Cryptosporidium parvum scavenges LDL-derived cholesterol and micellar cholesterol internalized into enterocytes

Karen Ehrenman, Jane W. Wanyiri, Najma Bhat, Honorine D. Ward, Isabelle Coppens

Research output: Contribution to journalArticle

Abstract

Cryptosporidium spp. are responsible for devastating diarrhoea in immunodeficient individuals. In the intestinal tract, the developmental stages of the parasite are confined to the apical surfaces of epithelial cells. Upon invasion, Cryptosporidium incorporates the microvillous membrane of the enterocyte to form the parasitophorous vacuole (PV) and sequesters itself from the host cytoplasm by rearranging the host cytoskeleton. Cryptosporidium parvum has minimal anabolic capabilities and relies on transporters and salvage pathways to meet its basic metabolic requirements. The cholesterol salvage pathway is crucial for the development of protozoan parasites. In this study, we have examined the sources of cholesterol from C.parvum infecting enterocytes. We illustrated that the intracellular stages of Cryptosporidium as well as the oocysts shed by the host, contain cholesterol. Incubation of infected enterocytes in lipoprotein-free medium impairs parasite development and results in substantial decrease in cholesterol content associated with the PV. Among lipoproteins, LDL constitutes an important source of cholesterol for Cryptosporidium. Dietary cholesterol incorporated into micelles is internalized into enterocytes by the NPC1L1 transporter. We showed that C.parvum also obtains cholesterol from micelles in enterocytes.Pharmacological blockade of NPC1L1 function by ezetimibe or moderate downregulation of NPC1L1 expression decreases parasite infectivity. These observations indicate that, despite its dual sequestration from the intestinal lumen and the host cytoplasm, C.parvum can, in fact, obtain cholesterol both from the gut's lumen and the host cell. This study highlights the evolutionary advantages for epicellular pathogens to access to nutrients from the outside and inside of the host cell.

Original languageEnglish (US)
Pages (from-to)1182-1197
Number of pages16
JournalCellular Microbiology
Volume15
Issue number7
DOIs
StatePublished - Jul 2013

Fingerprint

Cryptosporidium parvum
Enterocytes
LDL Cholesterol
Cholesterol
Cryptosporidium
Parasites
Micelles
Vacuoles
Cytoplasm
Dietary Cholesterol
Oocysts
Cytoskeleton
LDL Lipoproteins
Lipoproteins
Diarrhea
Down-Regulation
Epithelial Cells
Pharmacology
Food
Membranes

ASJC Scopus subject areas

  • Microbiology
  • Immunology
  • Virology

Cite this

Cryptosporidium parvum scavenges LDL-derived cholesterol and micellar cholesterol internalized into enterocytes. / Ehrenman, Karen; Wanyiri, Jane W.; Bhat, Najma; Ward, Honorine D.; Coppens, Isabelle.

In: Cellular Microbiology, Vol. 15, No. 7, 07.2013, p. 1182-1197.

Research output: Contribution to journalArticle

@article{b57d23ee023d48cf940dab0cee28bb36,
title = "Cryptosporidium parvum scavenges LDL-derived cholesterol and micellar cholesterol internalized into enterocytes",
abstract = "Cryptosporidium spp. are responsible for devastating diarrhoea in immunodeficient individuals. In the intestinal tract, the developmental stages of the parasite are confined to the apical surfaces of epithelial cells. Upon invasion, Cryptosporidium incorporates the microvillous membrane of the enterocyte to form the parasitophorous vacuole (PV) and sequesters itself from the host cytoplasm by rearranging the host cytoskeleton. Cryptosporidium parvum has minimal anabolic capabilities and relies on transporters and salvage pathways to meet its basic metabolic requirements. The cholesterol salvage pathway is crucial for the development of protozoan parasites. In this study, we have examined the sources of cholesterol from C.parvum infecting enterocytes. We illustrated that the intracellular stages of Cryptosporidium as well as the oocysts shed by the host, contain cholesterol. Incubation of infected enterocytes in lipoprotein-free medium impairs parasite development and results in substantial decrease in cholesterol content associated with the PV. Among lipoproteins, LDL constitutes an important source of cholesterol for Cryptosporidium. Dietary cholesterol incorporated into micelles is internalized into enterocytes by the NPC1L1 transporter. We showed that C.parvum also obtains cholesterol from micelles in enterocytes.Pharmacological blockade of NPC1L1 function by ezetimibe or moderate downregulation of NPC1L1 expression decreases parasite infectivity. These observations indicate that, despite its dual sequestration from the intestinal lumen and the host cytoplasm, C.parvum can, in fact, obtain cholesterol both from the gut's lumen and the host cell. This study highlights the evolutionary advantages for epicellular pathogens to access to nutrients from the outside and inside of the host cell.",
author = "Karen Ehrenman and Wanyiri, {Jane W.} and Najma Bhat and Ward, {Honorine D.} and Isabelle Coppens",
year = "2013",
month = "7",
doi = "10.1111/cmi.12107",
language = "English (US)",
volume = "15",
pages = "1182--1197",
journal = "Cellular Microbiology",
issn = "1462-5814",
publisher = "Wiley-Blackwell",
number = "7",

