hamidadiamoh2023distributionofanopheles pages 1-2, tsegaye2024genotypedistributionand pages 1-2, zeineddine2024latesporogonicstages pages 4-6).

Key sources with URLs and dates
- Blandin et al., Cell, Mar 5, 2004. Complement-like protein TEP1 is a determinant of vectorial capacity. https://doi.org/10.1016/S0092-8674(04)00173-4 (blandin2004complementlikeproteintep1 pages 1-2, blandin2004complementlikeproteintep1 pages 7-8).
- Volohonsky et al., PLOS Pathogens, Jan 17, 2017. Transgenic expression of TEP1 in A. gambiae. https://doi.org/10.1371/journal.ppat.1006113 (volohonsky2017transgenicexpressionof pages 2-3).
- Povelones et al., PLoS Pathogens, 2011/2013. LRIM1/APL1C interacts with TEP1; SPCLIP1 required for TEP1 recruitment. 2011: https://doi.org/10.1371/journal.ppat.1002023; 2013: https://doi.org/10.1371/journal.ppat.1003623 (summarized within review excerpts) (li2025comparativeimmunologicalroles pages 14-14).
- Hamid-Adiamoh et al., Malaria Journal, Mar 2023. TEP1 alleles along transmission gradients in The Gambia. https://doi.org/10.1186/s12936-023-04518-1 (hamidadiamoh2023distributionofanopheles pages 1-2, hamidadiamoh2023distributionofanopheles pages 7-8, hamidadiamoh2023distributionofanopheles pages 5-7, hamidadiamoh2023distributionofanopheles pages 4-5, hamidadiamoh2023distributionofanopheles pages 8-8).
- Tsegaye et al., PLOS ONE, Oct 9, 2024. TEP1 genotype distribution and oocyst development in Ethiopia. https://doi.org/10.1371/journal.pone.0311783 (tsegaye2024genotypedistributionand pages 1-2).
- Zeineddine et al., Frontiers in Cellular and Infection Microbiology, Aug 2024. Late-stage melanization requires TEP1 in sensitized backgrounds. https://doi.org/10.3389/fcimb.2024.1438019 (zeineddine2024latesporogonicstages pages 4-6, zeineddine2024latesporogonicstages pages 13-13).
- Li et al., Frontiers in Immunology, Oct 2025. Comparative TEP1 review (domains/motifs and pathway integration). https://doi.org/10.3389/fimmu.2025.1629262 (li2025comparativeimmunologicalroles pages 5-6, li2025comparativeimmunologicalroles pages 14-14, li2025comparativeimmunologicalroles pages 15-16).

Conclusion
- AgTEP1 (TEP1; UniProt C9XI63) is a complement-like thioester protein that acts as a central opsonin in the mosquito hemolymph, stabilized by LRIM1/APL1C and recruited via SPCLIP1, to bind and eliminate Plasmodium ookinetes and, in sensitized contexts, late sporogonic stages via lysis and melanization. Recent field genetics (2023–2024) refine our view of allele distributions (S predominance, low-frequency R) across regions and species, while mechanistic advances extend TEP1-dependent melanization to later parasite stages. These insights inform realistic expectations for TEP1-centric vector control strategies and emphasize the need to consider pathway co-factors and local allele landscapes (blandin2004complementlikeproteintep1 pages 1-2, volohonsky2017transgenicexpressionof pages 2-3, hamidadiamoh2023distributionofanopheles pages 1-2, tsegaye2024genotypedistributionand pages 1-2, zeineddine2024latesporogonicstages pages 4-6).

References

1. (blandin2004complementlikeproteintep1 pages 1-2): Stephanie Blandin, Shin-Hong Shiao, Luis F Moita, Chris J Janse, Andrew P Waters, Fotis C Kafatos, and Elena A Levashina. Complement-like protein tep1 is a determinant of vectorial capacity in the malaria vector anopheles gambiae. Cell, 116:661-670, Mar 2004. URL: https://doi.org/10.1016/s0092-8674(04)00173-4, doi:10.1016/s0092-8674(04)00173-4. This article has 757 citations and is from a highest quality peer-reviewed journal.

2. (blandin2004complementlikeproteintep1 pages 7-8): Stephanie Blandin, Shin-Hong Shiao, Luis F Moita, Chris J Janse, Andrew P Waters, Fotis C Kafatos, and Elena A Levashina. Complement-like protein tep1 is a determinant of vectorial capacity in the malaria vector anopheles gambiae. Cell, 116:661-670, Mar 2004. URL: https://doi.org/10.1016/s0092-8674(04)00173-4, doi:10.1016/s0092-8674(04)00173-4. This article has 757 citations and is from a highest quality peer-reviewed journal.

3. (volohonsky2017transgenicexpressionof pages 2-3): Gloria Volohonsky, Ann-Katrin Hopp, Mélanie Saenger, Julien Soichot, Heidi Scholze, Jens Boch, Stéphanie A. Blandin, and Eric Marois. Transgenic expression of the anti-parasitic factor tep1 in the malaria mosquito anopheles gambiae. PLOS Pathogens, 13:e1006113, Jan 2017. URL: https://doi.org/10.1371/journal.ppat.1006113, doi:10.1371/journal.ppat.1006113. This article has 81 citations and is from a highest quality peer-reviewed journal.

