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Nature Communications Nov 2023Trypanosomes are protozoan parasites that cycle between insect and mammalian hosts and are the causative agent of sleeping sickness. Here, we describe the changes of...
Trypanosomes are protozoan parasites that cycle between insect and mammalian hosts and are the causative agent of sleeping sickness. Here, we describe the changes of pseudouridine (Ψ) modification on rRNA in the two life stages of the parasite using four different genome-wide approaches. CRISPR-Cas9 knock-outs of all four snoRNAs guiding Ψ on helix 69 (H69) of the large rRNA subunit were lethal. A single knock-out of a snoRNA guiding Ψ530 on H69 altered the composition of the 80S monosome. These changes specifically affected the translation of only a subset of proteins. This study correlates a single site Ψ modification with changes in ribosomal protein stoichiometry, supported by a high-resolution cryo-EM structure. We propose that alteration in rRNA modifications could generate ribosomes preferentially translating state-beneficial proteins.
Topics: Animals; Parasites; Trypanosoma brucei brucei; Pseudouridine; RNA, Ribosomal; Ribosomes; RNA, Small Nucleolar; Mammals
PubMed: 37985661
DOI: 10.1038/s41467-023-43263-6 -
PLoS Pathogens Jul 2023Apicomplexans are widespread parasites of humans and other animals, and include the causative agents of malaria (Plasmodium species) and toxoplasmosis (Toxoplasma...
Apicomplexans are widespread parasites of humans and other animals, and include the causative agents of malaria (Plasmodium species) and toxoplasmosis (Toxoplasma gondii). Existing anti-apicomplexan therapies are beset with issues around drug resistance and toxicity, and new treatment options are needed. The mitochondrial electron transport chain (ETC) is one of the few processes that has been validated as a drug target in apicomplexans. To identify new inhibitors of the apicomplexan ETC, we developed a Seahorse XFe96 flux analyzer approach to screen the 400 compounds contained within the Medicines for Malaria Venture 'Pathogen Box' for ETC inhibition. We identified six chemically diverse, on-target inhibitors of the ETC in T. gondii, at least four of which also target the ETC of Plasmodium falciparum. Two of the identified compounds (MMV024937 and MMV688853) represent novel ETC inhibitor chemotypes. MMV688853 belongs to a compound class, the aminopyrazole carboxamides, that were shown previously to target a kinase with a key role in parasite invasion of host cells. Our data therefore reveal that MMV688853 has dual targets in apicomplexans. We further developed our approach to pinpoint the molecular targets of these inhibitors, demonstrating that all target Complex III of the ETC, with MMV688853 targeting the ubiquinone reduction (Qi) site of the complex. Most of the compounds we identified remain effective inhibitors of parasites that are resistant to Complex III inhibitors that are in clinical use or development, indicating that they could be used in treating drug resistant parasites. In sum, we have developed a versatile, scalable approach to screen for compounds that target the ETC in apicomplexan parasites, and used this to identify and characterize novel inhibitors.
Topics: Animals; Humans; Parasites; Electron Transport; Electron Transport Complex III; Toxoplasmosis; Toxoplasma; Plasmodium falciparum
PubMed: 37471441
DOI: 10.1371/journal.ppat.1011517 -
Nature Communications Nov 2023Transmission of Trypanosoma brucei by tsetse flies involves the deposition of the cell cycle-arrested metacyclic life cycle stage into mammalian skin at the site of the...
Transmission of Trypanosoma brucei by tsetse flies involves the deposition of the cell cycle-arrested metacyclic life cycle stage into mammalian skin at the site of the fly's bite. We introduce an advanced human skin equivalent and use tsetse flies to naturally infect the skin with trypanosomes. We detail the chronological order of the parasites' development in the skin by single-cell RNA sequencing and find a rapid activation of metacyclic trypanosomes and differentiation to proliferative parasites. Here we show that after the establishment of a proliferative population, the parasites enter a reversible quiescent state characterized by slow replication and a strongly reduced metabolism. We term these quiescent trypanosomes skin tissue forms, a parasite population that may play an important role in maintaining the infection over long time periods and in asymptomatic infected individuals.
