Exploring vulnerabilities of Cryptosporidium

Cryptosporidium parvum Cryptosporidium parvum is a gastrointestinal parasite that can cause moderate to severe diarrhoea in children and adults, and deadly opportunistic infection in AIDS patients. Because C. parvum is resistant to chlorine disinfectant treatment, it frequently causes water-borne outbreaks around the world. A new study looks at a C. parvum protein that is central to glycolysis – the only pathway by which the parasite can generate energy – and identifies it as a potential drug target.

Researchers studied the parasite’s metabolism during its complicated life-cycle. C. parvum exists both in free stages (where parasites are in the environment or in the host’s digestive tract) and intracellular stages following host cell invasion, during which the parasite occupies a specialized compartment – the parasitophorous vacuole – which is delineated by a host-cell derived border called the parasitophorous vacuole membrane. Glycolysis is the only metabolic process by which organisms like C. parvum that lack functional mitochondria to derive energy from oxygen can generate ATP, the universal biological energy storage molecule. They found that the C. parvum LDH (CpLDH) protein is found inside the parasite’s cells during the free stages, but is then transferred to the PVM during intracellular development, indicating involvement of the parasitophorous vacuole membrane in parasite energy metabolism, and specifically, in lactate fermentation. They also showed that two known LDH inhibitors can inhibit both CpLDH activity and parasite growth.

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.

 

Cryptosporidium Lactate Dehydrogenase Is Associated with the Parasitophorous Vacuole Membrane and Is a Potential Target for Developing Therapeutics. PLoS Pathog 11(11): e1005250. doi: 10.1371/journal.ppat.1005250
The apicomplexan, Cryptosporidium parvum, possesses a bacterial-type lactate dehydro- genase (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. 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.

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