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PLoS Pathogens Nov 2023Neuropilin-1 (Nrp-1) expression on CD8+ T cells has been identified in tumor-infiltrating lymphocytes and in persistent murine gamma-herpes virus infections, where it...
Neuropilin-1 (Nrp-1) expression on CD8+ T cells has been identified in tumor-infiltrating lymphocytes and in persistent murine gamma-herpes virus infections, where it interferes with the development of long-lived memory T cell responses. In parasitic and acute viral infections, the role of Nrp-1 expression on CD8+ T cells remains unclear. Here, we demonstrate a strong induction of Nrp-1 expression on CD8+ T cells in Plasmodium berghei ANKA (PbA)-infected mice that correlated with neurological deficits of experimental cerebral malaria (ECM). Likewise, the frequency of Nrp-1+CD8+ T cells was significantly elevated and correlated with liver damage in the acute phase of lymphocytic choriomeningitis virus (LCMV) infection. Transcriptomic and flow cytometric analyses revealed a highly activated phenotype of Nrp-1+CD8+ T cells from infected mice. Correspondingly, in vitro experiments showed rapid induction of Nrp-1 expression on CD8+ T cells after stimulation in conjunction with increased expression of activation-associated molecules. Strikingly, T cell-specific Nrp-1 ablation resulted in reduced numbers of activated T cells in the brain of PbA-infected mice as well as in spleen and liver of LCMV-infected mice and alleviated the severity of ECM and LCMV-induced liver pathology. Mechanistically, we identified reduced blood-brain barrier leakage associated with reduced parasite sequestration in the brain of PbA-infected mice with T cell-specific Nrp-1 deficiency. In conclusion, Nrp-1 expression on CD8+ T cells represents a very early activation marker that exacerbates deleterious CD8+ T cell responses during both, parasitic PbA and acute LCMV infections.
Topics: Mice; Animals; Neuropilin-1; Parasites; Malaria, Cerebral; Lymphocytic Choriomeningitis; Lymphocytic choriomeningitis virus; CD8-Positive T-Lymphocytes; Mice, Inbred C57BL
PubMed: 38019895
DOI: 10.1371/journal.ppat.1011837 -
Vaccine Dec 2023Long-term protection against malaria remains one of the greatest challenges of vaccination against this deadly parasitic disease. Whole-sporozoite (WSp) malaria vaccine...
Long-term protection against malaria remains one of the greatest challenges of vaccination against this deadly parasitic disease. Whole-sporozoite (WSp) malaria vaccine formulations, which target the Plasmodium parasite's pre-erythrocytic stages, include radiation-attenuated sporozoites (RAS), early- and late-arresting genetically-attenuated parasites (EA-GAP and LA-GAP, respectively), and chemoprophylaxis with sporozoites (CPS). Although all these four vaccine formulations induce protective immune responses in the clinic, data on the longevity of the antimalarial protection they afford remain scarce. We employed a mouse model of malaria to assess protection conferred by immunization with P. berghei (Pb)-based surrogates of these four WSp formulations over a 36-week period. We show that EA-GAP WSp provide the lowest overall protection against an infectious Pb challenge, and that while immunization with RAS and LA-GAP WSp elicits the most durable protection, the protective efficacy of CPS WSp wanes rapidly over the 36-week period, most notably at higher immunization dosages. Analyses of liver immune cells show that CD44 CD8 T cells in CPS WSp-immunized mice express increased levels of the co-inhibitory PD-1 and LAG-3 markers compared to mice immunized with the other WSp formulations. This indicates that memory CD8 T cells elicited by CPS WSp immunization display a more exhausted phenotype, which may explain the rapid waning of protection conferred by the former. These results emphasize the need for a detailed comparison of the duration of protection of different WSp formulations in humans and suggest a more beneficial effect of RAS and LA-GAP WSp compared to EA-GAP or CSP WSp.
Topics: Humans; Animals; Mice; Plasmodium berghei; Sporozoites; Vaccines, Attenuated; CD8-Positive T-Lymphocytes; Lead; Malaria; Malaria Vaccines
PubMed: 38007342
DOI: 10.1016/j.vaccine.2023.11.023 -
International Journal For Parasitology.... Dec 2023Malaria, an infectious disease with a tremendous impact on human health is caused by Plasmodium parasites, and transmitted by Anopheles mosquitoes. New approaches to...
Screening of the activity of sixty essential oils against plasmodium early mosquito stages in vitro and machine learning analysis reveals new putative inhibitors of malaria parasites.
Malaria, an infectious disease with a tremendous impact on human health is caused by Plasmodium parasites, and transmitted by Anopheles mosquitoes. New approaches to control the disease involve transmission blocking strategies aiming to target the parasite in the mosquito. Here, we investigated the putative inhibitory activity of essential oils and their components on the early mosquito stages of the parasite. We employed an in vitro assay of gametocyte-to-ookinete development of the rodent model parasite Plasmodium berghei combined with high content screening. 60 essential oils with known composition were tested. The results revealed that fifteen EOs had inhibitory activity. Furthermore, a machine learning approach was used to identify the putative inhibitory components. Five of the most important chemical components indicated by the machine learning-based models were actually confirmed by the experimental approach. This combined approach was used for the first time to identify the potential transmission blocking activity of essential oils and single components at the zygote and ookinete stages.