4. (li2025comparativeimmunologicalroles pages 5-6): Hongyu Li, Yilu Feng, Yuncheng Qian, Wenjie Jiang, Yunhuan Zhu, Jialu Xu, Xianwei Li, Xinyi Fei, Ruke Wang, Yuqing Shao, Lailing Du, Xiaofen Zhang, and Keda Chen. Comparative immunological roles of tep1 in anopheles gambiae and biomphalaria glabrata: implications for malaria and schistosomiasis control. Frontiers in Immunology, Oct 2025. URL: https://doi.org/10.3389/fimmu.2025.1629262, doi:10.3389/fimmu.2025.1629262. This article has 1 citations and is from a peer-reviewed journal.

5. (li2025comparativeimmunologicalroles pages 14-14): Hongyu Li, Yilu Feng, Yuncheng Qian, Wenjie Jiang, Yunhuan Zhu, Jialu Xu, Xianwei Li, Xinyi Fei, Ruke Wang, Yuqing Shao, Lailing Du, Xiaofen Zhang, and Keda Chen. Comparative immunological roles of tep1 in anopheles gambiae and biomphalaria glabrata: implications for malaria and schistosomiasis control. Frontiers in Immunology, Oct 2025. URL: https://doi.org/10.3389/fimmu.2025.1629262, doi:10.3389/fimmu.2025.1629262. This article has 1 citations and is from a peer-reviewed journal.

6. (li2025comparativeimmunologicalroles pages 15-16): Hongyu Li, Yilu Feng, Yuncheng Qian, Wenjie Jiang, Yunhuan Zhu, Jialu Xu, Xianwei Li, Xinyi Fei, Ruke Wang, Yuqing Shao, Lailing Du, Xiaofen Zhang, and Keda Chen. Comparative immunological roles of tep1 in anopheles gambiae and biomphalaria glabrata: implications for malaria and schistosomiasis control. Frontiers in Immunology, Oct 2025. URL: https://doi.org/10.3389/fimmu.2025.1629262, doi:10.3389/fimmu.2025.1629262. This article has 1 citations and is from a peer-reviewed journal.

7. (hamidadiamoh2023distributionofanopheles pages 1-2): Majidah Hamid-Adiamoh, Abdoulie Mai Janko Jabang, Kevin Ochieng Opondo, Mamadou Ousmane Ndiath, Benoit Sessinou Assogba, and Alfred Amambua-Ngwa. Distribution of anopheles gambiae thioester-containing protein 1 alleles along malaria transmission gradients in the gambia. Malaria Journal, Mar 2023. URL: https://doi.org/10.1186/s12936-023-04518-1, doi:10.1186/s12936-023-04518-1. This article has 7 citations and is from a peer-reviewed journal.

8. (hamidadiamoh2023distributionofanopheles pages 7-8): Majidah Hamid-Adiamoh, Abdoulie Mai Janko Jabang, Kevin Ochieng Opondo, Mamadou Ousmane Ndiath, Benoit Sessinou Assogba, and Alfred Amambua-Ngwa. Distribution of anopheles gambiae thioester-containing protein 1 alleles along malaria transmission gradients in the gambia. Malaria Journal, Mar 2023. URL: https://doi.org/10.1186/s12936-023-04518-1, doi:10.1186/s12936-023-04518-1. This article has 7 citations and is from a peer-reviewed journal.

9. (hamidadiamoh2023distributionofanopheles pages 5-7): Majidah Hamid-Adiamoh, Abdoulie Mai Janko Jabang, Kevin Ochieng Opondo, Mamadou Ousmane Ndiath, Benoit Sessinou Assogba, and Alfred Amambua-Ngwa. Distribution of anopheles gambiae thioester-containing protein 1 alleles along malaria transmission gradients in the gambia. Malaria Journal, Mar 2023. URL: https://doi.org/10.1186/s12936-023-04518-1, doi:10.1186/s12936-023-04518-1. This article has 7 citations and is from a peer-reviewed journal.

10. (hamidadiamoh2023distributionofanopheles pages 4-5): Majidah Hamid-Adiamoh, Abdoulie Mai Janko Jabang, Kevin Ochieng Opondo, Mamadou Ousmane Ndiath, Benoit Sessinou Assogba, and Alfred Amambua-Ngwa. Distribution of anopheles gambiae thioester-containing protein 1 alleles along malaria transmission gradients in the gambia. Malaria Journal, Mar 2023. URL: https://doi.org/10.1186/s12936-023-04518-1, doi:10.1186/s12936-023-04518-1. This article has 7 citations and is from a peer-reviewed journal.

