Iron sequestration by transferrin 1 mediates nutritional immunity in Drosophila melanogaster Original paper

What was studied?

This original research study tested how transferrin-mediated iron sequestration functions as an in vivo immune defense mechanism (“nutritional immunity”) in Drosophila melanogaster. The authors examined whether systemic infection triggers a hypoferremic response—withdrawal of iron from the hemolymph (insect “blood”)—and defined the immune signaling and iron-transport machinery responsible. They focused on Transferrin 1 (Tsf1), an iron-binding hemolymph protein induced by infection, and asked whether Tsf1 is required to redistribute iron to the fat body (a liver-like storage organ) and thereby restrict iron availability to pathogens. Using genetic loss-of-function, tissue-specific RNAi, and iron-binding–defective Tsf1 mutants, they connected iron trafficking to survival outcomes in infections where iron acquisition is known to drive virulence (notably Pseudomonas spp. and Mucorales fungi).

Who was studied?

The study used adult Drosophila melanogaster as the host organism, including wild-type flies and multiple immune-pathway mutants affecting NF-κB signaling (Toll and Imd) as well as a CRISPR-generated Tsf1 null mutant (Tsf1^JP94^) and RNAi knockdowns. Flies were challenged via systemic infection (septic injury) with diverse microbes (Gram-positive and Gram-negative bacteria, yeast, and fungi), with special emphasis on Pseudomonas aeruginosa,Pseudomonas entomophila, and Mucorales fungi (Cunninghamella bertholletiae, Rhizopus oryzae). The investigators also used bacterial mutants deficient in siderophore production or uptake to probe how pathogen iron-scavenging strategies interact with host iron withholding.

Most important findings

Across multiple infections, flies mounted a robust hypoferremic response characterized by decreased hemolymph iron and increased fat body iron, and this shift was host-driven because heat-killed bacteria triggered the same response. Critically, hemolymph iron withdrawal required the canonical NF-κB immune pathways: Toll signaling for Gram-positive challenge and Imd signaling for Gram-negative challenge, placing nutritional immunity downstream of core antimicrobial signaling. Tsf1 was strongly induced after infection in a pathway-dependent and fat body–restricted manner, and Tsf1^JP94^ mutants failed to relocate iron from hemolymph to fat body, leaving excess circulating iron. Functionally, Tsf1 deficiency did not broadly compromise survival against many pathogens, but it markedly increased susceptibility and pathogen burden for iron-sensitive infections, including P. aeruginosa, P. entomophila, and Mucorales fungi; chemical iron chelation rescued this susceptibility, supporting a causative role for iron availability. A key mechanistic insight came from siderophore genetics: P. aeruginosa pyoverdine mutants were attenuated in wild-type flies but regained full virulence in Tsf1 mutants, implying that Tsf1-mediated iron restriction forces reliance on pyoverdine, whereas iron-replete hemolymph makes pyoverdine dispensable. Together, these data define Tsf1 as an infection-induced iron transporter that enforces iron limitation as a defense strategy.

Key implications

This work establishes that insects deploy a mammal-like nutritional immunity program and clarifies that classic immune signaling (Toll/Imd) coordinates both antimicrobial effector production and systemic metal withholding. For clinicians and microbiome translation, the central concept is that host iron handling is a dominant ecological force shaping pathogen fitness: virulence traits such as siderophore production become essential specifically under iron-restricted host conditions, while host defects that leave iron accessible can collapse that dependency and worsen outcomes. The study also supports transferrin/iron-chelation strategies as host-aligned anti-virulence approaches, potentially lowering pathogen burden without directly targeting viability—an idea relevant to resistant Pseudomonas infections and iron-amplified fungal disease (Mucorales).

Citation

Iatsenko I, Marra A, Boquete J-P, Peña J, Lemaitre B. Iron sequestration by transferrin 1 mediates nutritional immunity in Drosophila melanogaster.Proc Natl Acad Sci U S A. 2020;117(13):7317-7325. doi:10.1073/pnas.1914830117