Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 55
Filtrar
Más filtros












Base de datos
Intervalo de año de publicación
1.
Curr Opin Cell Biol ; 88: 102366, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38705049

RESUMEN

EVs are nanoparticles enclosing proteins, nucleic acids and lipids released by cells and are essential for their metabolism and useful for intercellular communication. The importance of EVs has been highlighted by their use as biomarkers or as vaccine antigens. The release of vesicles is exploited by a wide range of organisms: from unicellular bacteria or protozoa to multicellular prokaryotes like fungi, helminths and arthropods. The mechanisms elucidated to date in each biological group are presented, as well as a discussion of interesting directions for future EV studies.


Asunto(s)
Vesículas Extracelulares , Vesículas Extracelulares/metabolismo , Vesículas Extracelulares/química , Animales , Humanos , Interacciones Huésped-Patógeno , Comunicación Celular
2.
Traffic ; 25(4): e12935, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38629580

RESUMEN

The protozoan parasites Plasmodium falciparum, Leishmania spp. and Trypanosoma cruzi continue to exert a significant toll on the disease landscape of the human population in sub-Saharan Africa and Latin America. Control measures have helped reduce the burden of their respective diseases-malaria, leishmaniasis and Chagas disease-in endemic regions. However, the need for new drugs, innovative vaccination strategies and molecular markers of disease severity and outcomes has emerged because of developing antimicrobial drug resistance, comparatively inadequate or absent vaccines, and a lack of trustworthy markers of morbid outcomes. Extracellular vesicles (EVs) have been widely reported to play a role in the biology and pathogenicity of P. falciparum, Leishmania spp. and T. cruzi ever since they were discovered. EVs are secreted by a yet to be fully understood mechanism in protozoans into the extracellular milieu and carry a cargo of diverse molecules that reflect the originator cell's metabolic state. Although our understanding of the biogenesis and function of EVs continues to deepen, the question of how EVs in P. falciparum, Leishmania spp. and T. cruzi can serve as targets for a translational agenda into clinical and public health interventions is yet to be fully explored. Here, as a consortium of protozoan researchers, we outline a plan for future researchers and pose three questions to direct an EV's translational agenda in P. falciparum, Leishmania spp. and T. cruzi. We opine that in the long term, executing this blueprint will help bridge the current unmet needs of these medically important protozoan diseases in sub-Saharan Africa and Latin America.


Asunto(s)
Enfermedad de Chagas , Vesículas Extracelulares , Leishmania , Parásitos , Trypanosoma cruzi , Animales , Humanos , Enfermedad de Chagas/epidemiología , Enfermedad de Chagas/parasitología
3.
Microbes Infect ; : 105314, 2024 Feb 16.
Artículo en Inglés | MEDLINE | ID: mdl-38367661

RESUMEN

Parasitic diseases remain a major global health problem for humans. Parasites employ a variety of strategies to invade and survive within their hosts and to manipulate host defense mechanisms, always in the pathogen's favor. Extracellular vesicles (EVs), membrane-bound nanospheres carrying a variety of bioactive compounds, were shown to be released by the parasites during all stages of the infection, enabling growth and expansion within the host and adaptation to frequently changing environmental stressors. In this review, we discuss how the use of existing nanotechnologies and high-resolution imaging tools assisted in revealing the role of EVs during parasitic infections, enabling the quantitation, visualization, and detailed characterization of EVs. We discuss here the cases of malaria, Chagas disease and leishmaniasis as examples of parasitic neglected tropical diseases (NTDs). Unraveling the EVs' role in the NTD pathogenesis may enormously contribute to their early and reliable diagnostic, effective treatment, and prevention.

4.
Biomedicines ; 12(2)2024 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-38398037

RESUMEN

Proteolysis of the extracellular matrix (ECM) by matrix metalloproteinases (MMPs) plays a crucial role in the immune response to bacterial infections. Here we report the secretion of MMPs associated with proteolytic extracellular vesicles (EVs) released by macrophages in response to Salmonella enterica serovar Typhimurium infection. Specifically, we used global proteomics, in vitro, and in vivo approaches to investigate the composition and function of these proteolytic EVs. Using a model of S. Typhimurium infection in murine macrophages, we isolated and characterized a population of small EVs. Bulk proteomics analysis revealed significant changes in protein cargo of naïve and S. Typhimurium-infected macrophage-derived EVs, including the upregulation of MMP-9. The increased levels of MMP-9 observed in immune cells exposed to S. Typhimurium were found to be regulated by the toll-like receptor 4 (TLR-4)-mediated response to bacterial lipopolysaccharide. Macrophage-derived EV-associated MMP-9 enhanced the macrophage invasion through Matrigel as selective inhibition of MMP-9 reduced macrophage invasion. Systemic administration of fluorescently labeled EVs into immunocompromised mice demonstrated that EV-associated MMP activity facilitated increased accumulation of EVs in spleen and liver tissues. This study suggests that macrophages secrete proteolytic EVs to enhance invasion and ECM remodeling during bacterial infections, shedding light on an essential aspect of the immune response.

