Post‐transcriptional silencing of <scp>UIS4</scp> in <scp>P</scp>lasmodium berghei sporozoites is important for host switch

Silvie, Olivier; Briquet, Sylvie; Müller, Katja; Manzoni, Giulia; Matuschewski, Kai

doi:10.1111/mmi.12528

Cited by 37 publications

(53 citation statements)

References 50 publications

(87 reference statements)

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“…As expected, the ER marker BiP and the mitochondrial marker HSP60 were localized to the sporozoite interior (Figure 3A), as has been described for sporozoites of other Plasmodium species. Interestingly, PvUIS4 was not detected in P. vivax sporozoites, in contrast to observations made for P. yoelii UIS4 (Kaiser et al, 2004) and P. falciparum UIS4 (Mackellar et al, 2010) but in agreement with P. berghei UIS4 (Silvie et al, 2014). Expression of ACP and PvMIF was also not observed in P. vivax sporozoites (Figure 3A).…”

Section: Resultscontrasting

confidence: 98%

Plasmodium vivax Liver Stage Development and Hypnozoite Persistence in Human Liver-Chimeric Mice

Mikolajczak

Vaughan

Kangwanrangsan

et al. 2015

Cell Host & Microbe

192

252

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Plasmodium vivax malaria is characterized by periodic relapses of symptomatic blood stage parasite infections likely initiated by activation of dormant liver stage parasites -hypnozoites. The lack of tractable animal models for P. vivax constitutes a severe obstacle to investigate this unique aspect of its biology and to test drug efficacy against liver stages. We show that the FRG KO huHep liver-humanized mice support P. vivax sporozoite infection, development of liver stages, and the formation of small non-replicating hypnozoites. Cellular characterization of P. vivax liver stage development in vivo demonstrates complete maturation into infectious exo-erythrocytic merozoites and continuing persistence of hypnozoites. Primaquine prophylaxis or treatment prevents and eliminates liver stage infection. Thus, the P. vivax/FRG KO huHep mouse infection model constitutes an important new tool to investigate the biology of liver stage development and dormancy and might aid in the discovery of new drugs for the prevention of relapsing malaria.

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Section: Resultscontrasting

confidence: 98%

Plasmodium vivax Liver Stage Development and Hypnozoite Persistence in Human Liver-Chimeric Mice

Mikolajczak

Vaughan

Kangwanrangsan

et al. 2015

Cell Host & Microbe

192

252

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“…1D), as expected for proteins expressed under the control of the UIS4 promoter (15, 34). We therefore excluded the possibility that OVA is present during blood infection.…”

Section: Resultssupporting

confidence: 70%

Antigen Export during Liver Infection of the Malaria Parasite Augments Protective Immunity

Montagna

Beigier-Bompadre

Becker

et al. 2014

mBio

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Protective immunity against preerythrocytic malaria parasite infection is difficult to achieve. Intracellular Plasmodium parasites likely minimize antigen presentation by surface-expressed major histocompatibility complex class I (MHC-I) molecules on infected cells, yet they actively remodel their host cells by export of parasite factors. Whether exported liver-stage proteins constitute better candidates for MHC-I antigen presentation to CD8+ T lymphocytes remains unknown. Here, we systematically characterized the contribution of protein export to the magnitude of antigen-specific T-cell responses against Plasmodium berghei liver-stage parasites in C57BL/6 mice. We generated transgenic sporozoites that secrete a truncated ovalbumin (OVA) surrogate antigen only in the presence of an amino-terminal protein export element. Immunization with live attenuated transgenic sporozoites revealed that antigen export was not critical for CD8+ T-cell priming but enhanced CD8+ T-cell proliferation in the liver. Upon transfer of antigen-specific CD8+ T cells, liver-stage parasites secreting the target protein were eliminated more efficiently. We conclude that Plasmodium parasites strictly control protein export during liver infection to minimize immune recognition. Strategies that enhance the discharge of parasite proteins into infected hepatocytes could improve the efficacy of candidate preerythrocytic malaria vaccines.

