Complete Plasmodium falciparum liver stage development in liver-chimeric mice

Ashley M. Vaughan, Sebastian A. Mikolajczak, Elizabeth M. Wilson, Markus Grompe, Alexis Kaushansky, Nelly Camargo, John Bial, Alexander Ploss, Stefan H I Kappe

Research output: Contribution to journalArticle

118 Citations (Scopus)

Abstract

Plasmodium falciparum, which causes the most lethal form of human malaria, replicates in the host liver during the initial stage of infection. However, in vivo malaria liver-stage (LS) studies in humans are virtually impossible, and in vitro models of LS development do not reconstitute relevant parasite growth conditions. To overcome these obstacles, we have adopted a robust mouse model for the study of P. falciparum LS in vivo: the immunocompromised and fumarylacetoacetate hydrolase-deficient mouse (Fah-/-, Rag2 -/-, Il2rg-/-, termed the FRG mouse) engrafted with human hepatocytes (FRG huHep). FRG huHep mice supported vigorous, quantifiable P. falciparum LS development that culminated in complete maturation of LS at approximately 7 days after infection, providing a relevant model for LS development in humans. The infections allowed observations of previously unknown expression of proteins in LS, including P. falciparum translocon of exported proteins 150 (PTEX150) and exported protein-2 (EXP-2), components of a known parasite protein export machinery. LS schizonts exhibited exoerythrocytic merozoite formation and merosome release. Furthermore, FRG mice backcrossed to the NOD background and repopulated with huHeps and human red blood cells supported reproducible transition from LS infection to blood-stage infection. Thus, these mice constitute reliable models to study human LS directly in vivo and demonstrate utility for studies of LS-to-blood-stage transition of a human malaria parasite.

Original languageEnglish (US)
Pages (from-to)3618-3628
Number of pages11
JournalJournal of Clinical Investigation
Volume122
Issue number10
DOIs
StatePublished - Oct 1 2012

Fingerprint

Plasmodium falciparum
Liver
Malaria
Infection
Parasites
Proteins
Schizonts
Merozoites
Human Development
Hepatocytes
Erythrocytes

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Vaughan, A. M., Mikolajczak, S. A., Wilson, E. M., Grompe, M., Kaushansky, A., Camargo, N., ... Kappe, S. H. I. (2012). Complete Plasmodium falciparum liver stage development in liver-chimeric mice. Journal of Clinical Investigation, 122(10), 3618-3628. https://doi.org/10.1172/JCI62684

Complete Plasmodium falciparum liver stage development in liver-chimeric mice. / Vaughan, Ashley M.; Mikolajczak, Sebastian A.; Wilson, Elizabeth M.; Grompe, Markus; Kaushansky, Alexis; Camargo, Nelly; Bial, John; Ploss, Alexander; Kappe, Stefan H I.

In: Journal of Clinical Investigation, Vol. 122, No. 10, 01.10.2012, p. 3618-3628.

Research output: Contribution to journalArticle

Vaughan, AM, Mikolajczak, SA, Wilson, EM, Grompe, M, Kaushansky, A, Camargo, N, Bial, J, Ploss, A & Kappe, SHI 2012, 'Complete Plasmodium falciparum liver stage development in liver-chimeric mice', Journal of Clinical Investigation, vol. 122, no. 10, pp. 3618-3628. https://doi.org/10.1172/JCI62684
Vaughan AM, Mikolajczak SA, Wilson EM, Grompe M, Kaushansky A, Camargo N et al. Complete Plasmodium falciparum liver stage development in liver-chimeric mice. Journal of Clinical Investigation. 2012 Oct 1;122(10):3618-3628. https://doi.org/10.1172/JCI62684
Vaughan, Ashley M. ; Mikolajczak, Sebastian A. ; Wilson, Elizabeth M. ; Grompe, Markus ; Kaushansky, Alexis ; Camargo, Nelly ; Bial, John ; Ploss, Alexander ; Kappe, Stefan H I. / Complete Plasmodium falciparum liver stage development in liver-chimeric mice. In: Journal of Clinical Investigation. 2012 ; Vol. 122, No. 10. pp. 3618-3628.
@article{93a6f6e37ea5418cb021662c77fc6535,
title = "Complete Plasmodium falciparum liver stage development in liver-chimeric mice",
abstract = "Plasmodium falciparum, which causes the most lethal form of human malaria, replicates in the host liver during the initial stage of infection. However, in vivo malaria liver-stage (LS) studies in humans are virtually impossible, and in vitro models of LS development do not reconstitute relevant parasite growth conditions. To overcome these obstacles, we have adopted a robust mouse model for the study of P. falciparum LS in vivo: the immunocompromised and fumarylacetoacetate hydrolase-deficient mouse (Fah-/-, Rag2 -/-, Il2rg-/-, termed the FRG mouse) engrafted with human hepatocytes (FRG huHep). FRG huHep mice supported vigorous, quantifiable P. falciparum LS development that culminated in complete maturation of LS at approximately 7 days after infection, providing a relevant model for LS development in humans. The infections allowed observations of previously unknown expression of proteins in LS, including P. falciparum translocon of exported proteins 150 (PTEX150) and exported protein-2 (EXP-2), components of a known parasite protein export machinery. LS schizonts exhibited exoerythrocytic merozoite formation and merosome release. Furthermore, FRG mice backcrossed to the NOD background and repopulated with huHeps and human red blood cells supported reproducible transition from LS infection to blood-stage infection. Thus, these mice constitute reliable models to study human LS directly in vivo and demonstrate utility for studies of LS-to-blood-stage transition of a human malaria parasite.",
author = "Vaughan, {Ashley M.} and Mikolajczak, {Sebastian A.} and Wilson, {Elizabeth M.} and Markus Grompe and Alexis Kaushansky and Nelly Camargo and John Bial and Alexander Ploss and Kappe, {Stefan H I}",
year = "2012",
month = "10",
day = "1",
doi = "10.1172/JCI62684",
language = "English (US)",
volume = "122",
pages = "3618--3628",
journal = "Journal of Clinical Investigation",
issn = "0021-9738",
publisher = "The American Society for Clinical Investigation",
number = "10",