Topics: Animals; Humans; Trypanosoma brucei brucei; Parasites; Skin; Trypanosoma; Tsetse Flies; Mammals
PubMed: 37996412
DOI: 10.1038/s41467-023-43437-2 -
Parasitology Dec 2023Avian haemosporidians are protozoan parasites transmitted by insect vectors that infect birds worldwide, negatively impacting avian fitness and survival. However, the...
Avian haemosporidians are protozoan parasites transmitted by insect vectors that infect birds worldwide, negatively impacting avian fitness and survival. However, the majority of haemosporidian diversity remains undescribed. Quantifying this diversity is critical to determining parasite–host relationships and host-switching potentials of parasite lineages as climate change induces both host and vector range shifts. In this study, we conducted a community survey of avian haemosporidians found in breeding birds on the Davis Mountains sky islands in west Texas, USA. We determined parasite abundance and host associations and compared our results to data from nearby regions. A total of 265 birds were screened and infections were detected in 108 birds (40.8%). Most positive infections were identified as (36.2%), followed by (6.8%) and (0.8%). A total of 71 haemosporidian lineages were detected of which 39 were previously undescribed. We found that regional similarity influenced shared lineages, as a higher number of lineages were shared with avian communities in the sky islands of New Mexico compared to south Texas, the Texas Gulf Coast and central Mexico. We found that migratory status of avian host did not influence parasite prevalence, but that host phylogeny is likely an important driver.
Topics: Animals; Texas; Haemosporida; Plasmodium; Parasites; Birds; Phylogeny; Prevalence; Bird Diseases; Protozoan Infections, Animal
PubMed: 38072659
DOI: 10.1017/S0031182023001087 -
Parasitology Research Dec 2023Apoptosis is a finely programmed process of cell death in which cells silently dismantle and actively participate in several operations such as immune response,... (Review)
Review
Apoptosis is a finely programmed process of cell death in which cells silently dismantle and actively participate in several operations such as immune response, differentiation, and cell growth. It can be initiated by three main pathways: the extrinsic, the perforin granzyme, and the intrinsic that culminate in the activation of several proteins in charge of tearing down the cell. On the other hand, apoptosis represents an ordeal for pathogens that live inside cells and maintain a strong dependency with them; thus, they have evolved multiple strategies to manipulate host cell apoptosis on their behalf. It has been widely documented that diverse intracellular bacteria, fungi, and parasites can interfere with most steps of the host cell apoptotic machinery to inhibit or induce apoptosis. Indeed, the inhibition of apoptosis is considered a virulence property shared by many intracellular pathogens to ensure productive replication. Some pathogens intervene at an early stage by interfering with the sensing of extracellular signals or transduction pathways. Others sense cellular stress or target the apoptosis regulator proteins of the Bcl-2 family or caspases. In many cases, the exact molecular mechanisms leading to the interference with the host cell apoptotic cascade are still unknown. However, intense research has been conducted to elucidate the strategies employed by intracellular pathogens to modulate host cell death. In this review, we summarize the main routes of activation of apoptosis and present several processes used by different bacteria, fungi, and parasites to modulate the apoptosis of their host cells.
Topics: Animals; Apoptosis; Caspases; Cell Death; Parasites; Fungi
PubMed: 38112844
DOI: 10.1007/s00436-023-08031-x -
Scientific Reports Sep 2023Intestinal parasitic infections (IPIs) caused by protozoan and helminth parasites are among the most common infections in humans in low-and-middle-income countries. IPIs...
