Nav: Home

Exploring vulnerabilities of the Cryptosporidium parasite

November 12, 2015

Cryptosporidium parvum is a gastrointestinal parasite that can cause moderate to severe diarrhea 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 study published on Nov. 12th in PLOS Pathogens provides a detailed analysis of 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.

Guan Zhu and colleagues, from Texas A&M University in College Station, USA, study 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 (PVM).

For this study, the researchers focused on lactate dehydrogenase (LDH), an enzyme central to glycolysis. 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 PVM in parasite energy metabolism, and specifically, in lactate fermentation. They also demonstrate that two known LDH inhibitors, gossypol and FX11, can inhibit both CpLDH activity and parasite growth.

The researchers summarize that their 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". Acknowledging that the ultimate validation of CpLDH as a drug target requires tools for knockout or knockdown of genes of interest in Cryptosporidium, they say recent advances towards this goal raise hope that such validation will be possible in the near future.

Overall, they conclude that "the present data, together with the fact that C. parvum relies on glycolysis for producing ATP, support the notion that CpLDH is worth exploring as a potential target for the development of anti-cryptosporidial therapeutics".
-end-


Contact:


Guan Zhu
e-mail: gzhu@cvm.tamu.edu
phone: +1.979.845.6981

Please use this URL to provide readers access to the paper (Link goes live upon article publication): http://dx.plos.org/10.1371/journal.ppat.1005250

Press-Only Preview Of The Article: https://www.plos.org/wp-content/uploads/2013/05/Pathogens_Zhu_NOV_12_preview.pdf

Related Image for Press Use: https://www.plos.org/wp-content/uploads/2013/05/press-image.jpg

Caption:


CpLDH on the parasitophorous vacuole membrane

Lactate dehydrogenase (LDH) is typically a cytosolic protein, which is true in the extracellular stages of the apicomplexan parasite Cryptosporidum parvum (oocysts and sporozoites). However, LDH becomes localized to the parasitophorous vacuole membrane (PVM) during the parasite intracellular development (LDH in red and nuclei in blue). The top panel show oocysts stained only for oocyst walls (green) and nuclei (blue).

Authors and Affiliations:

Haili Zhang, Texas A&M University, USA

Fengguang Guo, Texas A&M University, USA

Guan Zhu, Texas A&M University, USA

Please contact plospathogens@plos.org if you would like more information.

Funding: This study was supported in part by the National Institute of Food and Agriculture (NIFA), United States Department of Agriculture (USDA) (http://www.nifa.usda.gov) (project numbers TEX09529 and TEX09591 to GZ), and the Western Regional Center of Excellence for Biodefense and Emerging Infectious Diseases Research (WRCE) supported by grant number U54 AI057156 from the National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH) (http://www.utmb.edu/cbeid/) (subaward to GZ). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing Interests: The authors have declared that no competing interests exist.

Citation: Zhang H, Guo F, Zhu G (2015) 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

PLOS

Related Protein Articles:

Hi-res view of protein complex shows how it breaks up protein tangles
A new, high-resolution view of the structure of Hsp104 (heat shock protein 104), a natural yeast protein nanomachine with six subunits, may show news ways to dismantle harmful protein clumps in disease.
Breaking the protein-DNA bond
A new Northwestern University study finds that unbound proteins in a cell break up protein-DNA bonds as they compete for the single-binding site.
FASEB Science Research Conference: Protein Kinases and Protein Phosphorylation
This conference focuses on the biology of protein kinases and phosphorylation signaling.
Largest resource of human protein-protein interactions can help interpret genomic data
An international research team has developed the largest database of protein-to-protein interaction networks, a resource that can illuminate how numerous disease-associated genes contribute to disease development and progression.
STAT2: Much more than an antiviral protein
A protein known for guarding against viral infections leads a double life, new research shows, and can interfere with cell growth and the defense against parasites.
A protein makes the difference
It is well-established knowledge that blood vessels foster the growth of tumors.
Nuclear protein causes neuroblastoma to become more aggressive
Aggressive forms of neuroblastoma contain a specific protein in their cells' nuclei that is not found in the nuclei of more benign forms of the cancer, and the discovery, made through research from the University of Rochester Medical Center, could lead to new forms of targeted therapy.
How a protein could become the next big sweetener
High-fructose corn syrup and sugar are on the outs with calorie-wary consumers.
High animal protein intake associated with higher, plant protein with lower mortality rate
The largest study to examine the effects of different sources of dietary protein found that a high intake of proteins from animal sources -- particularly processed and unprocessed red meats -- was associated with a higher mortality rate, while a high intake of protein from plant sources was associated with a lower risk of death.
Protein in, ammonia out
A recent study has compiled and analyzed data from 25 previous studies.

Related Protein Reading:

Best Science Podcasts 2019

We have hand picked the best science podcasts for 2019. Sit back and enjoy new science podcasts updated daily from your favorite science news services and scientists.
Now Playing: TED Radio Hour

Climate Crisis
There's no greater threat to humanity than climate change. What can we do to stop the worst consequences? This hour, TED speakers explore how we can save our planet and whether we can do it in time. Guests include climate activist Greta Thunberg, chemical engineer Jennifer Wilcox, research scientist Sean Davis, food innovator Bruce Friedrich, and psychologist Per Espen Stoknes.
Now Playing: Science for the People

#527 Honey I CRISPR'd the Kids
This week we're coming to you from Awesome Con in Washington, D.C. There, host Bethany Brookshire led a panel of three amazing guests to talk about the promise and perils of CRISPR, and what happens now that CRISPR babies have (maybe?) been born. Featuring science writer Tina Saey, molecular biologist Anne Simon, and bioethicist Alan Regenberg. A Nobel Prize winner argues banning CRISPR babies won’t work Geneticists push for a 5-year global ban on gene-edited babies A CRISPR spin-off causes unintended typos in DNA News of the first gene-edited babies ignited a firestorm The researcher who created CRISPR twins defends...