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ELife Nov 2023Apicomplexan parasites use Ca-regulated exocytosis to secrete essential virulence factors from specialized organelles called micronemes. Ca-dependent protein kinases...
Apicomplexan parasites use Ca-regulated exocytosis to secrete essential virulence factors from specialized organelles called micronemes. Ca-dependent protein kinases (CDPKs) are required for microneme exocytosis; however, the molecular events that regulate trafficking and fusion of micronemes with the plasma membrane remain unresolved. Here, we combine sub-minute resolution phosphoproteomics and bio-orthogonal labeling of kinase substrates in to identify 163 proteins phosphorylated in a CDPK1-dependent manner. In addition to known regulators of secretion, we identify uncharacterized targets with predicted functions across signaling, gene expression, trafficking, metabolism, and ion homeostasis. One of the CDPK1 targets is a putative HOOK activating adaptor. In other eukaryotes, HOOK homologs form the FHF complex with FTS and FHIP to activate dynein-mediated trafficking of endosomes along microtubules. We show the FHF complex is partially conserved in , consisting of HOOK, an FTS homolog, and two parasite-specific proteins (TGGT1_306920 and TGGT1_316650). CDPK1 kinase activity and HOOK are required for the rapid apical trafficking of micronemes as parasites initiate motility. Moreover, parasites lacking HOOK or FTS display impaired microneme protein secretion, leading to a block in the invasion of host cells. Taken together, our work provides a comprehensive catalog of CDPK1 targets and reveals how vesicular trafficking has been tuned to support a parasitic lifestyle.
Topics: Animals; Toxoplasma; Microneme; Parasites; Organelles; Endosomes; Exocytosis; Protozoan Proteins
PubMed: 37933960
DOI: 10.7554/eLife.85654 -
Evolution; International Journal of... Jul 2023Multiparasite communities inhabiting individual hosts are common and often consist of parasites from multiple taxa. The effects of parasite community composition and...
Multiparasite communities inhabiting individual hosts are common and often consist of parasites from multiple taxa. The effects of parasite community composition and complexity on host fitness are critical for understanding how host-parasite coevolution is affected by parasite diversity. To test how naturally occurring parasites affect host fitness of multiple host genotypes, we performed a common-garden experiment where we inoculated four genotypes of host plant Plantago lanceolata with six microbial parasite treatments: three single-parasite treatments, a fungal mixture, a viral mixture, and a cross-kingdom treatment. Seed production was affected by both host genotype and parasite treatment, and their interaction jointly determined the growth of the hosts. Fungal parasites had more consistent negative effects than viruses in both single- and mixed-parasite treatments. These results demonstrate that parasite communities have the potential to affect the evolution and ecology of host populations through their effects on host growth and reproduction. Moreover, the results highlight the importance of accounting for the diversity of parasites as well as host genotypes when aiming to predict the consequences of parasites for epidemics as the effects of multiparasitism are not necessarily additive of single-parasite effects, nor uniform across all host genotypes.
Topics: Animals; Parasites; Host-Parasite Interactions; Reproduction; Symbiosis; Genotype
PubMed: 37195704
DOI: 10.1093/evolut/qpad090 -
ELife Sep 2023Reverse genetics is key to understanding protein function, but the mechanistic connection between a gene of interest and the observed phenotype is not always clear. Here...
Reverse genetics is key to understanding protein function, but the mechanistic connection between a gene of interest and the observed phenotype is not always clear. Here we describe the use of proximity labeling using TurboID and site-specific quantification of biotinylated peptides to measure changes to the local protein environment of selected targets upon perturbation. We apply this technique, which we call PerTurboID, to understand how the -exported kinase, FIKK4.1, regulates the function of the major virulence factor of the malaria-causing parasite, PfEMP1. We generated independent TurboID fusions of two proteins that are predicted substrates of FIKK4.1 in a FIKK4.1 conditional KO parasite line. Comparing the abundance of site-specific biotinylated peptides between wildtype and kinase deletion lines reveals the differential accessibility of proteins to biotinylation, indicating changes to localization, protein-protein interactions, or protein structure which are mediated by FIKK4.1 activity. We further show that FIKK4.1 is likely the only FIKK kinase that controls surface levels of PfEMP1, but not other surface antigens, on the infected red blood cell under standard culture conditions. We believe PerTurboID is broadly applicable to study the impact of genetic or environmental perturbation on a selected cellular niche.
Topics: Animals; Humans; Parasites; Protozoan Proteins; Plasmodium falciparum; Phosphotransferases; Erythrocytes; Peptides; Malaria; Malaria, Falciparum
PubMed: 37737226
DOI: 10.7554/eLife.86367 -
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 -
Frontiers in Cellular and Infection... 2023The protozoan parasite is an economically important parasite for the aquaculture- and ornamental fish industry. The parasite is abundant worldwide and infects the skin,...