5.
Trends Parasitol ; 39(11): 913-928, 2023 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-37758631

RESUMEN

Parasitic diseases continue to afflict millions of people globally. However, traditional vaccine development strategies are often difficult to apply to parasites, leaving an immense unmet need for new effective vaccines for the prevention and control of parasitic infections. As parasites commonly use extracellular vesicles (EVs) to interact with, interfere with, or modulate the host immune response from a distance, parasite-derived EVs may provide promising vaccine agents that induce immunity against parasitic infections. We here present achievements to date and the challenges and limitations associated with using parasitic EVs in a clinical context. Despite the many difficulties that need to be overcome, we believe this direction could offer a new and reliable source of therapeutics for various neglected parasitic diseases.

6.
J Invest Dermatol ; 143(12): 2494-2506.e4, 2023 12.
Artículo en Inglés | MEDLINE | ID: mdl-37236596

RESUMEN

Skin pigmentation is paused after sun exposure; however, the mechanism behind this pausing is unknown. In this study, we found that the UVB-induced DNA repair system, led by the ataxia telangiectasia mutated (ATM) protein kinase, represses MITF transcriptional activity of pigmentation genes while placing MITF in DNA repair mode, thus directly inhibiting pigment production. Phosphoproteomics analysis revealed ATM to be the most significantly enriched pathway among all UVB-induced DNA repair systems. ATM inhibition in mouse or human skin, either genetically or chemically, induces pigmentation. Upon UVB exposure, MITF transcriptional activation is blocked owing to ATM-dependent phosphorylation of MITF on S414, which modifies MITF activity and interactome toward DNA repair, including binding to TRIM28 and RBBP4. Accordingly, MITF genome occupancy is enriched in sites of high DNA damage that are likely repaired. This suggests that ATM harnesses the pigmentation key activator for the necessary rapid, efficient DNA repair, thus optimizing the chances of the cell surviving. Data are available from ProteomeXchange with the identifier PXD041121.


Asunto(s)
Ataxia Telangiectasia , Humanos , Animales , Ratones , Pigmentación de la Piel/genética , Reparación del ADN , Proteínas de la Ataxia Telangiectasia Mutada/genética , Proteínas de la Ataxia Telangiectasia Mutada/metabolismo , Transducción de Señal , Daño del ADN , Fosforilación , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Factor de Transcripción Asociado a Microftalmía/genética , Factor de Transcripción Asociado a Microftalmía/metabolismo
7.
EMBO Rep ; 24(5): e56114, 2023 05 04.
Artículo en Inglés | MEDLINE | ID: mdl-36929726

RESUMEN

Vesicular transport is a means of communication. While cells can communicate with each other via secretion of extracellular vesicles, less is known regarding organelle-to organelle communication, particularly in the case of mitochondria. Mitochondria are responsible for the production of energy and for essential metabolic pathways in the cell, as well as fundamental processes such as apoptosis and aging. Here, we show that functional mitochondria isolated from Saccharomyces cerevisiae release vesicles, independent of the fission machinery. We isolate these mitochondrial-derived vesicles (MDVs) and find that they are relatively uniform in size, of about 100 nm, and carry selective protein cargo enriched for ATP synthase subunits. Remarkably, we further find that these MDVs harbor a functional ATP synthase complex. We demonstrate that these vesicles have a membrane potential, produce ATP, and seem to fuse with naive mitochondria. Our findings reveal a possible delivery mechanism of ATP-producing vesicles, which can potentially regenerate ATP-deficient mitochondria and may participate in organelle-to-organelle communication.