Intestinal parasitic infections (IPIs) caused by protozoan and helminth parasites are among the most common infections in humans in low-and-middle-income countries. IPIs affect not only the health status of a country, but also the economic sector. Over the last decade, pattern recognition and image processing techniques have been developed to automatically identify parasitic eggs in microscopic images. Existing identification techniques are still suffering from diagnosis errors and low sensitivity. Therefore, more accurate and faster solution is still required to recognize parasitic eggs and classify them into several categories. A novel Chula-ParasiteEgg dataset including 11,000 microscopic images proposed in ICIP2022 was utilized to train various methods such as convolutional neural network (CNN) based models and convolution and attention (CoAtNet) based models. The experiments conducted show high recognition performance of the proposed CoAtNet that was tuned with microscopic images of parasitic eggs. The CoAtNet produced an average accuracy of 93%, and an average F1 score of 93%. The finding opens door to integrate the proposed solution in automated parasitological diagnosis.
Topics: Parasites; Datasets as Topic; Neural Networks, Computer; Ovum; Microscopy; Humans; Intestinal Diseases, Parasitic; Animals
PubMed: 37660120
DOI: 10.1038/s41598-023-41711-3 -
Nature Communications Feb 2024A novel cellular response of midgut progenitors (stem cells and enteroblasts) to Plasmodium berghei infection was investigated in Anopheles stephensi. The presence of...
A novel cellular response of midgut progenitors (stem cells and enteroblasts) to Plasmodium berghei infection was investigated in Anopheles stephensi. The presence of developing oocysts triggers proliferation of midgut progenitors that is modulated by the Jak/STAT pathway and is proportional to the number of oocysts on individual midguts. The percentage of parasites in direct contact with enteroblasts increases over time, as progenitors proliferate. Silencing components of key signaling pathways through RNA interference (RNAi) that enhance proliferation of progenitor cells significantly decreased oocyst numbers, while limiting proliferation of progenitors increased oocyst survival. Live imaging revealed that enteroblasts interact directly with oocysts and eliminate them. Midgut progenitors sense the presence of Plasmodium oocysts and mount a cellular defense response that involves extensive proliferation and tissue remodeling, followed by oocysts lysis and phagocytosis of parasite remnants by enteroblasts.
Topics: Animals; Parasites; Janus Kinases; STAT Transcription Factors; Signal Transduction; Plasmodium; Malaria; Anopheles; Oocysts; Stem Cells; Plasmodium berghei
PubMed: 38365823
DOI: 10.1038/s41467-024-45550-2 -
MSphere Dec 2023parasites cause malaria in humans. New multistage active antimalarial drugs are needed, and a promising class of drugs targets the core cellular process of translation,...
parasites cause malaria in humans. New multistage active antimalarial drugs are needed, and a promising class of drugs targets the core cellular process of translation, which has many potential molecular targets. During the obligate liver stage, parasites grow in metabolically active hepatocytes, making it challenging to study core cellular processes common to both host cells and parasites, as the signal from the host typically overwhelms that of the parasite. Here, we present and validate a flexible assay to quantify liver stage translation using a technique to fluorescently label the newly synthesized proteins of both host and parasite followed by computational separation of their respective nascent proteomes in confocal image sets. We use the assay to determine whether a test set of known compounds are direct or indirect liver stage translation inhibitors and show that the assay can also predict the mode of action for novel antimalarial compounds.
Topics: Animals; Humans; Plasmodium berghei; Liver; Hepatocytes; Malaria; Antimalarials; Parasites
PubMed: 37909773
DOI: 10.1128/msphere.00544-23 -
PLoS Neglected Tropical Diseases Jul 2023Although, approximately 30% of the world's population is estimated to be infected with Toxoplasma gondii (T. gondii) with serious manifestations in immunocompromised...
Zinc oxide nanoparticles produced by Zingiber officinale ameliorates acute toxoplasmosis-induced pathological and biochemical alterations and reduced parasite burden in mice model.
BACKGROUND
Although, approximately 30% of the world's population is estimated to be infected with Toxoplasma gondii (T. gondii) with serious manifestations in immunocompromised patients and pregnant females, the available treatment options for toxoplasmosis are limited with serious side effects. Therefore, it is of great importance to identify novel potent, well tolerated candidates for treatment of toxoplasmosis. The present study aimed to evaluate the effect of Zinc oxide nanoparticles (ZnO NPs) synthesized using Zingiber officinale against acute toxoplasmosis in experimentally infected mice.
