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MBio Aug 2023Maturation rates of malaria parasites within red blood cells (RBCs) can be influenced by host nutrient status and circadian rhythm; whether host inflammatory responses...
Maturation rates of malaria parasites within red blood cells (RBCs) can be influenced by host nutrient status and circadian rhythm; whether host inflammatory responses can also influence maturation remains less clear. Here, we observed that systemic host inflammation induced in mice by an innate immune stimulus, lipopolysaccharide (LPS), or by ongoing acute infection, slowed the progression of a single cohort of parasites from one generation of RBC to the next. Importantly, plasma from LPS-conditioned or acutely infected mice directly inhibited parasite maturation during in vitro culture, which was not rescued by supplementation, suggesting the emergence of inhibitory factors in plasma. Metabolomic assessments confirmed substantial alterations to the plasma of LPS-conditioned and acutely infected mice, and identified a small number of candidate inhibitory metabolites. Finally, we confirmed rapid parasite responses to systemic host inflammation using parasite scRNA-seq, noting broad impairment in transcriptional activity and translational capacity specifically in trophozoites but not rings or schizonts. Thus, we provide evidence that systemic host inflammation rapidly triggered transcriptional alterations in circulating blood-stage Plasmodium trophozoites and predict candidate inhibitory metabolites in the plasma that may impair parasite maturation . IMPORTANCE Malaria parasites cyclically invade, multiply, and burst out of red blood cells. We found that a strong inflammatory response can cause changes to the composition of host plasma, which directly slows down parasite maturation. Thus, our work highlights a new mechanism that limits malaria parasite growth in the bloodstream.
Topics: Mice; Animals; Parasites; Transcriptome; Lipopolysaccharides; Malaria; Inflammation; Erythrocytes
PubMed: 37449844
DOI: 10.1128/mbio.01129-23 -
Frontiers in Cellular and Infection... 2023
Topics: Animals; Parasites; Eukaryota
PubMed: 37808909
DOI: 10.3389/fcimb.2023.1293959 -
MBio Aug 2023The protozoan pathogen relies on tight regulation of gene expression to invade and establish infection in its host. The divergent gene regulatory mechanisms of and...
The protozoan pathogen relies on tight regulation of gene expression to invade and establish infection in its host. The divergent gene regulatory mechanisms of and related apicomplexan pathogens rely heavily on regulators of chromatin structure and histone modifications. The important contribution of histone acetylation for in both acute and chronic infection has been demonstrated, where histone acetylation increases at active gene loci. However, the direct consequences of specific histone acetylation marks and the chromatin pathway that influences transcriptional regulation in response to the modification are unclear. As a reader of lysine acetylation, the bromodomain serves as a mediator between the acetylated histone and transcriptional regulators. Here we show that the bromodomain protein, TgBDP1, which is conserved among Apicomplexa and within the Alveolata superphylum, is essential for asexual proliferation. Using cleavage under targets and tagmentation, we demonstrate that TgBDP1 is recruited to transcriptional start sites of a large proportion of parasite genes. Transcriptional profiling during TgBDP1 knockdown revealed that loss of TgBDP1 leads to major dysregulation of gene expression, implying multiple roles for TgBDP1 in both gene activation and repression. This is supported by interactome analysis of TgBDP1 demonstrating that TgBDP1 forms a core complex with two other bromodomain proteins and an ApiAP2 factor. This core complex appears to interact with other epigenetic factors such as nucleosome remodeling complexes. We conclude that TgBDP1 interacts with diverse epigenetic regulators to exert opposing influences on gene expression in the tachyzoite. IMPORTANCE Histone acetylation is critical for proper regulation of gene expression in the single-celled eukaryotic pathogen . Bromodomain proteins are "readers" of histone acetylation and may link the modified chromatin to transcription factors. Here, we show that the bromodomain protein TgBDP1 is essential for parasite survival and that loss of TgBDP1 results in global dysregulation of gene expression. TgBDP1 is recruited to the promoter region of a large proportion of parasite genes, forms a core complex with two other bromodomain proteins, and interacts with different transcriptional regulatory complexes. We conclude that TgBDP1 is a key factor for sensing specific histone modifications to influence multiple facets of transcriptional regulation in .
Topics: Animals; Toxoplasma; Histones; Chromatin; Gene Expression Regulation; Parasites; Epigenesis, Genetic; Acetylation; Protozoan Proteins
PubMed: 37350586
DOI: 10.1128/mbio.03573-22 -
Frontiers in Immunology 2023Deubiquitinating enzymes (DUBs) are emerging as key factors for the infection of human cells by pathogens such as bacteria and parasites. In this review, we discuss the... (Review)
Review
Deubiquitinating enzymes (DUBs) are emerging as key factors for the infection of human cells by pathogens such as bacteria and parasites. In this review, we discuss the most recent studies on the role of deubiquitinase activity in exploiting and manipulating ubiquitin (Ub)-dependent host processes during infection. The studies discussed here highlight the importance of DUB host-pathogen research and underscore the therapeutic potential of inhibiting pathogen-specific DUB activity to prevent infectious diseases.