Asunto(s)
Mitocondrias , Saccharomyces cerevisiae , Potenciales de la Membrana , Mitocondrias/metabolismo , Transporte Biológico , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Adenosina Trifosfato/metabolismo
8.
PLoS Pathog ; 19(2): e1011140, 2023 02.
Artículo en Inglés | MEDLINE | ID: mdl-36821560

RESUMEN

Extracellular vesicles (EVs) provide a central mechanism of cell-cell communication. While EVs are found in most organisms, their pathogenesis-promoting roles in parasites are of particular interest given the potential for medical insight and consequential therapeutic intervention. Yet, a key feature of EVs in human parasitic protozoa remains elusive: their mechanisms of biogenesis. Here, we survey the current knowledge on the biogenesis pathways of EVs secreted by the four main clades of human parasitic protozoa: apicomplexans, trypanosomatids, flagellates, and amoebae. In particular, we shine a light on findings pertaining to the Endosomal Sorting Complex Required for Transport (ESCRT) machinery, as in mammals it plays important roles in EV biogenesis. This review highlights the diversity in EV biogenesis in protozoa, as well as the related involvement of the ESCRT system in these unique organisms.


Asunto(s)
Vesículas Extracelulares , Parásitos , Animales , Humanos , Parásitos/metabolismo , Complejos de Clasificación Endosomal Requeridos para el Transporte/metabolismo , Vesículas Extracelulares/metabolismo , Transporte Biológico , Transporte de Proteínas , Mamíferos
9.
Parasit Vectors ; 16(1): 14, 2023 Jan 13.
Artículo en Inglés | MEDLINE | ID: mdl-36639683

RESUMEN

BACKGROUND: Plasmodium falciparum (Pf) is the leading protozoan causing malaria, the most devastating parasitic disease. To ensure transmission, a small subset of Pf parasites differentiate into the sexual forms (gametocytes). Since the abundance of these essential parasitic forms is extremely low within the human host, little is currently known about the molecular regulation of their sexual differentiation, highlighting the need to develop tools to investigate Pf gene expression during this fundamental mechanism. METHODS: We developed a high-throughput quantitative Reverse-Transcription PCR (RT-qPCR) platform to robustly monitor Pf transcriptional patterns, in particular, systematically profiling the transcriptional pattern of a large panel of gametocyte-related genes (GRG). Initially, we evaluated the technical performance of the systematic RT-qPCR platform to ensure it complies with the accepted quality standards for: (i) RNA extraction, (ii) cDNA synthesis and (iii) evaluation of gene expression through RT-qPCR. We then used this approach to monitor alterations in gene expression of a panel of GRG upon treatment with gametocytogenesis regulators. RESULTS: We thoroughly elucidated GRG expression profiles under treatment with the antimalarial drug dihydroartemisinin (DHA) or the metabolite choline over the course of a Pf blood cycle (48 h). We demonstrate that both significantly alter the expression pattern of PfAP2-G, the gametocytogenesis master regulator. However, they also markedly modify the developmental rate of the parasites and thus might bias the mRNA expression. Additionally, we screened the effect of the metabolites lactate and kynurenic acid, abundant in severe malaria, as potential regulators of gametocytogenesis. CONCLUSIONS: Our data demonstrate that the high-throughput RT-qPCR method enables studying the immediate transcriptional response initiating gametocytogenesis of the parasites from a very low volume of malaria-infected RBC samples. The obtained data expand the current knowledge of the initial alterations in mRNA profiles of GRG upon treatment with reported regulators. In addition, using this method emphasizes that asexual parasite stage composition is a crucial element that must be considered when interpreting changes in GRG expression by RT-qPCR, specifically when screening for novel compounds that could regulate Pf sexual differentiation.


Asunto(s)
Genes Protozoarios , Plasmodium falciparum , Humanos , Antimaláricos/metabolismo , Malaria , Plasmodium falciparum/genética , Reproducción
10.
J Extracell Biol ; 2(10): e117, 2023 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-38939734

RESUMEN

Parasites are responsible for the most neglected tropical diseases, affecting over a billion people worldwide (WHO, 2015) and accounting for billions of cases a year and responsible for several millions of deaths. Research on extracellular vesicles (EVs) has increased in recent years and demonstrated that EVs shed by pathogenic parasites interact with host cells playing an important role in the parasite's survival, such as facilitation of infection, immunomodulation, parasite adaptation to the host environment and the transfer of drug resistance factors. Thus, EVs released by parasites mediate parasite-parasite and parasite-host intercellular communication. In addition, they are being explored as biomarkers of asymptomatic infections and disease prognosis after drug treatment. However, most current protocols used for the isolation, size determination, quantification and characterization of molecular cargo of EVs lack greater rigor, standardization, and adequate quality controls to certify the enrichment or purity of the ensuing bioproducts. We are now initiating major guidelines based on the evolution of collective knowledge in recent years. The main points covered in this position paper are methods for the isolation and molecular characterization of EVs obtained from parasite-infected cell cultures, experimental animals, and patients. The guideline also includes a discussion of suggested protocols and functional assays in host cells.

