Complete Development of the Liver Stage of Plasmodium falciparum in a Human Hepatoma Cell Line

Karnasuta, Chitraporn; Pavanand, K; Chantakulkij, Somsak; Luttiwongsakorn, N; Rassamesoraj, M; Laohathai, K; Hk, Webster; Watt, George

doi:10.4269/ajtmh.1995.53.607

Cited by 33 publications

(23 citation statements)

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“…The reported sizes of late P. falciparum LSs obtained from in vitro culture range from only 15 to 40 μm in diameter (6,7,39,40), whereas we visualized LS sizes up to 80 μm in diameter, which, based on previous volume calculations (29), contain between 40,000 and 60,000 merozoites. A small number of studies on P. falciparum LS development in humans have been undertaken (41,42), and the size of 6 day LS ranged from 55 to 60 μm.…”

Section: Frg Huhep and Frg Nod Huhep Micementioning

confidence: 83%

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

et al. 2012

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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. IntroductionPlasmodium falciparum is the most deadly of the human malaria parasites. The disease continues to be a global health crisis and causes more than 250 million new clinical cases annually, resulting in over 800,000 deaths, mostly of children in sub-Saharan Africa (1). Female anopheline mosquitoes introduce infectious sporozoites into the host dermis when taking a blood meal. Sporozoites exit the bite site by migration, enter a blood vessel, and are carried to the liver (2). Here, each sporozoite traverses numerous hepatocytes before it invades a final hepatocyte with the formation of a parasitophorous vacuole (PV) (3). Ensconced in the PV, the parasite undergoes liver-stage (LS, also called exoerythrocytic form [EEF]) development, culminating in the formation and release of tens of thousands of first generation merozoites (4). This preerythrocytic phase of the parasite life cycle is asymptomatic, and all clinical pathologies are caused by the ensuing asexual erythrocytic stage of infection. The erythrocytic stages are routinely studied in vitro, made possible by the development of a continuous culture system that allows asexual parasite replication in human rbc (hurbc) (5). However, studying the biology and pathophysiology of P. falciparum in vivo is difficult and is hampered by the lack of adequate animal models. Sporogonic stages are generated by feeding female Anopheles mosquitoes on in vitro gametocyte cultures, allowing progression of the parasite life cycle in the mosquito and subsequent sporozoite accumulation...

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Section: Frg Huhep and Frg Nod Huhep Micementioning

confidence: 83%

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

et al. 2012

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“…Development of exoerythrocytic stage forms in vitro has only been demonstrated in the cytoplasm of primary human hepatocytes (61,62), HHS-102 hepatoma cells (63) and, recently, the HC-04 liver cell line (17). Presently, there is no human hepatocyte cell line available in which a high level of sporozoite infection and formation of parasitophorous vacuole during transformation of sporozoites to exoerythrocytic stage of P. falciparum have been demonstrated.…”

Section: Discussionmentioning

confidence: 99%

Early Transcriptional Responses of HepG2-A16 Liver Cells to Infection by Plasmodium falciparum Sporozoites

Chattopadhyay

Vega

Paik³

et al. 2011

Journal of Biological Chemistry

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Invasion of hepatocytes by Plasmodium sporozoites deposited by Anopheles mosquitoes, and their subsequent transformation into infective merozoites is an obligatory step in the initiation of malaria. Interactions between the sporozoites and hepatocytes lead to a distinct, complex and coordinated cellular and systemic host response. Little is known about host liver cell response to sporozoite invasion, or whether it is primarily adaptive for the parasite, for the host, or for both. Our present study used gene expression profiling of human HepG2-A16 liver cells infected with Plasmodium falciparum sporozoites to understand the host early cellular events and factors influencing parasite infectivity and sporozoite development. Our results show that as early as 30 min following wild-type, non-irradiated sporozoite exposure, the expressions of at least 742 genes was selectively altered. These genes regulate diverse biological functions, such as immune processes, cell adhesion and communications, metabolism pathways, cell cycle regulation, and signal transduction. These functions reflect cellular events consistent with initial host cell defense responses, as well as alterations in host cells to sustain sporozoites growth and survival. Irradiated sporozoites gave very similar gene expression pattern changes, but direct comparative analysis between liver gene expression profiles caused by irradiated and non-irradiated sporozoites identified 29 genes, including glypican-3, that were specifically up-regulated only in irradiated sporozoites. Elucidating the role of this subset of genes may help identify the molecular basis for the irradiated sporozoites inability to develop intrahepatically, and their usefulness as an immunogen for developing protective immunity against pre-erythrocytic stage malaria.

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“…The P. falciparum liver stage still remains a black box [11], because in vitro infection of human hepatocytes [12,13] and in vivo experiments using primates or humanized mice [14] rely on P. falciparum-infected Anopheles mosquitoes and all aspects are diYcult to perform, since they need to be carried out under high (S3) safety laboratory conditions. Therefore, mouse models using P. berghei and P. yoelii infections have successfully been introduced and the generation of Xuorescent rodent parasite strains has opened new avenues to investigate migration and development in the mammalian host [15,16].…”

Section: The Plasmodium Liver Stagementioning

confidence: 99%

Live and let die: manipulation of host hepatocytes by exoerythrocytic Plasmodium parasites

Sturm

Heussler

2007

Med Microbiol Immunol

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The generation of rodent Plasmodium strains expressing fluorescent proteins in all life cycle stages has had a big impact on malaria research. With this tool in hand, for the first time it was possible to follow in real time by in vivo microscopy the infection route of Plasmodium sporozoites transmitted to the mammalian host by Anopheles mosquitoes. Recently, this work has been extended to the analysis of both hepatocyte infection by Plasmodium sporozoites, as well as liver merozoite transport into blood vessels. The stunning results of these studies have considerably changed our understanding of hepatocyte invasion and parasite liberation. Here, we describe the most important findings of the last years and in addition, we elaborate on the molecular events during the intracellular development of Plasmodium exoerythrocytic forms that give rise to erythrocyte infecting merozoites.

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Complete Development of the Liver Stage of Plasmodium falciparum in a Human Hepatoma Cell Line

Cited by 33 publications

References 0 publications

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

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

Early Transcriptional Responses of HepG2-A16 Liver Cells to Infection by Plasmodium falciparum Sporozoites

Live and let die: manipulation of host hepatocytes by exoerythrocytic Plasmodium parasites

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