Topics: Animals; Humans; Parasites; Deubiquitinating Enzymes; Ubiquitin; Bacteria
PubMed: 38077335
DOI: 10.3389/fimmu.2023.1303072 -
Cellular and Molecular Life Sciences :... Nov 2023During macroautophagy, the Atg8 protein is conjugated to phosphatidylethanolamine (PE) in autophagic membranes. In Apicomplexan parasites, two cysteine proteases, Atg4...
During macroautophagy, the Atg8 protein is conjugated to phosphatidylethanolamine (PE) in autophagic membranes. In Apicomplexan parasites, two cysteine proteases, Atg4 and ovarian tumor unit (Otu), have been identified to delipidate Atg8 to release this protein from membranes. Here, we investigated the role of cysteine proteases in Atg8 conjugation and deconjugation and found that the Plasmodium parasite consists of both activities. We successfully disrupted the genes individually; however, simultaneously, they were refractory to deletion and essential for parasite survival. Mutants lacking Atg4 and Otu showed normal blood and mosquito stage development. All mice infected with Otu KO sporozoites became patent; however, Atg4 KO sporozoites either failed to establish blood infection or showed delayed patency. Through in vitro and in vivo analysis, we found that Atg4 KO sporozoites invade and normally develop into early liver stages. However, nuclear and organelle differentiation was severely hampered during late stages and failed to mature into hepatic merozoites. We found a higher level of Atg8 in Atg4 KO parasites, and the deconjugation of Atg8 was hampered. We confirmed Otu localization on the apicoplast; however, parasites lacking Otu showed no visible developmental defects. Our data suggest that Atg4 is the primary deconjugating enzyme and that Otu cannot replace its function completely because it cleaves the peptide bond at the N-terminal side of glycine, thereby irreversibly inactivating Atg8 during its recycling. These findings highlight a role for the Atg8 deconjugation pathway in organelle biogenesis and maintenance of the homeostatic cellular balance.
Topics: Animals; Mice; Cysteine Proteases; Parasites; Plasmodium berghei; Autophagy-Related Protein 8 Family; Autophagy; Malaria; Protozoan Proteins
PubMed: 37910326
DOI: 10.1007/s00018-023-05004-2 -
Frontiers in Immunology 2023The preventive situation of parasitosis, a global public health burden especially for developing countries, is not looking that good. Similar to other infections,... (Review)
Review
The preventive situation of parasitosis, a global public health burden especially for developing countries, is not looking that good. Similar to other infections, vaccines would be the best choice for preventing and controlling parasitic infection. However, ideal antigenic molecules for vaccine development have not been identified so far, resulting from the complicated life history and enormous genomes of the parasites. Furthermore, the suppression or down-regulation of anti-infectious immunity mediated by the parasites or their derived molecules can compromise the effect of parasitic vaccines. Comparing the early immune profiles of several parasites in the permissive and non-permissive hosts, a robust innate immune response is proposed to be a critical event to eliminate the parasites. Therefore, enhancing innate immunity may be essential for designing novel and effective parasitic vaccines. The newly emerging trained immunity (also termed innate immune memory) has been increasingly recognized to provide a novel perspective for vaccine development targeting innate immunity. This article reviews the current status of parasitic vaccines and anti-infectious immunity, as well as the conception, characteristics, and mechanisms of trained immunity and its research progress in Parasitology, highlighting the possible consideration of trained immunity in designing novel vaccines against parasitic diseases.
Topics: Animals; Trained Immunity; Vaccines; Parasitic Diseases; Immunity, Innate; Parasites
PubMed: 37868995
DOI: 10.3389/fimmu.2023.1252554 -
PLoS Computational Biology Mar 2024Plasmodium vivax is one of the most geographically widespread malaria parasites in the world, primarily found across South-East Asia, Latin America, and parts of Africa.... (Review)
Review
Plasmodium vivax is one of the most geographically widespread malaria parasites in the world, primarily found across South-East Asia, Latin America, and parts of Africa. One of the significant characteristics of the P. vivax parasite is its ability to remain dormant in the human liver as hypnozoites and subsequently reactivate after the initial infection (i.e. relapse infections). Mathematical modelling approaches have been widely applied to understand P. vivax dynamics and predict the impact of intervention outcomes. Models that capture P. vivax dynamics differ from those that capture P. falciparum dynamics, as they must account for relapses caused by the activation of hypnozoites. In this article, we provide a scoping review of mathematical models that capture P. vivax transmission dynamics published between January 1988 and May 2023. The primary objective of this work is to provide a comprehensive summary of the mathematical models and techniques used to model P. vivax dynamics. In doing so, we aim to assist researchers working on mathematical epidemiology, disease transmission, and other aspects of P. vivax malaria by highlighting best practices in currently published models and highlighting where further model development is required. We categorise P. vivax models according to whether a deterministic or agent-based approach was used. We provide an overview of the different strategies used to incorporate the parasite's biology, use of multiple scales (within-host and population-level), superinfection, immunity, and treatment interventions. In most of the published literature, the rationale for different modelling approaches was driven by the research question at hand. Some models focus on the parasites' complicated biology, while others incorporate simplified assumptions to avoid model complexity. Overall, the existing literature on mathematical models for P. vivax encompasses various aspects of the parasite's dynamics. We recommend that future research should focus on refining how key aspects of P. vivax dynamics are modelled, including spatial heterogeneity in exposure risk and heterogeneity in susceptibility to infection, the accumulation of hypnozoite variation, the interaction between P. falciparum and P. vivax, acquisition of immunity, and recovery under superinfection.