}

TY - JOUR

T1 - Complete Plasmodium falciparum liver stage development in liver-chimeric mice

AU - Vaughan, Ashley M.

AU - Mikolajczak, Sebastian A.

AU - Wilson, Elizabeth M.

AU - Grompe, Markus

AU - Kaushansky, Alexis

AU - Camargo, Nelly

AU - Bial, John

AU - Ploss, Alexander

AU - Kappe, Stefan H I

PY - 2012/10/1

Y1 - 2012/10/1

N2 - Plasmodium falciparum, which causes the most lethal form of human malaria, replicates in the host liver during the initial stage of infection. However, in vivo malaria liver-stage (LS) studies in humans are virtually impossible, and in vitro models of LS development do not reconstitute relevant parasite growth conditions. To overcome these obstacles, we have adopted a robust mouse model for the study of P. falciparum LS in vivo: the immunocompromised and fumarylacetoacetate hydrolase-deficient mouse (Fah-/-, Rag2 -/-, Il2rg-/-, termed the FRG mouse) engrafted with human hepatocytes (FRG huHep). FRG huHep mice supported vigorous, quantifiable P. falciparum LS development that culminated in complete maturation of LS at approximately 7 days after infection, providing a relevant model for LS development in humans. The infections allowed observations of previously unknown expression of proteins in LS, including P. falciparum translocon of exported proteins 150 (PTEX150) and exported protein-2 (EXP-2), components of a known parasite protein export machinery. LS schizonts exhibited exoerythrocytic merozoite formation and merosome release. Furthermore, FRG mice backcrossed to the NOD background and repopulated with huHeps and human red blood cells supported reproducible transition from LS infection to blood-stage infection. Thus, these mice constitute reliable models to study human LS directly in vivo and demonstrate utility for studies of LS-to-blood-stage transition of a human malaria parasite.

AB - Plasmodium falciparum, which causes the most lethal form of human malaria, replicates in the host liver during the initial stage of infection. However, in vivo malaria liver-stage (LS) studies in humans are virtually impossible, and in vitro models of LS development do not reconstitute relevant parasite growth conditions. To overcome these obstacles, we have adopted a robust mouse model for the study of P. falciparum LS in vivo: the immunocompromised and fumarylacetoacetate hydrolase-deficient mouse (Fah-/-, Rag2 -/-, Il2rg-/-, termed the FRG mouse) engrafted with human hepatocytes (FRG huHep). FRG huHep mice supported vigorous, quantifiable P. falciparum LS development that culminated in complete maturation of LS at approximately 7 days after infection, providing a relevant model for LS development in humans. The infections allowed observations of previously unknown expression of proteins in LS, including P. falciparum translocon of exported proteins 150 (PTEX150) and exported protein-2 (EXP-2), components of a known parasite protein export machinery. LS schizonts exhibited exoerythrocytic merozoite formation and merosome release. Furthermore, FRG mice backcrossed to the NOD background and repopulated with huHeps and human red blood cells supported reproducible transition from LS infection to blood-stage infection. Thus, these mice constitute reliable models to study human LS directly in vivo and demonstrate utility for studies of LS-to-blood-stage transition of a human malaria parasite.

UR - http://www.scopus.com/inward/record.url?scp=84867154422&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84867154422&partnerID=8YFLogxK

U2 - 10.1172/JCI62684

DO - 10.1172/JCI62684

M3 - Article

C2 - 22996664

AN - SCOPUS:84867154422

VL - 122

SP - 3618

EP - 3628

JO - Journal of Clinical Investigation

JF - Journal of Clinical Investigation

SN - 0021-9738

IS - 10

ER -