Parasites undergo complex life cycles that comprise a wide variety of cellular differentiation events in different host compartments and transmission across multiple hosts. As parasites depend on ...host resources, it is not surprising they have developed efficient mechanisms to sense alterations and adapt to the available resources in a wide range of environments. Here we provide an overview of the nutritional needs of different parasites throughout their diverse life stages and highlight recent insights into strategies that both hosts and parasites have developed to meet these nutritional requirements needed for defense, survival, and replication. These studies will provide the foundation for a systems-level understanding of host-parasite interactions, which will require the integration of molecular, epidemiologic, and mechanistic data and the application of interdisciplinary approaches to model parasite regulatory networks that are triggered by alterations in host resources.
Parasites require nutrients throughout their life cycle, and having a host that generates these resources is critical for parasite survival. Zuzarte-Luís and Mota review the mechanisms that parasites use to sense and respond to host nutrients and environmental cues and the importance of these pathways in successful parasite growth and transmission.
The development of therapies and vaccines for human hepatropic pathogens requires robust model systems that enable the study of host-pathogen interactions. However, in vitro liver models of infection ...typically use either hepatoma cell lines that exhibit aberrant physiology or primary human hepatocytes in culture conditions in which they rapidly lose their hepatic phenotype. To achieve stable and robust in vitro primary human hepatocyte models, we developed micropatterned cocultures (MPCCs), which consist of primary human hepatocytes organized into 2D islands that are surrounded by supportive fibroblast cells. By using this system, which can be established over a period of days, and maintained over multiple weeks, we demonstrate how to recapitulate in vitro hepatic life cycles for the hepatitis B and C viruses and the Plasmodium pathogens P. falciparum and P. vivax. The MPCC platform can be used to uncover aspects of host-pathogen interactions, and it has the potential to be used for drug and vaccine development.
Plasmodium sporozoites are deposited in the skin of their vertebrate hosts through the bite of an infected female Anopheles mosquito. Most of these parasites find a blood vessel and travel in the ...peripheral blood circulation until they reach the liver sinusoids. Once there, the sporozoites cross the sinusoidal wall and migrate through several hepatocytes before they infect a final hepatocyte, with the formation of a parasitophorous vacuole, in which the intrahepatic form of the parasite grows and multiplies. During this period, each sporozoite generates thousands of merozoites. As the development of Plasmodium sporozoites inside hepatocytes is an obligatory step before the onset of disease, understanding the parasite's requirements during this period is crucial for the development of any form of early intervention. This Review summarizes our current knowledge on this stage of the Plasmodium life cycle.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Human malaria infection begins with a one-time asymptomatic liver stage followed by a cyclic symptomatic blood stage. All high-throughput malaria drug discovery efforts have focused on the cyclic ...blood stage, which has limited potential for the prophylaxis, transmission blocking, and eradication efforts that will be needed in the future. To address these unmet needs, a high-throughput phenotypic liver-stage Plasmodium parasite screen was developed to systematically identify molecules with liver-stage efficacy. The screen recapitulates liver-stage infection by isolating luciferase-expressing Plasmodium berghei parasites directly from the salivary glands of infected mosquitoes, adding them to confluent human liver cells in 384-well plates, and measuring luciferase activity after a suitable incubation period. Screening 5,375 known bioactive compounds identified 37 liver-stage malaria inhibitors with diverse modes of action, as shown by inhibition time course experiments. Further analysis of the hits in the Food and Drug Administration-approved drug subset revealed compounds that seem to act specifically on the liver stage of infection, suggesting that this phase of the parasite’s life cycle presents a promising area for new drug discovery. Notably, many active compounds in this screen have molecular structures and putative targets distinctly different from those of known antimalarial agents.
During invasion, Plasmodium, the causative agent of malaria, wraps itself in a parasitophorous vacuole membrane (PVM), which constitutes a critical interface between the parasite and its host cell. ...Within hepatocytes, each Plasmodium sporozoite generates thousands of new parasites, creating high demand for lipids to support this replication and enlarge the PVM. Here, a global analysis of the total lipid repertoire of Plasmodium-infected hepatocytes reveals an enrichment of neutral lipids and the major membrane phospholipid, phosphatidylcholine (PC). While infection is unaffected in mice deficient in key enzymes involved in neutral lipid synthesis and lipolysis, ablation of rate-limiting enzymes in hepatic PC biosynthetic pathways significantly decreases parasite numbers. Host PC is taken up by both P. berghei and P. falciparum and is necessary for correct localization of parasite proteins to the PVM, which is essential for parasite survival. Thus, Plasmodium relies on the abundance of these lipids within hepatocytes to support infection.
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•Lipid composition of P. berghei-infected hepatocytes is altered during infection•Plasmodium liver stage infection does not require de-novo-synthesized neutral lipids•Plasmodium takes up host phosphatidylcholine (PC), which associates with the PVM•Host cell de novo PC synthesis contributes to PVM integrity and parasite survival
Plasmodium replication in hepatocytes requires abundant lipid resources. By analyzing the lipidome of P. berghei-infected cells, Itoe et al. reveal enrichment of phosphatidylcholine, a major membrane phospholipid. Targeted silencing of host genes involved in de novo phosphatidylcholine synthesis show that these pathways are critical for Plasmodium liver-stage infection.
