Cryptosporidium Lactate Dehydrogenase Is Associated with the Parasitophorous Vacuole Membrane and Is a Potential Target for

Developing Therapeutics

Haili Zhang, Fengguang Guo, Guan Zhu

PLOS Pathogens | DOI:10.1371/journal.ppat.1005250 November 12, 2015

Speaker: Shung-Hao Ku (顧聲豪)                                Time: 15:10~16:00, Oct, 25 2016

Commentator: Dr. Jyh-Wei Shin(辛致煒 老師)         Place: Room 601

Abstract:

        Cryptosporidium parvum is an intracellular protozoan parasite that causes moderate to severe diarrhea in children and adults, and deadly opportunistic infection in AIDS patients. In addition, because Cryptosporidium oocysts are resistant to chemical stresses, such as chlorine treatment, it also frequently causes water-borne outbreaks around the world. During the intracellular development, Cryptosporidium and most other apicomplexans reside within a vacuole termed parasitophorous vacuole. The vacuole is formed during the parasite invasion and defined by a host cell-derived membrane structure termed parasitophorous vacuole membrane (PVM). Cryptosporidia lacks both the Krebs cycle and the cytochrome-based respiration chain, therefore, this genus of parasites relies on glycolysis to produce ATP. To facilitate this“ anaerobic metabolism”, Cryptosporidium possesses an L-lactate dehydrogenase (LDH), two alcohol dehydrogenases (ADHs), and an acetyl-CoA synthetase, which potentially produce lactic acid, alcohol, or acetic acid as organic end products [1]. Among these enzymes, LDH is considered to be a drug target in some parasites, including the apicomplexans Plasmodium and Toxoplasma. The author show that the C.parvum LDH (CpLDH) protein is distributed in the cytosol of free sporozoites and merozoites, but becomes associated with the parasitophorous vacuole membrane (PVM) during the intracellular developmental stages. The LDH inhibitors gossypol and FX11 could inhibit both CpLDH activity. Finally, the author show LDH inhibitors, gossypol and FX11, can inhibit both enzymatic activity and parasite growth in vitro.

Reference:

1.         Abrahamsen MS, Templeton TJ, Enomoto S, Abrahante JE, Zhu G, Lancto CA, et al. Completegenome sequence of the apicomplexan,Cryptosporidium parvum. Science. 2004; 304(5669):441–5.Epub 2004/03/27. doi:10.1126/science.1094786PMID:15044751.