Topics: Animals; Humans; Plasmodium vivax; Superinfection; Malaria, Vivax; Malaria; Models, Theoretical; Malaria, Falciparum; Parasites; Recurrence
PubMed: 38483975
DOI: 10.1371/journal.pcbi.1011931 -
Genome Biology and Evolution Sep 2023The Transforming Growth Factor-β mimic (TGM) multigene family was recently discovered in the murine intestinal parasite Heligmosomoides polygyrus. This family was... (Review)
Review
The Transforming Growth Factor-β mimic (TGM) multigene family was recently discovered in the murine intestinal parasite Heligmosomoides polygyrus. This family was shaped by an atypical set of organismal and molecular evolutionary mechanisms along its path through the adaptive landscape. The relevant mechanisms are mimicry, convergence, exon modularity, new gene origination, and gene family neofunctionalization. We begin this review with a description of the TGM family and then address two evolutionary questions: "Why were TGM proteins needed for parasite survival" and "when did the TGM family originate"? For the former, we provide a likely answer, and for the latter, we identify multiple TGM building blocks in the ruminant intestinal parasite Haemonchus contortus. We close by identifying avenues for future investigation: new biochemical data to assign functions to more family members as well as new sequenced genomes in the Trichostrongyloidea superfamily and the Heligmosomoides genus to clarify TGM origins and expansion. Continued study of TGM proteins will generate increased knowledge of Transforming Growth Factor-β signaling, host-parasite interactions, and metazoan evolutionary mechanisms.
Topics: Animals; Mice; Parasites; Host-Parasite Interactions; Haemonchus; Immunity; Transforming Growth Factors
PubMed: 37625791
DOI: 10.1093/gbe/evad158 -
Virulence Dec 2024Bacterial biofilms have attracted significant attention due to their involvement in persistent infections, food and water contamination, and infrastructure corrosion.... (Review)
Review
Bacterial biofilms have attracted significant attention due to their involvement in persistent infections, food and water contamination, and infrastructure corrosion. This review delves into the intricate interactions between bacterial biofilms and unicellular parasites, shedding light on their impact on biofilm formation, structure, and function. Unicellular parasites, including protozoa, influence bacterial biofilms through grazing activities, leading to adaptive changes in bacterial communities. Moreover, parasites like and can shape biofilm composition in a grazing independent manner, potentially influencing disease outcomes. Biofilms, acting as reservoirs, enable the survival of protozoan parasites against environmental stressors and antimicrobial agents. Furthermore, these biofilms may influence parasite virulence and stress responses, posing challenges in disease treatment. Interactions between unicellular parasites and fungal-containing biofilms is also discussed, hinting at complex microbial relationships in various ecosystems. Understanding these interactions offers insights into disease mechanisms and antibiotic resistance dissemination, paving the way for innovative therapeutic strategies and ecosystem-level implications.
Topics: Animals; Parasites; Ecosystem; Biofilms; Drug Resistance, Microbial; Anti-Infective Agents; Bacteria
PubMed: 38058008
DOI: 10.1080/21505594.2023.2289775 -
Parasitology Sep 2023Combining the biogeography and phylogenetic patterns of parasite-host associations allows a better understanding of the history of parasite–host interactions, which...
Combining the biogeography and phylogenetic patterns of parasite-host associations allows a better understanding of the history of parasite–host interactions, which can be achieved biogeographic regionalization incorporating phylogenetic information. Recently, the concepts of evoregions (regions where a majority of species evolved from one or several ancestors inhabiting these regions) and evolutionary transition zones (regions of high phylogenetic turnover) have been proposed, coupled with a classification approach for these concepts. We applied this approach to 206 flea species and 265 host species of the Palearctic and aimed to identify evoregions and evolutionary transition zones for both fleas and hosts and to understand whether these evoregions and transition zones match each other. We identified 5 evoregions with 3 transition zones for either fleas or hosts, but neither the positions and boundaries of the flea and host evoregions nor the transition zones coincided. Indications of multiple geographic centres of diversification of the same flea lineages suggested that (a) the common evolutionary history of fleas and hosts was characterized by multiple events other than codiversification and that (b) dispersal played an important role in flea and host assemblies. Barriers to dispersal could be represented by landscape features (deserts and mountain ranges) and/or climate differences.
Topics: Animals; Siphonaptera; Phylogeny; Flea Infestations; Mammals; Parasites; Host-Parasite Interactions
PubMed: 37705252
DOI: 10.1017/S0031182023000884