Organism-like formation of Schistosoma hemozoin and its function suggest a mechanism for anti-malarial action of artemisinin.
The current theories of antimalarial mechanism of artemisinin are inadequate to fully explain the observed effects. In our study, "organism-like" formation of Schistosoma hemozoin granules by attaching to and utilizing erythrocytes to form new ones was observed. This indicates that heme iron is transferred from erythrocytes to hemozoin granules during their formation. However, as a disposal product of heme detoxification, these granules are not completely expelled from the Schistosoma gut, but decomposed again between microvilli in the posterior portion of the gut to transfer iron to eggs. Based on the function of iron transport supported by our observation of the unique process of Schistosoma hemozoin formation, here we propose a new viewpoint of antimalarial mechanism of artemisinin, which emphasizes the final outcome, i.e., interference of iron utilization in parasites by artemisinin, instead of focusing on the mode of interaction between artemisinin and heme or hemozoin. This suggests that artemisinin and its endoperoxides derivatives likely hit the Achilles' heel of hemozoin-producing and iron-dependent organisms.
Institute for Infectious Diseases and Vaccine Development, Tongji University School of Medicine, 1239 Siping Road, Shanghai 200092, P.R. China.
Jun
J
Sun
Institute for Infectious Diseases and Vaccine Development, Tongji University School of Medicine, 1239 Siping Road, Shanghai 200092, P.R. China.
Chen
C
Li
Institute for Infectious Diseases and Vaccine Development, Tongji University School of Medicine, 1239 Siping Road, Shanghai 200092, P.R. China.
Suwen
S
Wang
D000818:Animals; D000962:Antimalarials / Q000494:pharmacology*; D037621:Artemisinins / Q000494:pharmacology*; D005260:Female; D006420:Hemeproteins / Q000378:metabolism*; D007501:Iron / Q000378:metabolism*; D007783:Lactones / Q000494:pharmacology*; D012547:Schistosoma / Q000378:metabolism*; D012908:Snails
D000962:Antimalarials; D037621:Artemisinins; D006420:Hemeproteins; D007783:Lactones; C020753:hemozoin; D007501:Iron; C075875:artemisin
N Engl J Med. 2014 Jul 31;371(5):411-23
25075834
Org Lett. 2010 Apr 2;12(7):1420-3
20192248
Malar J. 2012 Apr 27;11:131
22540925
Nat Commun. 2015 Dec 22;6:10111
26694030
Ann Trop Med Parasitol. 1997 Jul;91(5):501-16
9329987
Nature. 2014 Jan 2;505(7481):50-5
24352242
Br J Haematol. 2013 Apr;161(2):262-9
23398516
Biochem Pharmacol. 2013 Jan 1;85(1):38-45
23085438
Angew Chem Int Ed Engl. 2007;46(33):6278-83
17640025
Nature. 2000 Feb 24;403(6772):906-9
10706290
Clin Infect Dis. 2012 Apr;54(8):1137-44
22354919
Proc Natl Acad Sci U S A. 2011 Jul 12;108(28):11405-10
21709259
PLoS One. 2012;7(8):e42703
22900042
Cell. 2014 Aug 14;158(4):916-28
25126794
Nature. 1995 Mar 16;374(6519):269-71
7885447
J Biol Chem. 1999 Jul 2;274(27):19383-8
10383451
J Antimicrob Chemother. 2002 Aug;50(2):177-87
12161397
ChemMedChem. 2007 Oct;2(10):1480-97
17768732
Antimicrob Agents Chemother. 2008 Jan;52(1):98-109
17938190
Nature. 1995 Nov 9;378(6553):138-9
7477315
Chem Biol. 2002 Mar;9(3):321-32
11927257
Int J Parasitol. 1996 May;26(5):519-25
8818732
Science. 2008 Apr 18;320(5874):330-4
18420924
Science. 2015 Jan 23;347(6220):428-31
25502314
PLoS One. 2010 Mar 08;5(3):e9582
20221395
Nature. 2003 Aug 21;424(6951):957-61
12931192
Nature. 2015 Apr 30;520(7549):683-7
25874676
Proc Natl Acad Sci U S A. 2016 Feb 23;113(8):2080-5
26858419
Phytomedicine. 2015 Oct 15;22(11):1045-54
26407947
Science. 2010 May 14;328(5980):844-6
20466917
PLoS One. 2013 Jul 23;8(7):e70025
23894579
Parasitol Res. 2013 Aug;112(8):2983-90
23733233
Mol Biochem Parasitol. 1991 Dec;49(2):181-9
1775162