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Author(s):  
Elizabeth K. K. Glennon ◽  
Tinotenda Tongogara ◽  
Veronica I. Primavera ◽  
Sophia M. Reeder ◽  
Ling Wei ◽  
...  

Upon transmission to the human host, Plasmodium sporozoites exit the skin, are taken up by the blood stream, and then travel to the liver where they infect and significantly modify a single hepatocyte. Low infection rates within the liver have made proteomic studies of infected hepatocytes challenging, particularly in vivo, and existing studies have been largely unable to consider how protein and phosphoprotein differences are altered at different spatial locations within the heterogeneous liver. Using digital spatial profiling, we characterized changes in host signaling during Plasmodium yoelii infection in vivo without disrupting the liver tissue. Moreover, we measured alterations in protein expression around infected hepatocytes and identified a subset of CD163+ Kupffer cells that migrate towards infected cells during infection. These data offer the first insight into the heterogeneous microenvironment that surrounds the infected hepatocyte and provide insights into how the parasite may alter its milieu to influence its survival and modulate immunity.


2021 ◽  
Vol 12 ◽  
Author(s):  
Oriana Kreutzfeld ◽  
Josephine Grützke ◽  
Alyssa Ingmundson ◽  
Katja Müller ◽  
Kai Matuschewski

Host cell remodeling is critical for successful Plasmodium replication inside erythrocytes and achieved by targeted export of parasite-encoded proteins. In contrast, during liver infection the malarial parasite appears to avoid protein export, perhaps to limit exposure of parasite antigens by infected liver cells. HSP101, the force-generating ATPase of the protein translocon of exported proteins (PTEX) is the only component that is switched off during early liver infection. Here, we generated transgenic Plasmodium berghei parasite lines that restore liver stage expression of HSP101. HSP101 expression in infected hepatocytes was achieved by swapping the endogenous promoter with the ptex150 promoter and by inserting an additional copy under the control of the elongation one alpha (ef1α) promoter. Both promoters drive constitutive and, hence, also pre-erythrocytic expression. Transgenic parasites were able to complete the life cycle, but failed to export PEXEL-proteins in early liver stages. Our results suggest that PTEX-dependent early liver stage export cannot be restored by addition of HSP101, indicative of alternative export complexes or other functions of the PTEX core complex during liver infection.


2021 ◽  
Author(s):  
Amichay Afriat ◽  
Vanessa Zuzarte-Luís ◽  
Keren Bahar Halpern ◽  
Lisa Buchauer ◽  
Sofia Marques ◽  
...  

AbstractMalaria infection involves an obligatory, yet clinically silent liver stage1,2. Hepatocytes operate in repeating units termed lobules, exhibiting heterogeneous gene expression patterns along the lobule axis3, but the effects of hepatocyte zonation on parasite development have not been molecularly explored. Here, we combine single-cell RNA sequencing4 and single-molecule transcript imaging5 to characterize the host’s and parasite’s temporal expression programs in a zonally-controlled manner for the rodent malaria parasite Plasmodium berghei ANKA. We identify differences in parasite gene expression in distinct zones, and a sub-population of periportally-biased hepatocytes that harbor abortive infections associated with parasitophorous vacuole breakdown. These ‘abortive hepatocytes’ up-regulate immune recruitment and key signaling programs. They exhibit reduced levels of Plasmodium transcripts, perturbed parasite mRNA localization, and may give rise to progressively lower abundance of periportal infections. Our study provides a resource for understanding the liver stage of Plasmodium infection at high spatial resolution and highlights heterogeneous behavior of both the parasite and the host hepatocyte.


2021 ◽  
Author(s):  
Melanie Pellisson ◽  
Anne-Marie Zeeman ◽  
Thierry Doll ◽  
Lucy Kirchhofer-Allan ◽  
Sven Schuierer ◽  
...  

Plasmodium cynomolgi (Pc) is one of the few parasite species that forms quiescent liver stage parasites known as hypnozoites and is therefore a suitable model for Plasmodium vivax. Very little is known about liver stage dormancy, which hampers the search for compounds with anti-hypnozoite activity. Here, we present the development of a Pc in vitro infection model using stem cell-derived hepatocytes from Macaca fascicularis. IPS cells were established on feeder free condition and differentiated into hepatocytes via inducible overexpression of key transcription factors. The generated hepatocytes were infected with Pc sporozoites and hypnozoite formation as well as schizont development were confirmed by immunofluorescence. This system is a promising tool to study the mechanisms underlying liver stage dormancy and facilitate drug discovery against hypnozoites.