11.
ACS Nano ; 16(8): 12276-12289, 2022 08 23.
Artículo en Inglés | MEDLINE | ID: mdl-35921522

RESUMEN

The elucidation of viral-receptor interactions and an understanding of virus-spreading mechanisms are of great importance, particularly in the era of a pandemic. Indeed, advances in computational chemistry, synthetic biology, and protein engineering have allowed precise prediction and characterization of such interactions. Nevertheless, the hazards of the infectiousness of viruses, their rapid mutagenesis, and the need to study viral-receptor interactions in a complex in vivo setup call for further developments. Here, we show the development of biocompatible genetically engineered extracellular vesicles (EVs) that display the receptor binding domain (RBD) of SARS-CoV-2 on their surface as coronavirus mimetics (EVsRBD). Loading EVsRBD with iron oxide nanoparticles makes them MRI-visible and, thus, allows mapping of the binding of RBD to ACE2 receptors noninvasively in live subjects. Moreover, we show that EVsRBD can be modified to display mutants of the RBD of SARS-CoV-2, allowing rapid screening of currently raised or predicted variants of the virus. The proposed platform thus shows relevance and cruciality in the examination of quickly evolving pathogenic viruses in an adjustable, fast, and safe manner. Relying on MRI for visualization, the presented approach could be considered in the future to map ligand-receptor binding events in deep tissues, which are not accessible to luminescence-based imaging.


Asunto(s)
COVID-19 , Vesículas Extracelulares , Humanos , SARS-CoV-2/genética , Enzima Convertidora de Angiotensina 2 , Glicoproteína de la Espiga del Coronavirus/química , Peptidil-Dipeptidasa A/metabolismo , Sitios de Unión , Unión Proteica , Vesículas Extracelulares/metabolismo , Imagen por Resonancia Magnética
12.
Faraday Discuss ; 240(0): 127-141, 2022 11 08.
Artículo en Inglés | MEDLINE | ID: mdl-35938388

RESUMEN

Malaria is a potentially fatal infectious disease caused by the obligate intracellular parasite Plasmodium falciparum. The parasite infects human red blood cells (RBC) and derives nutrition by catabolism of hemoglobin. As amino acids are assimilated from the protein component, the toxic heme is released. Molecular heme is detoxified by rapid sequestration to physiologically insoluble hemozoin crystals within the parasite's digestive vacuole (DV). Common antimalarial drugs interfere with this crystallization process, leaving the parasites vulnerable to the by-product of their own metabolism. A fundamental debate with important implications on drug mechanism regards the chemical environment of crystallization in situ, whether aqueous or lipid. This issue had been addressed previously by cryogenic soft X-ray tomography. We employ cryo-scanning transmission electron tomography (CSTET) to probe parasite cells throughout the life cycle in a fully hydrated, vitrified state at higher resolution. During the acquisition of CSTET data, Bragg diffraction from the hemozoin provides a uniquely clear view of the crystal boundary at nanometer resolution. No intermediate medium, such as a lipid coating or shroud, could be detected surrounding the crystals. The present study describes a unique application of CSTET in the study of malaria. The findings can be extended to evaluate new drug candidates affecting hemozoin crystal growth.


Asunto(s)
Tomografía con Microscopio Electrónico , Malaria , Humanos , Hemo/química , Hemo/metabolismo , Malaria/parasitología , Lípidos/química
13.
Methods Mol Biol ; 2470: 133-145, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35881344

RESUMEN

Malaria is one the most devastating infectious diseases in the world: of the five malaria-associated parasites, Plasmodium falciparum and P. vivax are the most pathogenic and widespread, respectively. P. falciparum invades human red blood cells (RBCs), releasing extracellular vesicles (Pf-EV) carrying DNA, RNA and protein cargo components involved in host-pathogen communications in the course of the disease. Different strategies have been used to analyze Pf-EV biophysically and chemically. Atomic force microscopy (AFM) stands out as a powerful tool for rendering high quality images of extracellular vesicles. In this technique, a sharp tip attached to a cantilever reconstructs the topographic surface of the extracellular vesicles and probes their nano-mechanical properties based on force-distance curves. Here, we describe a method to separate Pf-EV using differential ultracentrifugation, followed by nanoparticle tracking analysis (NTA) to quantify and estimate the size distribution. Finally, the AFM imaging procedure on Pf-EV adsorbed on a Mg2+-modified mica surface is detailed.


