-
Frontiers in Immunology 2024Despite decades of effort, malaria remains a leading killer of children. The absence of a highly effective vaccine and the emergence of parasites resistant to both...
BACKGROUND
Despite decades of effort, malaria remains a leading killer of children. The absence of a highly effective vaccine and the emergence of parasites resistant to both diagnosis as well as treatment hamper effective public health interventions.
METHODS AND RESULTS
To discover new vaccine candidates, we used our whole proteome differential screening method and identified PfGBP130 as a parasite protein uniquely recognized by antibodies from children who had developed resistance to infection but not from those who remained susceptible. We formulated PfGBP130 as lipid encapsulated mRNA, DNA plasmid, and recombinant protein-based immunogens and evaluated the efficacy of murine polyclonal anti-PfGBP130 antisera to inhibit parasite growth in vitro. Immunization of mice with PfGBP130-A (aa 111-374), the region identified in our differential screen, formulated as a DNA plasmid or lipid encapsulated mRNA, but not as a recombinant protein, induced antibodies that inhibited RBC invasion . mRNA encoding the full ectodomain of PfGBP130 (aa 89-824) also generated parasite growth-inhibitory antibodies.
CONCLUSION
We are currently advancing PfGBP130-A formulated as a lipid-encapsulated mRNA for efficacy evaluation in non-human primates.
Topics: Animals; Plasmodium falciparum; Antibodies, Protozoan; Mice; Erythrocytes; Malaria, Falciparum; Humans; Malaria Vaccines; Protozoan Proteins; Antigens, Protozoan; Immunization; Female
PubMed: 38863702
DOI: 10.3389/fimmu.2024.1350560 -
Open Biology Jun 2024species encode a unique set of six modular proteins named LCCL lectin domain adhesive-like proteins (LAPs) that operate as a complex and that are essential for malaria...
species encode a unique set of six modular proteins named LCCL lectin domain adhesive-like proteins (LAPs) that operate as a complex and that are essential for malaria parasite transmission from mosquito to vertebrate. LAPs possess complex architectures obtained through unique assemblies of conserved domains associated with lipid, protein and carbohydrate interactions, including the name-defining LCCL domain. Here, we assessed the prevalence of LAP orthologues across eukaryotic life. Our findings show orthologous conservation in all apicomplexans, with lineage-specific repertoires acquired through differential gene loss and duplication. Besides Apicomplexa, LAPs are found in their closest relatives: the photosynthetic chromerids, which encode the broadest repertoire including a novel membrane-bound LCCL protein. LAPs are notably absent from other alveolate lineages (dinoflagellates, perkinsids and ciliates), but are encoded by predatory colponemids, a sister group to the alveolates. These results reveal that the LAPs are much older than previously thought and pre-date not only the Apicomplexa but the Alveolata altogether.
Topics: Protozoan Proteins; Phylogeny; Evolution, Molecular; Plasmodium; Alveolata; Protein Domains; Apicomplexa; Lectins
PubMed: 38862023
DOI: 10.1098/rsob.230451 -
Immunobiology Jul 2024Acute lung injury caused by severe malaria (SM) is triggered by a dysregulated immune response towards the infection with Plasmodium parasites. Postmortem analysis of...
Acute lung injury caused by severe malaria (SM) is triggered by a dysregulated immune response towards the infection with Plasmodium parasites. Postmortem analysis of human lungs shows diffuse alveolar damage (DAD), the presence of CD8 lymphocytes, neutrophils, and increased expression of Intercellular Adhesion Molecule 1 (ICAM-1). P. berghei ANKA (PbA) infection in C57BL/6 mice reproduces many SM features, including acute lung injury characterized by DAD, CD8 T lymphocytes and neutrophils in the lung parenchyma, and tissular expression of proinflammatory cytokines and adhesion molecules, such as IFNγ, TNFα, ICAM, and VCAM. Since this is related to a dysregulated immune response, immunomodulatory agents are proposed to reduce the complications of SM. The monocyte locomotion inhibitory factor (MLIF) is an immunomodulatory pentapeptide isolated from axenic cultures of Entamoeba hystolitica. Thus, we evaluated if the MLIF intraperitoneal (i.p.) treatment prevented SM-induced acute lung injury. The peptide prevented SM without a parasiticidal effect, indicating that its protective effect was related to modifications in the immune response. Furthermore, peripheral CD8 leukocytes and neutrophil proportions were higher in infected treated mice. However, the treatment prevented DAD, CD8 cell infiltration into the pulmonary tissue and downregulated IFNγ. Moreover, VCAM-1 expression was abrogated. These results indicate that the MLIF treatment downregulated adhesion molecule expression, impeding cell migration and proinflammatory cytokine tissular production, preventing acute lung injury induced by SM. Our findings represent a potential novel strategy to avoid this complication in various events where a dysregulated immune response triggers lung injury.
