CoChat
Sign Up
Cited by 2Invertebrate Immune Response MechanismsImmune Response and InflammationNeurobiology and Insect Physiology Research

The DOI matches its Crossref record; its reference list is not available.

Sex bias in iron sequestration by transferrin 1 modulates sexually dimorphic infection outcomes in Drosophila melanogaster

Open access
Hrdina, Alexandra, Iatsenko, Igor·2026·GENETICS
DOI 10.1093/genetics/iyag058

Published version of a preprint

Open this paper in CoChat — free account

Abstract

Host sexual dimorphism in the outcome of infections is a ubiquitous phenomenon across taxa. However, the immunological differences between males and females and the mechanisms underlying them remain poorly characterized. Here, we used Drosophila melanogaster to test the hypothesis that sex differences in nutritional immunity, particularly iron sequestration, contribute to sexual dimorphism in infection outcome. Using the natural Drosophila pathogen Providencia alcalifaciens, which is controlled by host-mediated iron sequestration, we established an infection model in which males demonstrate increased resistance. Leveraging this model, we showed that males exhibit higher basal and infection-induced expression levels of Transferrin 1 (Tsf1)—an iron transporter mediating iron sequestration during infection. Consequently, males contained lower iron levels in the hemolymph compared to females. Importantly, sex differences in iron content and in survival after P. alcalifaciens infection were abolished in Tsf1 mutants, demonstrating that Tsf1 mediates sexual dimorphism in iron sequestration and susceptibility to P. alcalifaciens infection. Finally, we found that the Toll pathway mediates sex differences in Tsf1 expression and susceptibility to infection. Altogether, our study demonstrates that Tsf1-mediated iron sequestration differs between male and female D. melanogaster, thereby identifying nutritional immunity as a determinant of sexual dimorphism in the outcome of infection.

Overview

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1093/genetics/iyag058

Cites

Statistics

Verification

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Citations

No citation lists for this paper

No citation lists for this paper yet — checked again daily.