Asunto(s)
Vesículas Extracelulares , Malaria Falciparum , Malaria , Eritrocitos/metabolismo , Vesículas Extracelulares/metabolismo , Humanos , Malaria/parasitología , Malaria Falciparum/parasitología , Microscopía de Fuerza Atómica , Plasmodium falciparum , Plasmodium vivax
14.
EMBO Rep ; 23(7): e54755, 2022 07 05.
Artículo en Inglés | MEDLINE | ID: mdl-35642585

RESUMEN

Malaria is the most serious mosquito-borne parasitic disease, caused mainly by the intracellular parasite Plasmodium falciparum. The parasite invades human red blood cells and releases extracellular vesicles (EVs) to alter its host responses. It becomes clear that EVs are generally composed of sub-populations. Seeking to identify EV subpopulations, we subject malaria-derived EVs to size-separation analysis, using asymmetric flow field-flow fractionation. Multi-technique analysis reveals surprising characteristics: we identify two distinct EV subpopulations differing in size and protein content. Small EVs are enriched in complement-system proteins and large EVs in proteasome subunits. We then measure the membrane fusion abilities of each subpopulation with three types of host cellular membranes: plasma, late and early endosome. Remarkably, small EVs fuse to early endosome liposomes at significantly greater levels than large EVs. Atomic force microscope imaging combined with machine-learning methods further emphasizes the difference in biophysical properties between the two subpopulations. These results shed light on the sophisticated mechanism by which malaria parasites utilize EV subpopulations as a communication tool to target different cellular destinations or host systems.


Asunto(s)
Vesículas Extracelulares , Malaria , Parásitos , Animales , Eritrocitos/parasitología , Vesículas Extracelulares/metabolismo , Humanos , Plasmodium falciparum
15.
PNAS Nexus ; 1(4): pgac156, 2022 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-36714848

RESUMEN

Extracellular vesicles (EVs) transfer bioactive molecules between cells in a process reminiscent of enveloped viruses. EV cargo delivery is thought to occur by protein-mediated and pH-dependent membrane fusion of the EV and the cellular membrane. However, there is a lack of methods to identify the fusion proteins and resolve their mechanism. We developed and benchmarked an in vitro biophysical assay to investigate EV membrane fusion. The assay was standardized by directly comparing EV and viral fusion with liposomes. We show that EVs and retroviruses fuse with liposomes mimicking the membrane composition of the late endosome in a pH- and protein-dependent manner. Moreover, we directly visualize the stages of membrane fusion using cryo-electron tomography. We find that, unlike most retroviruses, EVs remain fusogenic after acidification and reneutralization. These results provide novel insights into the EV cargo delivery mechanism and an experimental approach to identify the EV fusion machinery.

16.
J Extracell Biol ; 1(2): e33, 2022 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-38938665

RESUMEN

Glycoconjugates on extracellular vesicles (EVs) play a vital role in internalization and mediate interaction as well as regulation of the host immune system by viruses, bacteria, and parasites. During their intraerythrocytic life-cycle stages, malaria parasites, Plasmodium falciparum (Pf) mediate the secretion of EVs by infected red blood cells (RBCs) that carry a diverse range of parasitic and host-derived molecules. These molecules facilitate parasite-parasite and parasite-host interactions to ensure parasite survival. To date, the number of identified Pf genes associated with glycan synthesis and the repertoire of expressed glycoconjugates is relatively low. Moreover, the role of Pf glycans in pathogenesis is mostly unclear and poorly understood. As a result, the expression of glycoconjugates on Pf-derived EVs or their involvement in the parasite life-cycle has yet to be reported. Herein, we show that EVs secreted by Pf-infected RBCs carry significantly higher sialylated complex N-glycans than EVs derived from healthy RBCs. Furthermore, we reveal that EV uptake by host monocytes depends on N-glycoproteins and demonstrate that terminal sialic acid on the N-glycans is essential for uptake by human monocytes. Our results provide the first evidence that Pf exploits host sialylated N-glycans to mediate EV uptake by the human immune system cells.

