Abstract
The apicomplexan, Cryptosporidium parvum, possesses a bacterial-type lactate dehydrogenase (CpLDH). This is considered to be an essential enzyme, as this parasite lacks the Krebs cycle and cytochrome-based respiration, and mainly–if not solely, relies on glycolysis to produce ATP. Here, we provide evidence that in extracellular parasites (e.g., sporozoites and merozoites), CpLDH is localized in the cytosol. However, it becomes associated with the parasitophorous vacuole membrane (PVM) during the intracellular developmental stages, suggesting involvement of the PVM in parasite energy metabolism. We characterized the biochemical features of CpLDH and observed that, at lower micromolar levels, the LDH inhibitors gossypol and FX11 could inhibit both CpLDH activity (K i = 14.8 μM and 55.6 μM, respectively), as well as parasite growth in vitro (IC50 = 11.8 μM and 39.5 μM, respectively). These observations not only reveal a new function for the poorly understood PVM structure in hosting the intracellular development of C. parvum, but also suggest LDH as a potential target for developing therapeutics against this opportunistic pathogen, for which fully effective treatments are not yet available.
Highlights
Cryptosporidium parvum is a gastrointestinal parasite that can cause moderate to severe diarrhea in children and adults, and deadly opportunistic infection in AIDS patients [1, 2]
Cryptosporidians are unique among the apicomplexans in regards to their parasitic life style and their metabolism
We discovered that the Cryptosporidium parvum bacterial-type Llactate dehydrogenase (CpLDH) enzyme is cytosolic during the parasite’s motile, extracellular, stages, but becomes associated with the parasitophorous vacuole membrane (PVM) during intracellular development, indicating the involvement of the PVM in lactate fermentation
Summary
Cryptosporidium parvum is a gastrointestinal parasite that can cause moderate to severe diarrhea in children and adults, and deadly opportunistic infection in AIDS patients [1, 2]. Cryptosporidium shares many biological features with other apicomplexans They all undergo similar stages of life cycle development, including the invasion of sporozoites into host cells after excystation from oocysts, followed by varied cycles of merogony to form merozoites, gametogenesis to form micro- and macro-gametes, fertilization, and oocyst formation. Cryptosporidium differs from other apicomplexans in that these parasites lack both an apicoplast and a typical mitochondrion, and are incapable of the de novo synthesis of amino acids, fatty acids, and nucleosides. They undergo a unique intracellular, but extracytoplasmic development, in which the PVM faces the extracellular environment, rather than the host cell cytosol [9,10,11]
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