Regulation of Differentiation to the Infective Stage of the Protozoan Parasite Leishmania major by Tetrahydrobiopterin

Abstract

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 (H 4 B) levels as an important factor controlling the extent of metacyclogenesis. H 4 B levels decline substantially during normal development, and genetic or nutritional manipulations showed that low H 4 B caused elevated metacyclogenesis. Mutants lacking pteridine reductase 1 (PTR1) had low levels of H 4 B, 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.