Genetic Iron Overload Hampers Development of Cutaneous Leishmaniasis in Mice.
Edouard CharleboisYupeng LiVictoria WagnerKostas PantopoulosMartin OlivierPublished in: International journal of molecular sciences (2023)
The survival, growth, and virulence of Leishmania spp., a group of protozoan parasites, depends on the proper access and regulation of iron. Macrophages, Leishmania's host cell, may divert iron traffic by reducing uptake or by increasing the efflux of iron via the exporter ferroportin. This parasite has adapted by inhibiting the synthesis and inducing the degradation of ferroportin. To study the role of iron in leishmaniasis, we employed Hjv -/- mice, a model of hemochromatosis. The disruption of hemojuvelin (Hjv) abrogates the expression of the iron hormone hepcidin. This allows unrestricted iron entry into the plasma from ferroportin-expressing intestinal epithelial cells and tissue macrophages, resulting in systemic iron overload. Mice were injected with Leishmania major in hind footpads or intraperitoneally. Compared with wild-type controls, Hjv -/- mice displayed transient delayed growth of L. major in hind footpads, with a significant difference in parasite burden 4 weeks post-infection. Following acute intraperitoneal exposure to L. major , Hjv -/- peritoneal cells manifested increased expression of inflammatory cytokines and chemokines ( Il1b , Tnfa , Cxcl2 , and Ccl2) . In response to infection with L. infantum , the causative agent of visceral leishmaniasis, Hjv -/- and control mice developed similar liver and splenic parasite burden despite vastly different tissue iron content and ferroportin expression. Thus, genetic iron overload due to hemojuvelin deficiency appears to mitigate the early development of only cutaneous leishmaniasis.
Keyphrases
- iron deficiency
- wild type
- poor prognosis
- high fat diet induced
- escherichia coli
- genome wide
- risk factors
- staphylococcus aureus
- induced apoptosis
- mesenchymal stem cells
- air pollution
- cystic fibrosis
- drug induced
- gene expression
- metabolic syndrome
- pseudomonas aeruginosa
- intensive care unit
- hepatitis b virus
- copy number
- liver injury
- dna methylation
- brain injury
- endoplasmic reticulum stress
- candida albicans