The protozoan parasite is an economically important parasite for the aquaculture- and ornamental fish industry. The parasite is abundant worldwide and infects the skin, gills and fins of freshwater fish species. For approximately the last fifty years the innate and protective immune mechanisms induced by have been in focus in different fish hosts. By utilizing transgenic zebrafish, new tools to investigate this have emerged. The aim of this study was therefore to elucidate early immune responses in zebrafish larvae by using gene expression and imaging of neutrophil and macrophage behavior during infection. For the first time, zebrafish larvae were infected with the parasite and infection dynamics, parasite size and host-parasite interactions were investigated. Results showed that the larvae responded with mild inflammation and that the 12 compared to 5 days post fertilization larvae were significantly less susceptible. It was furthermore observed that neutrophils and macrophages were attracted to the parasites and that neutrophils reacted with neutrophil extracellular traps (NETs) when fighting the parasite. The parasite was rotating vigorously, presumably to impede the neutrophils and macrophages from attaching to it but on rare occasions, neutrophils and macrophages were able to kill the parasite. Based on these observations, we concluded that the parasite uses the rotation as an immune evasive strategy and that the zebrafish larvae respond with high activity from neutrophils and macrophages locally but systemically only with mild inflammation.
Topics: Animals; Zebrafish; Parasites; Ciliophora Infections; Immunity, Innate; Neutrophils; Larva; Inflammation; Fish Diseases
PubMed: 37475962
DOI: 10.3389/fcimb.2023.1190931 -
The Journal of Animal Ecology Nov 2023Diet composition modulates animals' ability to resist parasites and recover from stress. Broader diet breadths enable omnivores to mount dynamic responses to parasite...
Diet composition modulates animals' ability to resist parasites and recover from stress. Broader diet breadths enable omnivores to mount dynamic responses to parasite attack, but little is known about how plant/prey mixing might influence responses to infection. Using omnivorous deer mice (Peromyscus maniculatus) as a model, we examine how varying plant and prey concentrations in blended diets influence resistance and body condition following infestation by Rocky Mountain wood ticks (Dermacentor andersoni). In two repeated experiments, deer mice fed for 4 weeks on controlled diets that varied in proportions of seeds and insects were then challenged with 50 tick larvae in two sequential infestations. The numbers of ticks successfully feeding on mice declined by 25% and 66% after the first infestation (in the first and second experiments, respectively), reflecting a pattern of acquired resistance, and resistance was strongest when plant/prey ratios were more equally balanced in mouse diets, relative to seed-dominated diets. Diet also dramatically impacted the capacity of mice to cope with tick infestations. Mice fed insect-rich diets lost 15% of their body weight when parasitized by ticks, while mice fed seed-rich diets lost no weight at all. While mounting/maintaining an immune response may be energetically demanding, mice may compensate for parasitism with fat and carbohydrate-rich diets. Altogether, these results suggest that a diverse nutritional landscape may be key in enabling omnivores' resistance and resilience to infection and immune stressors in their environments.
Topics: Animals; Parasites; Peromyscus; Larva; Tick Infestations; Diet; Rodent Diseases
PubMed: 37732627
DOI: 10.1111/1365-2656.14004 -
Parasitology Research Nov 2023In the present study, we investigated the effect of habitat heterogeneity, elevation gradient, and phylogenetic distance of host species on the abundance and richness of...
In the present study, we investigated the effect of habitat heterogeneity, elevation gradient, and phylogenetic distance of host species on the abundance and richness of anuran endoparasites, assuming that parasites follow the distribution of their hosts independently of environmental variation. We collected 192 anurans distributed in three altitude ranges: 100-200 m, 400-500 m, and 700-800 m. We performed discriminant principal component analysis to analyze the interrelationships between environmental heterogeneity and the distribution of parasite and host species in the formation of species groups in each altitude range. We estimated the niche width and parasite overlap, using host species as a variable, and assessed whether parasite abundance is more influenced by historical (distance host phylogeny) or ecological effects in each altitude category and overall. Finally, we use network analyses to understand how interactions between parasites and hosts are formed along the altitude gradient. We found 22 parasite species, and the overall prevalence of infection was 74%. In our study, we did not identify environmental (altitude gradients and heterogeneity) or phylogenetic effects acting on the parasite species diversity. Overall, our results suggest that the parasites are distributed following the dispersal of their hosts and are dispersed among most anuran species.
Topics: Animals; Host-Parasite Interactions; Brazil; Phylogeny; Helminths; Altitude; Parasites; Anura; Forests
PubMed: 37707610
DOI: 10.1007/s00436-023-07965-6 -
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 -
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