-Mediated Inhibition of Iron Export Promotes Parasite Replication in Macrophages

English version České info

Leishmania parasites infect macrophages, cells that play an important role in organismal iron homeostasis. By expressing ferroportin, a membrane protein specialized in iron export, macrophages release iron stored intracellularly into the circulation. Iron is essential for the intracellular replication of Leishmania, but how the parasites compete with the iron export function of their host cell is unknown. Here, we show that infection with Leishmania amazonensis inhibits ferroportin expression in macrophages. In a TLR4-dependent manner, infected macrophages upregulated transcription of hepcidin, a peptide hormone that triggers ferroportin degradation. Parasite replication was inhibited in hepcidin-deficient macrophages and in wild type macrophages overexpressing mutant ferroportin that is resistant to hepcidin-induced degradation. Conversely, intracellular growth was enhanced by exogenously added hepcidin, or by expression of dominant-negative ferroportin. Importantly, dominant-negative ferroportin and macrophages from flatiron mice, a mouse model for human type IV hereditary hemochromatosis, restored the infectivity of mutant parasite strains defective in iron acquisition. Thus, inhibition of ferroportin expression is a specific strategy used by L. amazonensis to inhibit iron export and promote their own intracellular growth.

Vyšlo v časopise: -Mediated Inhibition of Iron Export Promotes Parasite Replication in Macrophages. PLoS Pathog 10(1): e32767. doi:10.1371/journal.ppat.1003901
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1003901

Souhrn

Zdroje

1. DonovanA, LimaCA, PinkusJL, PinkusGS, ZonLI, et al. (2005) The iron exporter ferroportin/Slc40a1 is essential for iron homeostasis. Cell Metab 1 : 191–200.

2. NemethE, TuttleMS, PowelsonJ, VaughnMB, DonovanA, et al. (2004) Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization. Science 306 : 2090–2093.

3. AndrewsNC, SchmidtPJ (2007) Iron homeostasis. Annu Rev Physiol 69 : 69–85.

4. WardDM, KaplanJ (2012) Ferroportin-mediated iron transport: expression and regulation. Biochim Biophys Acta 1823 : 1426–1433.

5. PietrangeloA (2004) The ferroportin disease. Blood Cells Mol Dis 32 : 131–138.

6. FlanneryAR, HuynhC, MittraB, MortaraRA, AndrewsNW (2011) LFR1 ferric iron reductase of Leishmania amazonensis is essential for the generation of infective parasite forms. J Biol Chem 286 : 23266–23279.

7. HuynhC, SacksDL, AndrewsNW (2006) A Leishmania amazonensis ZIP family iron transporter is essential for parasite replication within macrophage phagolysosomes. J Exp Med 203 : 2363–2375.

8. HuynhC, YuanX, MiguelDC, RenbergRL, ProtchenkoO, et al. (2012) Heme uptake by Leishmania amazonensis is mediated by the transmembrane protein LHR1. PLoS Pathog 8: e1002795.

9. Campos-SalinasJ, Cabello-DonayreM, Garcia-HernandezR, Perez-VictoriaI, CastanysS, et al. (2011) A new ATP-binding cassette protein is involved in intracellular haem trafficking in Leishmania. Mol Microbiol 79 : 1430–1444.

10. KnutsonMD, VafaMR, HaileDJ, Wessling-ResnickM (2003) Iron loading and erythrophagocytosis increase ferroportin 1 (FPN1) expression in J774 macrophages. Blood 102 : 4191–4197.

11. DelabyC, PilardN, HetetG, DrissF, GrandchampB, et al. (2005) A physiological model to study iron recycling in macrophages. Exp Cell Res 310 : 43–53.

12. DelabyC, PilardN, GoncalvesAS, BeaumontC, Canonne-HergauxF (2005) Presence of the iron exporter ferroportin at the plasma membrane of macrophages is enhanced by iron loading and down-regulated by hepcidin. Blood 106 : 3979–3984.

