Regulation of differentiation to the infective stage of the protozoan parasite Leishmania major by tetrahydrobiopterin.
A critical step in the infectious cycle of Leishmania is the differentiation of parasites within the sand fly vector to the highly infective metacyclic promastigote stage. Here, we establish tetrahydrobiopterin (H4B) levels as an important factor controlling the extent of metacyclogenesis. H4B levels decline substantially during normal development, and genetic or nutritional manipulations showed that low H4B caused elevated metacyclogenesis. Mutants lacking pteridine reductase 1 (PTR1) had low levels of H4B, remained infectious to mice, and induced larger cutaneous lesions (hypervirulence). Thus, the control of pteridine metabolism has relevance to the mechanism of Leishmania differentiation and the limitation of virulence during evolution.
Cunningham
M L
ML
Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO 63110, USA.
Titus
R G
RG
Turco
S J
SJ
Beverley
S M
SM
D000818:Animals; D001708:Biopterins / Q000031:analogs & derivatives* / Q000378:metabolism* / Q000494:pharmacology; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D005492:Folic Acid / Q000378:metabolism; D017125:Genes, Protozoan; D006028:Glycosphingolipids / Q000032:analysis; D018320:Leishmania major / Q000235:genetics / Q000254:growth & development* / Q000378:metabolism* / Q000472:pathogenicity; D016773:Leishmaniasis, Cutaneous / Q000469:parasitology*; D026901:Membrane Transport Proteins; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D009154:Mutation; D010088:Oxidoreductases / Q000235:genetics / Q000378:metabolism; D015800:Protozoan Proteins; D015398:Signal Transduction; D014774:Virulence
D002352:Carrier Proteins; D006028:Glycosphingolipids; D026901:Membrane Transport Proteins; D015800:Protozoan Proteins; C424383:biopterin transporter 1 protein, Leishmania; C008290:lipophosphonoglycan; D001708:Biopterins; D005492:Folic Acid; D010088:Oxidoreductases; C085592:pteridine reductase; C003402:sapropterin