Topics: Animals; Acute Lung Injury; Mice; Disease Models, Animal; Malaria; Plasmodium berghei; Mice, Inbred C57BL; Neutrophils; CD8-Positive T-Lymphocytes; Cytokines; Lung; Humans; Female; Oligopeptides
PubMed: 38861873
DOI: 10.1016/j.imbio.2024.152823 -
Journal of Korean Medical Science Jun 2024Herein, we report a case of uncomplicated falciparum malaria with late parasitological failure in a 45-year-old businessman returning from Ghana. The patient visited the...
Herein, we report a case of uncomplicated falciparum malaria with late parasitological failure in a 45-year-old businessman returning from Ghana. The patient visited the emergency department with high fever, headache, and dizziness. He traveled without antimalarial chemoprophylaxis. Laboratory tests led to the diagnosis of uncomplicated falciparum malaria with an initial density of 37,669 parasites per μL of blood (p/μL). The patient was treated with intravenous artesunate followed by atovaquone/proguanil. He was discharged with improved condition and decreased parasite density of 887 p/μL. However, at follow-up, parasite density increased to 7,630 p/μL despite the absence of any symptoms. Suspecting treatment failure, the patient was administered intravenous artesunate and doxycycline for seven days and then artemether/lumefantrine for three days. Blood smear was negative for asexual parasitemia after re-treatment but positive for gametocytemia until day 101 from the initial diagnosis. Overall, this case highlights the risk of late parasitological failure in patients with imported uncomplicated falciparum malaria.
Topics: Humans; Malaria, Falciparum; Ghana; Antimalarials; Middle Aged; Male; Plasmodium falciparum; Proguanil; Atovaquone; Travel; Artemisinins; Artesunate; Parasitemia; Doxycycline; Drug Combinations; Treatment Failure; Artemether, Lumefantrine Drug Combination
PubMed: 38859743
DOI: 10.3346/jkms.2024.39.e186 -
Journal of Korean Medical Science Jun 2024Malaria elimination strategies in the Republic of Korea (ROK) have decreased malaria incidence but face challenges due to delayed case detection and response. To improve...
BACKGROUND
Malaria elimination strategies in the Republic of Korea (ROK) have decreased malaria incidence but face challenges due to delayed case detection and response. To improve this, machine learning models for predicting malaria, focusing on high-risk areas, have been developed.
METHODS
The study targeted the northern region of ROK, near the demilitarized zone, using a 1-km grid to identify areas for prediction. Grid cells without residential buildings were excluded, leaving 8,425 cells. The prediction was based on whether at least one malaria case was reported in each grid cell per month, using spatial data of patient locations. Four algorithms were used: gradient boosted (GBM), generalized linear (GLM), extreme gradient boosted (XGB), and ensemble models, incorporating environmental, sociodemographic, and meteorological data as predictors. The models were trained with data from May to October (2019-2021) and tested with data from May to October 2022. Model performance was evaluated using the area under the receiver operating characteristic curve (AUROC).
RESULTS
The AUROC of the prediction models performed excellently (GBM = 0.9243, GLM = 0.9060, XGB = 0.9180, and ensemble model = 0.9301). Previous malaria risk, population size, and meteorological factors influenced the model most in GBM and XGB.
CONCLUSION
Machine-learning models with properly preprocessed malaria case data can provide reliable predictions. Additional predictors, such as mosquito density, should be included in future studies to improve the performance of models.
Topics: Republic of Korea; Humans; Malaria, Vivax; Machine Learning; Plasmodium vivax; ROC Curve; Algorithms; Area Under Curve; Incidence; Risk Factors
PubMed: 38859739
DOI: 10.3346/jkms.2024.39.e176 -
Parasites & Vectors Jun 2024Toxoplasma gondii is an intracellular protozoan parasite that is widely distributed in humans and warm-blooded animals. T. gondii chronic infections can cause...
BACKGROUND
Toxoplasma gondii is an intracellular protozoan parasite that is widely distributed in humans and warm-blooded animals. T. gondii chronic infections can cause toxoplasmic encephalopathy, adverse pregnancy, and male reproductive disorders. In male reproduction, the main function of the testis is to provide a stable place for spermatogenesis and immunological protection. The disorders affecting testis tissue encompass abnormalities in the germ cell cycle, spermatogenic retardation, or complete cessation of sperm development. However, the mechanisms of interaction between T. gondii and the reproductive system is unclear. The aims were to study the expression levels of genes related to spermatogenesis, following T. gondii infection, in mouse testicular tissue.