METHODS
The ethanolic extract of ginger was used to prepare ZnO NPs. The produced ZnO NPs were characterized in terms of structure and morphology using Fourier Transformed Infrared Spectroscopy (FTIR), X-Ray Diffraction (XRD), UV- spectroscopy and scanning electron microscopy (SEM). The prepared formula was used in treatment of T. gondii RH virulent strain. Forty animals were divided into four groups, with ten mice per group. The first group was the uninfected, control group. The second group was infected but untreated. The third and the fourth groups received ZnO NPs and Spiramycin orally in a dose of 10 mg/kg and 200 mg/kg/day respectively. The effect of the used formulas on the animals survival rate, parasite burden, liver enzymes -including Alanine transaminase (ALT) and aspartate transaminase (AST)-, nitric oxide (NO) and Catalase antioxidant enzyme (CAT) activity was measured. Moreover, the effect of treatment on histopathological alterations associated with toxoplasmosis was examined.
RESULTS
Mice treated with ZnO NPs showed the longest survival time with significant reduction in the parasite load in the livers and peritoneal fluids of the same group. Moreover, ZnO NPs treatment was associated with a significant reduction in the level of liver enzymes (ALT, AST) and NO and a significant increase in the antioxidant activity of CAT enzyme. SEM examination of tachyzoites from the peritoneal fluid showed marked distortion of T. gondii tachyzoites isolated from mice treated with ZnO NPs in comparison to untreated group. T. gondii induced histopathological alterations in the liver and brain were reversed by ZnO NPs treatment with restoration of normal tissue morphology.
CONCLUSION
The produced formula showed a good therapeutic potential in treatment of murine toxoplasmosis as demonstrated by prolonged survival rate, reduced parasite burden, improved T. gondii associated liver injury and histopathological alterations. Thus, we assume that the protective effect observed in the current research is attributed to the antioxidant capability of NPs. Based on the results obtained from the current work, we suggest greenly produced ZnO NPs as a chemotherapeutic agent with good therapeutic potential and high levels of safety in the treatment of toxoplasmosis.
Topics: Female; Mice; Animals; Zingiber officinale; Zinc Oxide; Parasites; Antioxidants; Toxoplasmosis; Nanoparticles; Toxoplasma; Disease Models, Animal
PubMed: 37410712
DOI: 10.1371/journal.pntd.0011447 -
Parasites, Hosts and Diseases Nov 2023Paleoparasitology is a discipline that applies existing conventional and molecular techniques to study parasites found in ancient ruins. This review focuses on the... (Review)
Review
Paleoparasitology is a discipline that applies existing conventional and molecular techniques to study parasites found in ancient ruins. This review focuses on the history of the discovery of parasites (mostly helminth eggs and larvae) in archaeological soil samples and mummies in Korea from the Three Kingdoms Period to the Joseon Dynasty (100 BCE-1910 CE). We also briefly review important milestones in global paleoparasitology. The helminth species reported so far in Korea included Ascaris lumbricoides, Trichuris trichiura, Strongyloides stercoralis (larva), Trichostrongylus sp. (larva), Paracapillaria philippinensis (syn. Capillaria philippinensis), Enterobius vermicularis, Fasciola hepatica, dicrocoeliids, Paragonimus westermani, Clonorchis sinensis, Metagonimus yokogawai, Pygidiopsis summa, Gymnophalloides seoi, Isthmiophora hortensis, Dibothriocephalus nihonkaiensis (syn. Diphyllobothrium nihonkaiense), and Taenia spp. tapeworms. The findings obtained by Korean paleoparasitologists/archaeologists have brought about deep insight into the status of helminthic infections in Korea's past populations. Continued paleoparasitological research is essential for further understanding of ancient parasites and parasitic diseases in Korea.
Topics: Animals; Larva; Republic of Korea; Parasitic Diseases; Helminthiasis; Trematoda; Parasites; Heterophyidae
PubMed: 38043533
DOI: 10.3347/PHD.23085