References 53 · Cited by 2

Research works printed but not linked: 44

  1. Albrecht, 2011, In vivo mapping of hydrogen peroxide and oxidized glutathione reveals chemical and regional specificity of redox homeostasis, Cell Metab., 14, 819, 10.1016/J.CMET.2011.10.010 · DOI
  2. Arias-Rojas, 2023, Resistance to host antimicrobial peptides mediates resilience of gut commensals during infection and aging in Drosophila, Proc Natl Acad Sci U S A., 120, e2305649120, 10.1073/PNAS.2305649120 · DOI
  3. Becker, 2010, FOXO-dependent regulation of innate immune homeostasis, Nature, 463, 369, 10.1038/nature08698 · DOI
  4. Belmonte, 2020, Sexual dimorphisms in innate immunity and responses to infection in Drosophila melanogaster, Front Immunol., 10, 3075, 10.3389/fimmu.2019.03075 · DOI
  5. Biswas, 2025, Insulin/insulin-like growth factor signaling pathway promotes higher fat storage in Drosophila females, Cell Rep., 44, 115915, 10.1016/j.celrep.2025.115915 · DOI
  6. Cao, 2023, Lactoferrin: a glycoprotein that plays an active role in human health, Front Nutr, 9, 1018336, 10.3389/fnut.2022.1018336 · DOI
  7. Dähn, 2025, Drosophila melanogaster as a model organism to investigate sex specific differences, Sci Rep, 15, 19648, 10.1038/s41598-025-04497-0 · DOI
  8. Dimarcq, 1997, Treatment of l(2)mbn Drosophila tumorous blood cells with the steroid hormone ecdysone amplifies the inducibility of antimicrobial peptide gene expression, Insect Biochem Mol Biol., 27, 877, 10.1016/S0965-1748(97)00072-6 · DOI
  9. Dudzic, 2019, More than black or white: melanization and Toll share regulatory serine proteases in Drosophila, Cell Rep., 27, 1050, 10.1016/J.CELREP.2019.03.101 · DOI
  10. Duneau, 2017, Stochastic variation in the initial phase of bacterial infection predicts the probability of survival in D. melanogaster, eLife, 6, 28298, 10.7554/eLife.28298 · DOI
  11. Duneau, 2017, The Toll pathway underlies host sexual dimorphism in resistance to both Gram-negative and Gram-positive bacteria in mated Drosophila, BMC Biol., 15, 124, 10.1186/s12915-017-0466-3 · DOI
  12. Flatt, 2008, Hormonal regulation of the humoral innate immune response in Drosophila melanogaster, J Exp Biol, 211, 2712, 10.1242/jeb.014878 · DOI
  13. Galac, 2011, Comparative pathology of bacteria in the genus Providencia to a natural host, Drosophila melanogaster, Microbes Infect., 13, 673, 10.1016/J.MICINF.2011.02.005 · DOI
  14. Golonka, 2019, The iron tug-of-war between bacterial siderophores and innate immunity, J Innate Immun., 11, 249, 10.1159/000494627 · DOI
  15. Gomes, 2023, Increased iron levels and oxidative stress mediate age-related impairments in male and female Drosophila melanogaster, Oxid Med Cell Longev., 2023, 7222462, 10.1155/2023/7222462 · DOI
  16. Gordon, 2025, Trade-off between antibacterial immune defense and oogenesis progression in female Drosophila melanogaster, Genetics, 231, iyaf151, 10.1093/genetics/iyaf151 · DOI
  17. Helmann, 2025, Microbial metal physiology: ions to ecosystems, Nat Rev Microbiol, 23, 805, 10.1038/s41579-025-01213-7 · DOI
  18. Hider, 2010, Chemistry and biology of siderophores, Nat Prod Rep, 27, 637, 10.1039/B906679A · DOI · Paper page
  19. Hood, 2012, Nutritional immunity: transition metals at the pathogen–host interface, Nat Rev Microbiol., 10, 525, 10.1038/nrmicro2836 · DOI · Paper page
  20. Hrdina, 2022, The roles of metals in insect–microbe interactions and immunity, Curr Opin Insect Sci., 49, 71, 10.1016/j.cois.2021.12.004 · DOI
  21. Hrdina, 2024, The endosymbiont Spiroplasma poulsonii increases Drosophila melanogaster resistance to pathogens by enhancing iron sequestration and melanization, mBio, 15, e00936–24, 10.1128/mbio.00936-24 · DOI
  22. Kaplan, 2013, The essential nature of iron usage and regulation, Curr Biol, 23, R642, 10.1016/j.cub.2013.05.033 · DOI
  23. Khan, 2024, 10.1101/2024.07.27.605461 · DOI
  24. Klein, 2016, Sex differences in immune responses, Nat Rev Immunol., 16, 626, 10.1038/nri.2016.90 · DOI · Paper page
  25. Krause, 2022, FlyAtlas 2 in 2022: enhancements to the Drosophila melanogaster expression atlas, Nucleic Acids Res, 50, D1010, 10.1093/nar/gkab971 · DOI
  26. Leech, 2021, Social environment drives sex and age-specific variation in Drosophila melanogaster microbiome composition and predicted function, Mol Ecol., 30, 5831, 10.1111/MEC.16149 · DOI
  27. Marra, 2021, The iron transporter transferrin 1 mediates homeostasis of the endosymbiotic relationship between Drosophila melanogaster and Spiroplasma poulsonii, microLife, 2, uqab008, 10.1093/femsml/uqab008 · DOI
  28. Millington, 2018, Sex differences in Drosophila development and physiology, Curr Opin Physiol., 6, 46, 10.1016/j.cophys.2018.04.002 · DOI
  29. Missirlis, 2021, Regulation and biological function of metal ions in Drosophila, Curr Opin Insect Sci., 47, 18, 10.1016/j.cois.2021.02.002 · DOI
  30. Ratnu, 2017, Genetic and epigenetic factors underlying sex differences in the regulation of gene expression in the brain, J Neurosci Res, 95, 301, 10.1002/jnr.23886 · DOI · Paper page
  31. Regan, 2013, Steroid hormone signaling is essential to regulate innate immune cells and fight bacterial infection in Drosophila, PLoS Pathog., 9, e1003720, 10.1371/journal.ppat.1003720 · DOI
  32. Rodríguez-García, 2021, Transferrin-mediated iron sequestration suggests a novel therapeutic strategy for controlling Nosema disease in the honey bee, Apis mellifera, PLoS Pathog., 17, e1009270, 10.1371/JOURNAL.PPAT.1009270 · DOI
  33. Rubinić, 2025, 10.1101/2025.05.22.655590 · DOI
  34. Schwenke, 2017, Juvenile hormone suppresses resistance to infection in mated female Drosophila melanogaster, Curr Biol., 27, 596, 10.1016/j.cub.2017.01.004 · DOI
  35. Schwenke, 2016, Reproduction–immunity trade-offs in insects, Annu Rev Entomol., 61, 239, 10.1146/annurev-ento-010715-023924 · DOI
  36. Shaka, 2022, Lipopolysaccharide -mediated resistance to host antimicrobial peptides and hemocyte-derived reactive-oxygen species are the major Providencia alcalifaciens virulence factors in Drosophila melanogaster, PLoS Pathog., 18, e1010825, 10.1371/JOURNAL.PPAT.1010825 · DOI
  37. Shan, 2023, An evolutionarily conserved serine protease network mediates melanization and Toll activation in Drosophila, Sci Adv., 9, eadk2756, 10.1126/sciadv.adk2756 · DOI
  38. Snell, 2018, Sex chromosome effects on male–female differences in mammals, Curr Biol., 28, R1313, 10.1016/j.cub.2018.09.018 · DOI
  39. Tafesh-Edwards, 2023, The role of Drosophila microbiota in gut homeostasis and immunity, Gut Microbes, 15, 2208503, 10.1080/19490976.2023.2208503 · DOI
  40. Takahashi, 2021, Sex differences in immune responses, Science, 371, 347, 10.1126/science.abe7199 · DOI · Paper page
  41. Weber, 2022, Phenotypic analyses, protein localization, and bacteriostatic activity of Drosophila melanogaster transferrin-1, Insect Biochem Mol Biol., 147, 103811, 10.1016/j.ibmb.2022.103811 · DOI
  42. Westlake, 2024, The Drosophila Immunity Handbook, 10.55430/6304TDIHVA01 · DOI
  43. Xiao, 2019, Transferrin 1 functions in iron trafficking and genetically interacts with ferritin in Drosophila melanogaster, Cell Rep., 26, 748, 10.1016/J.CELREP.2018.12.053 · DOI
  44. Yu, 2025, Drosophila symbionts in infection: when a friend becomes an enemy, Infect Immun., 93, e00511-24, 10.1128/iai.00511-24 · DOI