METHODS
RNA-seq sequencing was carried out on mouse testicular tissues from mice infected or uninfected with the T. gondii type II Prugniaud (PRU) strain and validated in combination with real-time quantitative PCR and immunofluorescence assays.
RESULTS
The results showed that there were 250 significant differentially expressed genes (DEGs) (P < 0.05, |logfold change| ≧ 1). Bioinformatics analysis showed that 101 DEGs were annotated to the 1696 gene ontology (GO) term. While there was a higher number of DEGs in the biological process classification as a whole, the GO enrichment revealed a significant presence of DEGs in the cellular component classification. The Arhgap18 and Syne1 genes undergo regulatory changes following T. gondii infection, and both were involved in shaping the cytoskeleton of the blood-testis barrier (BTB). The number of DEGs enriched in the MAPK signaling pathway, the ERK1/2 signaling pathway, and the JNK signaling pathway were significant. The PTGDS gene is located in the Arachidonic acid metabolism pathway, which plays an important role in the formation and maintenance of BTB in the testis. The expression of PTGDS is downregulated subsequent to T. gondii infection, potentially exerting deleterious effects on the integrity of the BTB and the spermatogenic microenvironment within the testes.
CONCLUSIONS
Overall, our research provides in-depth insights into how chronic T. gondii infection might affect testicular tissue and potentially impact male fertility. These findings offer a new perspective on the impact of T. gondii infection on the male reproductive system.
Topics: Animals; Male; Mice; Testis; Toxoplasma; Transcriptome; Toxoplasmosis, Animal; Spermatogenesis; Gene Expression Profiling; Chronic Disease; Computational Biology
PubMed: 38858789
DOI: 10.1186/s13071-024-06247-z -
Malaria Journal Jun 2024Plasmodium vivax malaria is a leading cause of morbidity in Ethiopia. The first-line treatment for P. vivax is chloroquine (CQ) and primaquine (PQ), but there have been...
BACKGROUND
Plasmodium vivax malaria is a leading cause of morbidity in Ethiopia. The first-line treatment for P. vivax is chloroquine (CQ) and primaquine (PQ), but there have been local reports of CQ resistance. A clinical study was conducted to determine the efficacy of CQ for the treatment of P. vivax malaria in southern Ethiopia.
METHODS
In 2021, patients with P. vivax mono-infection and uncomplicated malaria were enrolled and treated with 25 mg/kg CQ for 3 consecutive days. Patients were followed for 28 days according to WHO guidelines. The data were analysed using per-protocol (PP) and Kaplan‒Meier (K‒M) analyses to estimate the risk of recurrent P. vivax parasitaemia on day 28.
RESULTS
A total of 88 patients were enrolled, 78 (88.6%) of whom completed the 28 days of follow-up. Overall, 76 (97.4%) patients had adequate clinical and parasitological responses, and two patients had late parasitological failures. The initial therapeutic response was rapid, with 100% clearance of asexual parasitaemia within 48 h.
CONCLUSION
Despite previous reports of declining chloroquine efficacy against P. vivax, CQ retains high therapeutic efficacy in southern Ethiopia, supporting the current national treatment guidelines. Ongoing clinical monitoring of CQ efficacy supported by advanced molecular methods is warranted to inform national surveillance and ensure optimal treatment guidelines.
Topics: Malaria, Vivax; Chloroquine; Ethiopia; Humans; Antimalarials; Male; Adult; Female; Adolescent; Young Adult; Child; Middle Aged; Child, Preschool; Plasmodium vivax; Treatment Outcome; Aged; Parasitemia
PubMed: 38858696
DOI: 10.1186/s12936-024-05009-7 -
PLoS Biology Jun 2024As Toxoplasma gondii disseminates through its host, the parasite must sense and adapt to its environment and scavenge nutrients. Oxygen (O2) is one such environmental...