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“…Thus, we determined whether LC3 similarly decorates the PVM of P. vivax in response to IFN-γ, by staining the P. vivax surface with CSP and the PVM with UIS4. Both CSP and UIS4 are markers for P. vivax; previous studies in P. berghei showed decreased expression of CSP, but increased expression of UIS4, over the course of hepatocyte infection (30). The results show increased interaction between LC3 and P. vivax during IFN-γ treatment for 4 h postinvasion.…”

Section: Liver-stage P Vivax Colocalizes With Lc3 and Ltrmentioning

confidence: 51%

LAP-like process as an immune mechanism downstream of IFN-γ in control of the human malariaPlasmodium vivaxliver stage

Boonhok

Rachaphaew

Duangmanee

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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IFN-γ is a major regulator of immune functions and has been shown to induce liver-stage Plasmodium elimination both in vitro and in vivo. The molecular mechanism responsible for the restriction of liver-stage Plasmodium downstream of IFN-γ remains uncertain, however. Autophagy, a newly described immune defense mechanism, was recently identified as a downstream pathway activated in response to IFN-γ in the control of intracellular infections. We thus hypothesized that the killing of liver-stage malarial parasites by IFN-γ involves autophagy induction. Our results show that whereas IFN-γ treatment of human hepatocytes activates autophagy, the IFN-γ-mediated restriction of liver-stage Plasmodium vivax depends only on the downstream autophagy-related proteins Beclin 1, PI3K, and ATG5, but not on the upstream autophagy-initiating protein ULK1. In addition, IFN-γ enhanced the recruitment of LC3 onto the parasitophorous vacuole membrane (PVM) and increased the colocalization of lysosomal vesicles with P. vivax compartments. Taken together, these data indicate that IFN-γ mediates the control of liver-stage P. vivax by inducing a noncanonical autophagy pathway resembling that of LC3-associated phagocytosis, in which direct decoration of the PVM with LC3 promotes the fusion of P. vivax compartments with lysosomes and subsequent killing of the pathogen. Understanding the hepatocyte response to IFN-γ during Plasmodium infection and the roles of autophagy-related proteins may provide an urgently needed alternative strategy for the elimination of this human malaria.autophagy | LC3-associated phagocytosis | IFN-γ | malaria S everal hundred million cases of human malaria are reported annually, and nearly 600,000 people die from the disease each year (1). Of the five species that infect humans, Plasmodium vivax is not only the most geographically widespread, but also the most prevalent malarial parasite in areas outside Africa. As such, it has caused massive morbidity in these regions of the world. Although malaria caused by P. vivax was previously regarded as benign compared with that caused by Plasmodium falciparum, the recent alarming increase in both the severity and the drug resistance of P. vivax infection has raised concern (2).The widespread distribution of P. vivax has been attributed to the parasite's ability to remain dormant in the liver for years before reactivation (3). The molecular mechanism responsible for P. vivax dormancy is unknown, and knowledge of Plasmodiumhepatocyte interactions remains very limited. Nonetheless, because the number of liver-stage parasites is in the range of 100, whereas in the blood stage as many as 10 13 organisms may be found (4), intervention at the liver stage would seem to offer a better strategy for parasite elimination. A prerequisite to this route of malaria control and the development of novel therapies is a better understanding of liver-stage Plasmodium and its interactions with host hepatocytes. IFN-γ was previously shown to exhibit antimalarial activity against the liver stag...

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Post‐transcriptional silencing of UIS4 in Plasmodium berghei sporozoites is important for host switch

Cited by 37 publications

References 50 publications

Plasmodium vivax Liver Stage Development and Hypnozoite Persistence in Human Liver-Chimeric Mice

Plasmodium vivax Liver Stage Development and Hypnozoite Persistence in Human Liver-Chimeric Mice

Antigen Export during Liver Infection of the Malaria Parasite Augments Protective Immunity

LAP-like process as an immune mechanism downstream of IFN-γ in control of the human malariaPlasmodium vivaxliver stage

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