13. ZohnIE, De DomenicoI, PollockA, WardDM, GoodmanJF, et al. (2007) The flatiron mutation in mouse ferroportin acts as a dominant negative to cause ferroportin disease. Blood 109 : 4174–4180.

14. FernandesA, PrezaGC, PhungY, DeD, I, KaplanJ, et al. (2009) The molecular basis of hepcidin-resistant hereditary hemochromatosis. Blood 114 : 437–443.

15. SchaibleUE, KaufmannSH (2004) Iron and microbial infection. Nat Rev Microbiol 2 : 946–953.

16. TortiFM, TortiSV (2002) Regulation of ferritin genes and protein. Blood 99 : 3505–3516.

17. FariaMS, ReisFC, LimaAP (2012) Toll-like receptors in leishmania infections: guardians or promoters? J Parasitol Res 2012 : 930257.

18. KropfP, FreudenbergMA, ModolellM, PriceHP, HerathS, et al. (2004) Toll-like receptor 4 contributes to efficient control of infection with the protozoan parasite Leishmania major. Infect Immun 72 : 1920–1928.

19. ShweashM, Adrienne McGachyH, SchroederJ, NeamatallahT, BryantCE, et al. (2011) Leishmania mexicana promastigotes inhibit macrophage IL-12 production via TLR-4 dependent COX-2, iNOS and arginase-1 expression. Mol Immunol 48 : 1800–1808.

20. ZhaoN, ZhangAS, EnnsCA (2013) Iron regulation by hepcidin. J Clin Invest 123 : 2337–2343.

21. PeyssonnauxC, ZinkernagelAS, DattaV, LauthX, JohnsonRS, et al. (2006) TLR4-dependent hepcidin expression by myeloid cells in response to bacterial pathogens. Blood 107 : 3727–3732.

22. SowFB, FlorenceWC, SatoskarAR, SchlesingerLS, ZwillingBS, et al. (2007) Expression and localization of hepcidin in macrophages: a role in host defense against tuberculosis. J Leukoc Biol 82 : 934–945.

23. PinnixZK, MillerLD, WangW, D'AgostinoRJr, KuteT, et al. (2010) Ferroportin and iron regulation in breast cancer progression and prognosis. Sci Transl Med 2 : 43ra56.

24. ParadkarPN, DeD, I, DurchfortN, ZohnI, KaplanJ, et al. (2008) Iron depletion limits intracellular bacterial growth in macrophages. Blood 112 : 866–874.

25. NairzM, TheurlI, LudwiczekS, TheurlM, MairSM, et al. (2007) The co-ordinated regulation of iron homeostasis in murine macrophages limits the availability of iron for intracellular Salmonella typhimurium. Cell Microbiol 9 : 2126–2140.

26. DasNK, BiswasS, SolankiS, MukhopadhyayCK (2009) Leishmania donovani depletes labile iron pool to exploit iron uptake capacity of macrophage for its intracellular growth. Cell Microbiol 11 : 83–94.

27. Lesbordes-BrionJC, ViatteL, BennounM, LouDQ, RameyG, et al. (2006) Targeted disruption of the hepcidin 1 gene results in severe hemochromatosis. Blood 108 : 1402–1405.

28. RabhiI, RabhiS, Ben-OthmanR, RascheA, DaskalakiA, et al. (2012) Transcriptomic signature of Leishmania infected mice macrophages: a metabolic point of view. PLoS Negl Trop Dis 6: e1763.

29. CortezM, HuynhC, FernandesMC, KennedyKA, AderemA, et al. (2011) Leishmania promotes its own virulence by inducing expression of the host immune inhibitory ligand CD200. Cell Host Microbe 9 : 463–471.

30. RiemerJ, HoepkenHH, CzerwinskaH, RobinsonSR, DringenR (2004) Colorimetric ferrozine-based assay for the quantitation of iron in cultured cells. Anal Biochem 331 : 370–375.