As Toxoplasma gondii disseminates through its host, the parasite must sense and adapt to its environment and scavenge nutrients. Oxygen (O2) is one such environmental factor and cytoplasmic prolyl 4-hydroxylases (PHDs) are evolutionarily conserved O2 cellular sensing proteins that regulate responses to changes in O2 availability. Toxoplasma expresses 2 PHDs. One of them, TgPHYa hydroxylates SKP1, a subunit of the SCF-E3 ubiquitin ligase complex. In vitro, TgPHYa is important for growth at low O2 levels. However, studies have yet to examine the role that TgPHYa or any other pathogen-encoded PHD plays in virulence and disease. Using a type II ME49 Toxoplasma TgPHYa knockout, we report that TgPHYa is important for Toxoplasma virulence and brain cyst formation in mice. We further find that while TgPHYa mutant parasites can establish an infection in the gut, they are unable to efficiently disseminate to peripheral tissues because the mutant parasites are unable to survive within recruited immune cells. Since this phenotype was abrogated in IFNγ knockout mice, we studied how TgPHYa mediates survival in IFNγ-treated cells. We find that TgPHYa is not required for release of parasite-encoded effectors into host cells that neutralize anti-parasitic processes induced by IFNγ. In contrast, we find that TgPHYa is required for the parasite to scavenge tryptophan, which is an amino acid whose levels are decreased after IFNγ up-regulates the tryptophan-catabolizing enzyme, indoleamine dioxygenase (IDO). We further find, relative to wild-type mice, that IDO knockout mice display increased morbidity when infected with TgPHYa knockout parasites. Together, these data identify the first parasite mechanism for evading IFNγ-induced nutritional immunity and highlight a novel role that oxygen-sensing proteins play in pathogen growth and virulence.
Topics: Animals; Toxoplasma; Interferon-gamma; Mice; Protozoan Proteins; Oxygen; Mice, Inbred C57BL; Virulence; Indoleamine-Pyrrole 2,3,-Dioxygenase; Female; Brain; Toxoplasmosis, Animal; Toxoplasmosis
PubMed: 38857298
DOI: 10.1371/journal.pbio.3002690 -
Nature Communications Jun 2024Host immune responses are tightly controlled by various immune factors during infection, and protozoan parasites also manipulate the immune system to evade surveillance,...
Host immune responses are tightly controlled by various immune factors during infection, and protozoan parasites also manipulate the immune system to evade surveillance, leading to an evolutionary arms race in host‒pathogen interactions; however, the underlying mechanisms are not fully understood. We observed that the level of superoxide dismutase 3 (SOD3) was significantly elevated in both Plasmodium falciparum malaria patients and mice infected with four parasite species. SOD3-deficient mice had a substantially longer survival time and lower parasitemia than control mice after infection, whereas SOD3-overexpressing mice were much more vulnerable to parasite infection. We revealed that SOD3, secreted from activated neutrophils, bound to T cells, suppressed the interleukin-2 expression and concomitant interferon-gamma responses crucial for parasite clearance. Overall, our findings expose active fronts in the arms race between the parasites and host immune system and provide insights into the roles of SOD3 in shaping host innate immune responses to parasite infection.
Topics: Animals; Superoxide Dismutase; Humans; Mice; Neutrophils; Mice, Inbred C57BL; Mice, Knockout; Malaria, Falciparum; Immunity, Cellular; T-Lymphocytes; Plasmodium falciparum; Female; Host-Parasite Interactions; Interferon-gamma; Male; Immunity, Innate; Interleukin-2; Parasitemia
PubMed: 38851821
DOI: 10.1038/s41467-024-49348-0 -
Ecotoxicology and Environmental Safety Jul 2024Toxoplasma gondii is an opportunistic and pathogenic obligate intracellular parasitic protozoan that is widespread worldwide and can infect most warm-blooded animals,... (Review)
Review
Toxoplasma gondii is an opportunistic and pathogenic obligate intracellular parasitic protozoan that is widespread worldwide and can infect most warm-blooded animals, seriously endangering human health and affecting livestock production. Toxoplasmosis caused by T. gondii infection has different clinical manifestations, which are mainly determined by the virulence of T. gondii and host differences. Among the manifestations of this condition, abortion, stillbirth, and fetal malformation can occur if a woman is infected with T. gondii in early pregnancy. Here, we discuss how the T. gondii rhoptry protein affects host pregnancy outcomes and speculate on the related signaling pathways involved. The effects of rhoptry proteins of T. gondii on the placental barrier are complex. Rhoptry proteins not only regulate interferon-regulated genes (IRGs) to ensure the survival of parasites in activated cells but also promote the spread of worms in tissues and the invasive ability of the parasites. The functions of these rhoptry proteins and the associated signaling pathways highlight relevant mechanisms by which Toxoplasma crosses the placental barrier and influences fetal development and will guide future studies to uncover the complexity of the host-pathogen interactions.
Topics: Female; Signal Transduction; Placenta; Pregnancy; Toxoplasma; Protozoan Proteins; Animals; Humans; Toxoplasmosis; Pregnancy Complications, Parasitic
PubMed: 38850700
DOI: 10.1016/j.ecoenv.2024.116567