Hostile Takeover by Plasmodium: Reorganization of Parasite and Host Cell Membranes during Liver Stage Egress

Graewe, Stefanie; Rankin, Kathleen E.; Lehmann, Christine; Deschermeier, Christina; Hecht, Leonie; Froehlke, Ulrike; Stanway, Rebecca R.; Heussler, Volker

doi:10.1371/journal.ppat.1002224

Cited by 94 publications

(86 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…PVM breakdown was previously shown to be a critical step in rodent malaria models preceding merozoite release (29)(30)(31). Furthermore, MSP1 protein expression as well as transcript abundance of the maturing merozoite markers MSP1, EBA-175, and AMA-1 at 7 days of development suggested that complete LS development had occurred.…”

Section: Frg Huhep and Frg Nod Huhep Micementioning

confidence: 88%

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

et al. 2012

View full text Add to dashboard Cite

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...

show abstract

Section: Frg Huhep and Frg Nod Huhep Micementioning

confidence: 88%

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

et al. 2012

View full text Add to dashboard Cite

show abstract

“…2). The rupture of the parasitophorous vacuolar membrane (PVM) occurs first (14,66). In vitro studies indicated that PVM permeabilization is protease dependent (126,139,140).…”

Section: Budding From the Plasma Membranementioning

confidence: 99%

“…The released vesicles have been termed merosomes and are estimated to contain up to thousands of merozoites as well as host cell organelles and undefined vesicular structures (14). The merosome membrane is derived from the host cell (66). During this process, the parasite induces host cell death different from classical apoptosis or necrosis, leading to the detachment of the hepatocyte from neighboring cells (66).…”

Section: Budding From the Plasma Membranementioning

confidence: 99%

“…The merosome membrane is derived from the host cell (66). During this process, the parasite induces host cell death different from classical apoptosis or necrosis, leading to the detachment of the hepatocyte from neighboring cells (66). Remarkably, the asymmetric distribution of phosphatidylserine, a hallmark of viable cells, is maintained at the surrounding membrane of the hepatocyte and merosomes (14,139).…”

Section: Budding From the Plasma Membranementioning

confidence: 99%

See 1 more Smart Citation

Prison Break: Pathogens' Strategies To Egress from Host Cells

Friedrich

Hagedorn

Soldati‐Favre

et al. 2012

Microbiol Mol Biol Rev

View full text Add to dashboard Cite

SUMMARYA wide spectrum of pathogenic bacteria and protozoa has adapted to an intracellular life-style, which presents several advantages, including accessibility to host cell metabolites and protection from the host immune system. Intracellular pathogens have developed strategies to enter and exit their host cells while optimizing survival and replication, progression through the life cycle, and transmission. Over the last decades, research has focused primarily on entry, while the exit process has suffered from neglect. However, pathogen exit is of fundamental importance because of its intimate association with dissemination, transmission, and inflammation. Hence, to fully understand virulence mechanisms of intracellular pathogens at cellular and systemic levels, it is essential to consider exit mechanisms to be a key step in infection. Exit from the host cell was initially viewed as a passive process, driven mainly by physical stress as a consequence of the explosive replication of the pathogen. It is now recognized as a complex, strategic process termed “egress,” which is just as well orchestrated and temporally defined as entry into the host and relies on a dynamic interplay between host and pathogen factors. This review compares egress strategies of bacteria, pathogenic yeast, and kinetoplastid and apicomplexan parasites. Emphasis is given to recent advances in the biology of egress in mycobacteria and apicomplexans.

show abstract

“…We generated transgenic Plasmodium berghei parasites expressing OVA either in the cytoplasm, under the control of the heat shock protein 70 (HSP70) promoter, or on the parasitophorous vacuole membrane (PVM), through fusion of OVA to the PVM protein EXP1/HEP17 (exported protein 1, hepatocyte erythrocyte protein 17 kDa) (13)(14)(15). We found that while both cytoplasmic and PVM-anchored OVA could activate OVA-specific CD8 ϩ T cells (OT-I) and CD4 ϩ T cells (OT-II), OVA fused to the PVM induced the strongest antigen-specific T-cell responses.…”

mentioning

confidence: 99%

The Subcellular Location of Ovalbumin in Plasmodium berghei Blood Stages Influences the Magnitude of T-Cell Responses

et al. 2014

View full text Add to dashboard Cite

bModel antigens are frequently introduced into pathogens to study determinants that influence T-cell responses to infections. To address whether an antigen's subcellular location influences the nature and magnitude of antigen-specific T-cell responses, we generated Plasmodium berghei parasites expressing the model antigen ovalbumin (OVA) either in the parasite cytoplasm or on the parasitophorous vacuole membrane (PVM). For cytosolic expression, OVA alone or conjugated to mCherry was expressed from a strong constitutive promoter (OVA hsp70 or OVA::mCherry hsp70 ); for PVM expression, OVA was fused to HEP17/EXP1 (OVA::Hep17 hep17 ). Unexpectedly, OVA expression in OVA hsp70 parasites was very low, but when OVA was fused to mCherry (OVA::mCherry hsp70 ), it was highly expressed. OVA expression in OVA::Hep17 hep17 parasites was strong but significantly less than that in OVA::mCherry hsp70 parasites. These transgenic parasites were used to examine the effects of antigen subcellular location and expression level on the development of T-cell responses during blood-stage infections. While all OVA-expressing parasites induced activation and proliferation of OVA-specific CD8؉ T cells (OT-I) and CD4 ؉ T cells (OT-II), the level of activation varied: OVA::Hep17 hep17 parasites induced significantly stronger splenic and intracerebral OT-I and OT-II responses than those of OVA::mCherry hsp70 parasites, but OVA::mCherry hsp70 parasites promoted stronger OT-I and OT-II responses than those of OVA hsp70 parasites. Despite lower OVA expression levels, OVA::Hep17 hep17 parasites induced stronger T-cell responses than those of OVA::mCherry hsp70 parasites. These results indicate that unconjugated cytosolic OVA is not stably expressed in Plasmodium parasites and, importantly, that its cellular location and expression level influence both the induction and magnitude of parasite-specific T-cell responses. These parasites represent useful tools for studying the development and function of antigenspecific T-cell responses during malaria infection.T cells play a central role in the immune response to malaria and can help to control blood-stage infections (1, 2). For example, in human and rodent malaria infections, effector CD4 ϩ T cells promote antiparasitic antibody production and regulate macrophage-based antiparasitic effector responses (1, 2). However, it is also clear that proinflammatory T-cell responses, if not regulated appropriately or if present in the wrong environment, can contribute to the development of immunopathology during malaria infection (3, 4). Thus, understanding how malarial proteins are recognized by the immune system to initiate adaptive T-cell responses and identifying the antigen-specific T-cell responses involved in protection and pathology during infection have significant importance for vaccine development and for identification of predictive immunological biomarkers for severe malarial disease.Difficulties in identifying endogenous T-cell epitopes within blood-stage malaria parasites have hampered the inves...

show abstract

Hostile Takeover by Plasmodium: Reorganization of Parasite and Host Cell Membranes during Liver Stage Egress

Cited by 94 publications

References 37 publications

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

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

Prison Break: Pathogens' Strategies To Egress from Host Cells

The Subcellular Location of Ovalbumin in Plasmodium berghei Blood Stages Influences the Magnitude of T-Cell Responses

Contact Info

Product

Resources

About