弓形虫戊糖磷酸途径的代谢可塑性与抗寄生虫靶点发掘

Abstract

Metabolic pathways underpin the growth and virulence of intracellular parasites and are therefore promising antiparasitic targets. The pentose phosphate pathway (PPP) is vital in most organisms, providing a reduced form of nicotinamide adenine dinucleotide phosphate (NADPH) and ribose sugar for nucleotide synthesis; however, it has not yet been studied in Toxoplasma gondii , a widespread intracellular pathogen and a model protozoan organism. Herein, we show that T . gondii has a functional PPP distributed in the cytoplasm and nucleus of its acutely-infectious tachyzoite stage. We produced eight parasite mutants disrupting seven enzymes of the PPP in T . gondii . Our data show that of the seven PPP proteins, the two glucose-6-phosphate dehydrogenases ( Tg G6PDH1, Tg G6PDH2), one of the two 6-phosphogluconate dehydrogenases ( Tg 6PGDH1), ribulose-5-phosphate epimerase ( Tg RuPE) and transaldolase ( Tg TAL) are dispensable in vitro as well as in vivo , disclosing substantial metabolic plasticity in T . gondii . Among these, Tg G6PDH2 plays a vital role in defense against oxidative stress by the pathogen. Further, we show that Tg 6PGDH2 and ribulose-5-phosphate isomerase ( Tg RPI) are critical for tachyzoite growth. The depletion of Tg RPI impairs the flux of glucose in central carbon pathways, and causes decreased expression of ribosomal, microneme and rhoptry proteins. In summary, our results demonstrate the physiological need of the PPP in T . gondii while unraveling metabolic flexibility and antiparasitic targets. Metabolic pathways are intimately associated with the survival and replication of parasitic Toxoplasma gondii and thus represent potential targets for antiparasitic strategies. Herein, we focused on the pentose phosphate pathway (PPP) in T . gondii and examined its roles in supporting the growth of this ubiquitous pathogen. We found