Metadata

Authors
Hrdina, A., & Iatsenko, I.
Affiliations
  • Humboldt-Universität zu Berlin (DE)
  • Max Planck Institute for Infection Biology (DE)
Corresponding author
Iatsenko, Igor
ORCID
Venue
GENETICS
Publisher
Oxford University Press (OUP)
Published
2026-03-02
Volume
233
Issue
1
ISSN
  • 0016-6731 (ISSN-L)
  • 1943-2631
DOI
10.1093/genetics/iyag058
OpenAlex
W7133193777
Cited by
2
References
53
Citations by year
2026: 2
FWCI
5.33
Type
journal article
Language
en
Open access
Licence
Locations
  • Genetics (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • MPG.PuRe (Max Planck Society) (submittedVersion, other-oa)
Funders
  • Max Planck Society
  • Deutsche Forschungsgemeinschaft (IA 81/2-1, IA81/3-1)
  • Boehringer Ingelheim Foundation
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › Invertebrate Immune Response Mechanisms
  • Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurobiology and Insect Physiology Research
Keywords
iron sequestration, nutritional immunity, sexual dimorphism, Providencia alcalifaciens, Drosophila melanogaster, Toll pathway, host-pathogen interaction, innate immunity
MeSH terms
Animals, Drosophila melanogaster, Female, Hemolymph, Iron, Male, Providencia, Receptors, Transferrin, Sex Characteristics, Transferrin, Antigens, CD, Drosophila Proteins, Host-Pathogen Interactions

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review