17.
Cell Death Dis ; 12(11): 1059, 2021 11 08.
Artículo en Inglés | MEDLINE | ID: mdl-34750357

RESUMEN

Necroptosis is a regulated and inflammatory form of cell death. We, and others, have previously reported that necroptotic cells release extracellular vesicles (EVs). We have found that necroptotic EVs are loaded with proteins, including the phosphorylated form of the key necroptosis-executing factor, mixed lineage kinase domain-like kinase (MLKL). However, neither the exact protein composition, nor the impact, of necroptotic EVs have been delineated. To characterize their content, EVs from necroptotic and untreated U937 cells were isolated and analyzed by mass spectrometry-based proteomics. A total of 3337 proteins were identified, sharing a high degree of similarity with exosome proteome databases, and clearly distinguishing necroptotic and control EVs. A total of 352 proteins were significantly upregulated in the necroptotic EVs. Among these were MLKL and caspase-8, as validated by immunoblot. Components of the ESCRTIII machinery and inflammatory signaling were also upregulated in the necroptotic EVs, as well as currently unreported components of vesicle formation and transport, and necroptotic signaling pathways. Moreover, we found that necroptotic EVs can be phagocytosed by macrophages to modulate cytokine and chemokine secretion. Finally, we uncovered that necroptotic EVs contain tumor neoantigens, and are enriched with components of antigen processing and presentation. In summary, our study reveals a new layer of regulation during the early stage of necroptosis, mediated by the secretion of specific EVs that influences the microenvironment and may instigate innate and adaptive immune responses. This study sheds light on new potential players in necroptotic signaling and its related EVs, and uncovers the functional tasks accomplished by the cargo of these necroptotic EVs.


Asunto(s)
Muerte Celular/inmunología , Vesículas Extracelulares/metabolismo , Inmunidad/inmunología , Necroptosis/inmunología , Proteómica/métodos , Humanos
18.
Beilstein J Nanotechnol ; 12: 878-901, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34476169

RESUMEN

Progress in computing capabilities has enhanced science in many ways. In recent years, various branches of machine learning have been the key facilitators in forging new paths, ranging from categorizing big data to instrumental control, from materials design through image analysis. Deep learning has the ability to identify abstract characteristics embedded within a data set, subsequently using that association to categorize, identify, and isolate subsets of the data. Scanning probe microscopy measures multimodal surface properties, combining morphology with electronic, mechanical, and other characteristics. In this review, we focus on a subset of deep learning algorithms, that is, convolutional neural networks, and how it is transforming the acquisition and analysis of scanning probe data.

19.
Nat Commun ; 12(1): 4851, 2021 08 11.
Artículo en Inglés | MEDLINE | ID: mdl-34381047

RESUMEN

Pathogens are thought to use host molecular cues to control when to initiate life-cycle transitions, but these signals are mostly unknown, particularly for the parasitic disease malaria caused by Plasmodium falciparum. The chemokine CXCL10 is present at high levels in fatal cases of cerebral malaria patients, but is reduced in patients who survive and do not have complications. Here we show a Pf 'decision-sensing-system' controlled by CXCL10 concentration. High CXCL10 expression prompts P. falciparum to initiate a survival strategy via growth acceleration. Remarkably, P. falciparum inhibits CXCL10 synthesis in monocytes by disrupting the association of host ribosomes with CXCL10 transcripts. The underlying inhibition cascade involves RNA cargo delivery into monocytes that triggers RIG-I, which leads to HUR1 binding to an AU-rich domain of the CXCL10 3'UTR. These data indicate that when the parasite can no longer keep CXCL10 at low levels, it can exploit the chemokine as a cue to shift tactics and escape.


Asunto(s)
Quimiocina CXCL10/metabolismo , Malaria Falciparum/parasitología , Plasmodium falciparum/fisiología , Regiones no Traducidas 3' , Quimiocina CXCL10/genética , Proteína 58 DEAD Box/metabolismo , Proteína 1 Similar a ELAV/metabolismo , Vesículas Extracelulares/metabolismo , Interacciones Huésped-Parásitos , Humanos , Estadios del Ciclo de Vida , Malaria Falciparum/inmunología , Monocitos/metabolismo , Plasmodium falciparum/crecimiento & desarrollo , Plasmodium falciparum/metabolismo , Biosíntesis de Proteínas , ARN Protozoario/metabolismo , Receptores Inmunológicos/metabolismo , Ribosomas/metabolismo , Células THP-1
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA
...