The most common treatments for infectious diseases target the invading pathogen. The efficacy of such an approach may, however, be countered by the possibility of the development of resistance to a ...pharmacophore, through mutation(s) in pathogen molecules required for activity. Given the fact that pathogens exploit host factors in order to grow in an otherwise hostile environment, one possible way to circumvent the emergence of resistance is to develop drugs that target non-essential host factors hijacked by the pathogen, rather than the pathogen's own molecules. Such solutions are already being developed for various viral and bacterial pathogens, but much less has been achieved with infections caused by protozoan parasites, as is the case of Plasmodium. Here, we highlight recent progress in host target-based anti-viral and anti-bacterial approaches and discuss possible host targets that may be used for anti-malarial interventions. Host molecules that play a role during either the liver or the blood stage of Plasmodium infection are outlined and their potential merits as anti-malarial targets are discussed.
Malaria eradication is a major goal in public health but is challenged by relapsing malaria species, expanding drug resistance, and the influence of host genetics on antimalarial drug efficacy. To ...overcome these hurdles, it is imperative to establish in vitro assays of liver-stage malaria for drug testing. Induced pluripotent stem cells (iPSC) potentially allow the assessment of donor-specific drug responses, and iPSC-derived hepatocyte-like cells (iHLCs) can facilitate the study of host genetics on host-pathogen interactions and the discovery of novel targets for antimalarial drug development. We establish in vitro liver-stage malaria infections in iHLCs using P. berghei, P. yoelii, P. falciparum, and P. vivax and show that differentiating cells acquire permissiveness to malaria infection at the hepatoblast stage. We also characterize antimalarial drug metabolism capabilities of iHLCs using prototypical antimalarial drugs and demonstrate that chemical maturation of iHLCs can improve their potential for antimalarial drug testing applications.
•iPSC-derived hepatocyte-like cells (iHLCs) can host liver-stage malaria in vitro•iHLCs become permissive to Plasmodium infection at the hepatoblast stage•Plasmodium-infected iHLCs are sensitive to atovaquone but not primaquine•Small molecule-mediated maturation of iHLCs confers primaquine sensitivity
In this article, Bhatia and colleagues show that iPSC-derived hepatocyte-like cells (iHLCs) can be infected with Plasmodium parasites of the species that cause human malaria, starting from the hepatoblast stage. They also demonstrate that further maturation of iHLCs by small molecules confers drug sensitivity to a model antimalarial, primaquine, that requires hepatic bioactivation.
Consumption of tree nuts and legume seeds is associated with a reduction in cardiovascular risk. The reduction in blood lipids and in inflammatory and oxidative processes exhibited by bioactive ...compounds such as monounsaturated and polyunsaturated fatty acids, fibers, phenolic compounds, tocopherols, phospholipids, carotenoids, some minerals, and arginine, has stimulated research on the mechanisms of action of these substances through distinct experimental approaches. It is, therefore, important to know the metabolic effect of each nut and legume seed or the mixture of them to choose the most suitable nutritional interventions in clinical practice. The aim of this narrative bibliographic review was to investigate the effects of tree nuts and legume seeds on biomarkers of cardiovascular risk, as well as their mechanisms of action with regard to lipid profiles, insulin resistance, arterial pressure, oxidative stress, and inflammation. The findings indicate that a mixture of nuts and legume seeds optimizes the protective effect against cardiovascular risk.
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•The liver and blood stages of Plasmodium infection exert a marked influence on each other.•In high-transmission settings, concomitant liver and blood stage infections are the rule ...rather than the exception.•Blood-stage Plasmodium infection negatively influences the protective efficacy of pre-erythrocytic malaria vaccines.•The liver stage of Plasmodium infection impacts the outcome of erythrocytic infection and pathology.
While the liver and blood stages of the Plasmodium life cycle are commonly regarded as two separate fields of malaria research, several studies have pointed towards the existence of a bidirectional cross-talk, where one stage of mammalian infection may impact the establishment and progression of the other. Despite the constraints in experimentally addressing concurrent liver and blood stage Plasmodium infections, animal models and clinical studies have unveiled a plethora of molecular interactions between the two. Here, we review the current knowledge on the reciprocal influence of hepatic and erythrocytic infection by malaria parasites, and discuss its impacts on immunity, pathology and vaccination against this deadly disease.
The Plasmodium liver stage is an attractive target for the development of antimalarial drugs and vaccines, as it provides an opportunity to interrupt the life cycle of the parasite at a critical ...early stage. However, targeting the liver stage has been difficult. Undoubtedly, a major barrier has been the lack of robust, reliable, and reproducible in vitro liver-stage cultures. Here, we establish the liver stages for both Plasmodium falciparum and Plasmodium vivax in a microscale human liver platform composed of cryopreserved, micropatterned human primary hepatocytes surrounded by supportive stromal cells. Using this system, we have successfully recapitulated the full liver stage of P. falciparum, including the release of infected merozoites and infection of overlaid erythrocytes, as well as the establishment of small forms in late liver stages of P. vivax. Finally, we validate the potential of this platform as a tool for medium-throughput antimalarial drug screening and vaccine development.
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•Established human malaria liver-stage culture using cryopreserved components (MPCC)•MPCC recapitulates full P. falciparum liver stage, merozoite release, and RBC infection•MPCC allows establishment and detection of small forms in late liver stages of P. vivax•MPCC’s potential for antimalarial drug screening and vaccine development is validated
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