title: Erythrocyte stages of Plasmodium falciparum exhibit a high nitric oxide synthase (NOS) activity and release an NOS-inducing soluble factor.
abstract: Nitric oxide (NO), a highly diffusible cellular mediator involved in a wide range of biological effects, has been indicated as one of the cytotoxic agents released by leukocytes to counteract malaria infection. On the other hand, NO has been implicated as a mediator of the neuropathological symptoms of cerebral malaria. In such circumstances NO production has been thought to be induced in host tissues by host-derived cytokines. Here we provide evidence for the first time that human red blood cells infected by Plasmodium falciparum (IRBC) synthesize NO. The synthesis of NO (measured as citrulline and nitrate production) appeared to be very high in comparison with human endothelial cells; no citrulline and nitrate production was detectable in noninfected red blood cells. The NO synthase (NOS) activity was very high in the lysate of IRBC (while not measurable in that of normal red blood cells) and was inhibited in a dose-dependent way by three different NOS inhibitors (L-canavanine, NG-amino-L-arginine, and NG-nitro-L-arginine). NOS activity in P. falciparum IRBC is Ca++ independent, and the enzyme shows an apparent molecular mass < 100 kD, suggesting that the parasite expresses an isoform different from those found in mammalian cells. IRBC release a soluble factor able to induce NOS in human endothelial cells. Such NOS-inducing activity is not tissue specific, is time and dose dependent, requires de novo protein synthesis, and is probably associated with a thermolabile protein having a molecular mass > 100 kD. Our data suggest that an increased NO synthesis in P. falciparum malaria can be directly elicited by soluble factor(s) by the blood stages of the parasite, without necessarily requiring the intervention of host cytokines.
authors.affiliation: Department of Genetics, Biology and Medical Chemistry, University of Torino, Italy.
authors.forename: D
authors.initials: D
authors.lastname: Ghigo
authors.forename: R
authors.initials: R
authors.lastname: Todde
authors.forename: H
authors.initials: H
authors.lastname: Ginsburg
authors.forename: C
authors.initials: C
authors.lastname: Costamagna
authors.forename: P
authors.initials: P
authors.lastname: Gautret
authors.forename: F
authors.initials: F
authors.lastname: Bussolino
authors.forename: D
authors.initials: D
authors.lastname: Ulliers
authors.forename: G
authors.initials: G
authors.lastname: Giribaldi
authors.forename: E
authors.initials: E
authors.lastname: Deharo
authors.forename: G
authors.initials: G
authors.lastname: Gabrielli
authors.forename: G
authors.initials: G
authors.lastname: Pescarmona
authors.forename: A
authors.initials: A
authors.lastname: Bosia
mesh_terms: D000594:Amino Acid Oxidoreductases / Q000037:antagonists & inhibitors / Q000097:blood / Q000502:physiology*; D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D001685:Biological Factors / Q000378:metabolism / Q000494:pharmacology; D002172:Canavanine / Q000494:pharmacology; D002448:Cell Adhesion; D002478:Cells, Cultured; D002956:Citrulline / Q000096:biosynthesis; D017077:Culture Media, Conditioned / Q000494:pharmacology; D006152:Cyclic GMP / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D004790:Enzyme Induction; D004912:Erythrocytes / Q000469:parasitology*; D006790:Host-Parasite Interactions; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D009566:Nitrates / Q000378:metabolism; D009569:Nitric Oxide / Q000502:physiology; D019001:Nitric Oxide Synthase; D009573:Nitrites / Q000378:metabolism; D019335:Nitroarginine; D010961:Plasmodium / Q000201:enzymology / Q000254:growth & development; D010963:Plasmodium falciparum / Q000187:drug effects / Q000201:enzymology* / Q000254:growth & development; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors / Q000097:blood / Q000494:pharmacology / Q000502:physiology*; D013045:Species Specificity; D014471:Umbilical Veins
chemical_list: D001685:Biological Factors; D017077:Culture Media, Conditioned; D009566:Nitrates; D009573:Nitrites; D015800:Protozoan Proteins; D019335:Nitroarginine; D002956:Citrulline; D009569:Nitric Oxide; D002172:Canavanine; C063904:N(G)-aminoarginine; D001120:Arginine; D019001:Nitric Oxide Synthase; D000594:Amino Acid Oxidoreductases; D006152:Cyclic GMP