11. (hamidadiamoh2023distributionofanopheles pages 8-8): Majidah Hamid-Adiamoh, Abdoulie Mai Janko Jabang, Kevin Ochieng Opondo, Mamadou Ousmane Ndiath, Benoit Sessinou Assogba, and Alfred Amambua-Ngwa. Distribution of anopheles gambiae thioester-containing protein 1 alleles along malaria transmission gradients in the gambia. Malaria Journal, Mar 2023. URL: https://doi.org/10.1186/s12936-023-04518-1, doi:10.1186/s12936-023-04518-1. This article has 7 citations and is from a peer-reviewed journal.

12. (tsegaye2024genotypedistributionand pages 1-2): Arega Bedasso Tsegaye, Assalif Demissew, Ashenafi Abossie, Hallelujah Getachew, Kassahun Habtamu, T. Degefa, Xiaoming Wang, Ming-Chieh Lee, Daibin Zhong, James W. Kazura, Guiyun Yan, and Delenasaw Yewhalaw. Genotype distribution and allele frequency of thioester-containing protein 1(tep1) and its effect on development of plasmodium oocyst in populations of anopheles arabiensis in ethiopia. PLOS ONE, 19:e0311783, Oct 2024. URL: https://doi.org/10.1371/journal.pone.0311783, doi:10.1371/journal.pone.0311783. This article has 0 citations and is from a peer-reviewed journal.

13. (zeineddine2024latesporogonicstages pages 4-6): Suheir Zeineddine, Sana Jaber, Sally A. Saab, Johnny Nakhleh, George Dimopoulos, and Mike A. Osta. Late sporogonic stages of plasmodium parasites are susceptible to the melanization response in anopheles gambiae mosquitoes. Frontiers in Cellular and Infection Microbiology, Aug 2024. URL: https://doi.org/10.3389/fcimb.2024.1438019, doi:10.3389/fcimb.2024.1438019. This article has 8 citations and is from a poor quality or predatory journal.

14. (zeineddine2024latesporogonicstages pages 13-13): Suheir Zeineddine, Sana Jaber, Sally A. Saab, Johnny Nakhleh, George Dimopoulos, and Mike A. Osta. Late sporogonic stages of plasmodium parasites are susceptible to the melanization response in anopheles gambiae mosquitoes. Frontiers in Cellular and Infection Microbiology, Aug 2024. URL: https://doi.org/10.3389/fcimb.2024.1438019, doi:10.3389/fcimb.2024.1438019. This article has 8 citations and is from a poor quality or predatory journal.

15. (onyango2022molecularcharacterizationand pages 1-2): Shirley A. Onyango, Kevin O. Ochwedo, Maxwell G. Machani, Julius O. Olumeh, Isaiah Debrah, Collince J. Omondi, Sidney O. Ogolla, Ming-Chieh Lee, Guofa Zhou, Elizabeth Kokwaro, James W. Kazura, Yaw A. Afrane, Andrew K. Githeko, Daibin Zhong, and Guiyun Yan. Molecular characterization and genotype distribution of thioester-containing protein 1 gene in anopheles gambiae mosquitoes in western kenya. Malaria Journal, Aug 2022. URL: https://doi.org/10.1186/s12936-022-04256-w, doi:10.1186/s12936-022-04256-w. This article has 10 citations and is from a peer-reviewed journal.

Citations

1. volohonsky2017transgenicexpressionof pages 2-3
2. tsegaye2024genotypedistributionand pages 1-2
3. zeineddine2024latesporogonicstages pages 4-6
4. li2025comparativeimmunologicalroles pages 5-6
5. li2025comparativeimmunologicalroles pages 14-14
6. li2025comparativeimmunologicalroles pages 15-16
7. hamidadiamoh2023distributionofanopheles pages 1-2
8. hamidadiamoh2023distributionofanopheles pages 7-8
9. hamidadiamoh2023distributionofanopheles pages 5-7
10. hamidadiamoh2023distributionofanopheles pages 4-5
11. hamidadiamoh2023distributionofanopheles pages 8-8
12. zeineddine2024latesporogonicstages pages 13-13
13. onyango2022molecularcharacterizationand pages 1-2
14. https://doi.org/10.1186/s12936-023-04518-1
15. https://doi.org/10.1371/journal.pone.0311783
16. https://doi.org/10.3389/fcimb.2024.1438019
17. https://doi.org/10.1371/journal.ppat.1006113
18. https://doi.org/10.1016/S0092-8674(04
19. https://doi.org/10.3389/fimmu.2025.1629262
20. https://doi.org/10.1371/journal.ppat.1002023;
21. https://doi.org/10.1186/s12936-022-04256-w;
22. https://doi.org/10.1371/journal.ppat.1003623
23. https://doi.org/10.1016/s0092-8674(04
24. https://doi.org/10.1371/journal.ppat.1006113,
25. https://doi.org/10.3389/fimmu.2025.1629262,
26. https://doi.org/10.1186/s12936-023-04518-1,
27. https://doi.org/10.1371/journal.pone.0311783,
28. https://doi.org/10.3389/fcimb.2024.1438019,
29. https://doi.org/10.1186/s12936-022-04256-w,