2021 ◽  
Author(s):  
Selma Belhimeur ◽  
Sylvie Briquet ◽  
Roger Peronet ◽  
Jennifer Pham ◽  
Pierre-Henri Commere ◽  
...  

Plasmodium sporozoites inoculated by Anopheles mosquitoes into the skin of the mammalian host migrate to the liver before infecting hepatocytes. Previous work demonstrated that early production of IL-6 in the liver was found to be detrimental for the parasite growth, leading to the acquisition of a long-lasting immune protection. Considering IL-6 as a critical pro-inflammatory signal, we explored a novel approach whereby the parasite itself encodes for the murine IL-6 gene. We generated transgenic P.berghei parasites that express murine IL-6 during liver stage development. Though IL-6 transgenic sporozoites develop into exo-erythrocytic forms in cultured hepatocytes in vitro, these parasites were not capable of inducing a blood stage infection in mice. Furthermore, immunization of mice with transgenic IL-6 sporozoites elicited a long-lasting CD8+ T cell-mediated protective immunity against a subsequent infectious sporozoite challenge. Collectively, this study demonstrates that parasite-encoded IL-6 impairs Plasmodium infection at the liver stage, forming the basis of a novel suicide vaccine strategy to elicit protective antimalarial immunity.


Author(s):  
William R. Heath ◽  
Lauren E. Holz ◽  
Daniel Fernandez-Ruiz
Keyword(s):  

2021 ◽  
Author(s):  
Alona Botnar ◽  
Grant Lawrence ◽  
Steven P. Maher ◽  
Amèlie Vantaux ◽  
Benoît Witkowski ◽  
...  

Malaria is a major global health problem which predominantly afflicts developing countries. Although many antimalarial therapies are currently available, the protozoan parasite causing this disease, Plasmodium spp., continues to evade eradication efforts. One biological phenomenon hampering eradication efforts is the ability of. the parasite to arrest development, transform into a drug-insensitive form, and then resume growth post-therapy. Currently, the mechanisms by which the parasite enters arrested development, or dormancy, and later recrudesces or reactivates to continue development, are unknown and the malaria field lacks techniques to study these elusive mechanisms. Since Plasmodium spp. salvage purines for DNA synthesis, we hypothesized that alkyne-containing purine nucleosides could be used to develop a DNA synthesis marker which could be used to investigate mechanisms behind dormancy. Using copper-catalyzed click chemistry methods, we observe incorporation of alkyne modified adenosine, inosine, and hypoxanthine in actively replicating asexual blood stages of P. falciparum and incorporation of modified adenosine in actively replicating liver stage schizonts of P. vivax. Notably, these modified purines were not incorporated in dormant liver stage hypnozoites, suggesting this marker could be used as a tool to differentiate replicating and non-replicating liver forms and, more broadly, a tool for advancing our understanding Plasmodium dormancy mechanisms.


2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Steven P. Maher ◽  
Amélie Vantaux ◽  
Victor Chaumeau ◽  
Adeline C. Y. Chua ◽  
Caitlin A. Cooper ◽  
...  

AbstractImproved control of Plasmodium vivax malaria can be achieved with the discovery of new antimalarials with radical cure efficacy, including prevention of relapse caused by hypnozoites residing in the liver of patients. We screened several compound libraries against P. vivax liver stages, including 1565 compounds against mature hypnozoites, resulting in one drug-like and several probe-like hits useful for investigating hypnozoite biology. Primaquine and tafenoquine, administered in combination with chloroquine, are currently the only FDA-approved antimalarials for radical cure, yet their activity against mature P. vivax hypnozoites has not yet been demonstrated in vitro. By developing an extended assay, we show both drugs are individually hypnozonticidal and made more potent when partnered with chloroquine, similar to clinically relevant combinations. Post-hoc analyses of screening data revealed excellent performance of ionophore controls and the high quality of single point assays, demonstrating a platform able to support screening of greater compound numbers. A comparison of P. vivax liver stage activity data with that of the P. cynomolgi blood, P. falciparum blood, and P. berghei liver stages reveals overlap in schizonticidal but not hypnozonticidal activity, indicating that the delivery of new radical curative agents killing P. vivax hypnozoites requires an independent and focused drug development test cascade.


2021 ◽  
Author(s):  
Matthew P. Gibbins ◽  
Katja Müller ◽  
Kai Matuschewski ◽  
Olivier Silvie ◽  
Julius Clemence R. Hafalla

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