}

TY - JOUR

T1 - Cryptosporidium parvum scavenges LDL-derived cholesterol and micellar cholesterol internalized into enterocytes

AU - Ehrenman, Karen

AU - Wanyiri, Jane W.

AU - Bhat, Najma

AU - Ward, Honorine D.

AU - Coppens, Isabelle

PY - 2013/7

Y1 - 2013/7

N2 - Cryptosporidium spp. are responsible for devastating diarrhoea in immunodeficient individuals. In the intestinal tract, the developmental stages of the parasite are confined to the apical surfaces of epithelial cells. Upon invasion, Cryptosporidium incorporates the microvillous membrane of the enterocyte to form the parasitophorous vacuole (PV) and sequesters itself from the host cytoplasm by rearranging the host cytoskeleton. Cryptosporidium parvum has minimal anabolic capabilities and relies on transporters and salvage pathways to meet its basic metabolic requirements. The cholesterol salvage pathway is crucial for the development of protozoan parasites. In this study, we have examined the sources of cholesterol from C.parvum infecting enterocytes. We illustrated that the intracellular stages of Cryptosporidium as well as the oocysts shed by the host, contain cholesterol. Incubation of infected enterocytes in lipoprotein-free medium impairs parasite development and results in substantial decrease in cholesterol content associated with the PV. Among lipoproteins, LDL constitutes an important source of cholesterol for Cryptosporidium. Dietary cholesterol incorporated into micelles is internalized into enterocytes by the NPC1L1 transporter. We showed that C.parvum also obtains cholesterol from micelles in enterocytes.Pharmacological blockade of NPC1L1 function by ezetimibe or moderate downregulation of NPC1L1 expression decreases parasite infectivity. These observations indicate that, despite its dual sequestration from the intestinal lumen and the host cytoplasm, C.parvum can, in fact, obtain cholesterol both from the gut's lumen and the host cell. This study highlights the evolutionary advantages for epicellular pathogens to access to nutrients from the outside and inside of the host cell.

AB - Cryptosporidium spp. are responsible for devastating diarrhoea in immunodeficient individuals. In the intestinal tract, the developmental stages of the parasite are confined to the apical surfaces of epithelial cells. Upon invasion, Cryptosporidium incorporates the microvillous membrane of the enterocyte to form the parasitophorous vacuole (PV) and sequesters itself from the host cytoplasm by rearranging the host cytoskeleton. Cryptosporidium parvum has minimal anabolic capabilities and relies on transporters and salvage pathways to meet its basic metabolic requirements. The cholesterol salvage pathway is crucial for the development of protozoan parasites. In this study, we have examined the sources of cholesterol from C.parvum infecting enterocytes. We illustrated that the intracellular stages of Cryptosporidium as well as the oocysts shed by the host, contain cholesterol. Incubation of infected enterocytes in lipoprotein-free medium impairs parasite development and results in substantial decrease in cholesterol content associated with the PV. Among lipoproteins, LDL constitutes an important source of cholesterol for Cryptosporidium. Dietary cholesterol incorporated into micelles is internalized into enterocytes by the NPC1L1 transporter. We showed that C.parvum also obtains cholesterol from micelles in enterocytes.Pharmacological blockade of NPC1L1 function by ezetimibe or moderate downregulation of NPC1L1 expression decreases parasite infectivity. These observations indicate that, despite its dual sequestration from the intestinal lumen and the host cytoplasm, C.parvum can, in fact, obtain cholesterol both from the gut's lumen and the host cell. This study highlights the evolutionary advantages for epicellular pathogens to access to nutrients from the outside and inside of the host cell.

UR - http://www.scopus.com/inward/record.url?scp=84879220113&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84879220113&partnerID=8YFLogxK

U2 - 10.1111/cmi.12107

DO - 10.1111/cmi.12107

M3 - Article

C2 - 23311949

AN - SCOPUS:84879220113

VL - 15

SP - 1182

EP - 1197

JO - Cellular Microbiology

JF - Cellular Microbiology

SN - 1462-5814

IS - 7

ER -