Topics: Animals; Humans; Parasites; Malaria; Plasmodium berghei; Anopheles
PubMed: 38000094
DOI: 10.1016/j.ijpddr.2023.11.002 -
European Journal of Medicinal Chemistry Jan 2024Ivermectin is a sixteen-membered macrolactone "wonder drug" of Nobel prize-honored distinction that exhibits a wide range of antiparasitic activities. It has been used...
Ivermectin is a sixteen-membered macrolactone "wonder drug" of Nobel prize-honored distinction that exhibits a wide range of antiparasitic activities. It has been used for almost four decades in the treatment of various parasitic diseases in humans and animals. In this paper, we describe the synthesis of the first-in-class ivermectin derivatives obtained via derivatization of the C13 position, along with the unexpected rearrangement of the oxahydrindene (hexahydrobenzofuran) unit of the macrolide ring. The structural investigation of the rearrangement has been performed using the single-crystal X-ray diffraction method. The antiparasitic and cytotoxic activities of the newly synthesized derivatives were determined in vitro with the bloodstream form of Trypanosoma brucei brucei, the hepatic stage of Plasmodium berghei, and human leukemia HL-60 cells. The compounds with the highest trypanocidal activity were the C13-epi-2-chloroacetamide analogs of native (6h) or rearranged (7h) ivermectin. Both 6h and 7h displayed trypanocidal activities within a similar mid-nanomolar concentration range as the commercially used trypanocides suramin and ethidium bromide. Furthermore, 6h and 7h exhibited a comparable cytotoxic to trypanocidal ratio as the reference drug ethidium bromide. The double-modified compound 7a (C13-epi-acetamide of rearranged ivermectin) exhibited the highest activity against P. berghei grown in human hepatoma cells, which was 2.5 times higher than that of ivermectin. The findings of this study suggest that C13-epi-amide derivatives of ivermectin are suitable leads in the rational development of new antiparasitic agents.
Topics: Animals; Humans; Antimalarials; Ivermectin; Ethidium; Trypanosoma brucei brucei; Trypanocidal Agents
PubMed: 37988797
DOI: 10.1016/j.ejmech.2023.115951 -
Infection and Drug Resistance 2023Malaria is a life-threatening disease prevalent in tropical and subtropical regions. Artemisinin combination therapy (ACT) used as an antimalarial treatment has reduced... (Review)
Review
BACKGROUND
Malaria is a life-threatening disease prevalent in tropical and subtropical regions. Artemisinin combination therapy (ACT) used as an antimalarial treatment has reduced efficacy due to resistance, not only to the parasite but also to the vector. Therefore, it is important to find alternatives to overcome malaria cases through medicinal plants such as and other related plants within family.
PURPOSE
This review summarizes the antimalarial and insecticidal activities of and other plants belonging to family.
DATA SOURCE
Google Scholar, PubMed, Science Direct, and Springer link.
STUDY SELECTION
Online databases were used to retrieve journals using specific keywords combined with Boolean operators. The inclusion criteria were articles with experimental studies either in vivo or in vitro, in English or Indonesian, published after 1st January 2000, and full text available for inclusion in this review.
DATA EXTRACTION
The antimalarial activity, insecticidal activity, and structure of the isolated compounds were retrieved from the selected studies.
DATA SYNTHESIS
Antimalarial in vitro study showed that the dichloromethane extract was the most widely studied with an IC50 value <10 μg/mL. Among 84 isolated active compounds, 2-hydroxymethyl-non-3-ynoic acid 2-[2,2']-bithiophenyl-5- ethyl ester, a bithienyl compound from the plant show the smallest IC50 with value 0.01 and 0.02 µg/mL in MRC-pf-2 and MRC-pf-56, respectively. In vivo studies showed that the aqueous extract of showed the best activity, with a 98.8% inhibition percentage using a 100 mg/kg dose of (NK65 Strain). (Z)- γ-Bisabolene from showed very good insecticidal activity against and with LC50 values of 2.04 μg/mL and 4.05 μg/mL.
CONCLUSION
and other plants of family are promising reservoirs of natural compounds that exert antimalarial or insecticidal activity.
PubMed: 37954507
DOI: 10.2147/IDR.S433328 -
Cell Reports Nov 2023Plasmodium parasites contribute to one of the highest global infectious disease burdens. To achieve this success, the parasite has evolved a range of specialized...
Plasmodium parasites contribute to one of the highest global infectious disease burdens. To achieve this success, the parasite has evolved a range of specialized subcellular compartments to extensively remodel the host cell for its survival. The information to fully understand these compartments is likely hidden in the so far poorly characterized Plasmodium species spatial proteome. To address this question, we determined the steady-state subcellular location of more than 12,000 parasite proteins across five different species by extensive subcellular fractionation of erythrocytes infected by Plasmodium falciparum, Plasmodium knowlesi, Plasmodium yoelii, Plasmodium berghei, and Plasmodium chabaudi. This comparison of the pan-species spatial proteomes and their expression patterns indicates increasing species-specific proteins associated with the more external compartments, supporting host adaptations and post-transcriptional regulation. The spatial proteome offers comprehensive insight into the different human, simian, and rodent Plasmodium species, establishing a powerful resource for understanding species-specific host adaptation processes in the parasite.
Topics: Humans; Proteomics; Malaria; Proteome; Plasmodium berghei; Erythrocytes
PubMed: 37952150
DOI: 10.1016/j.celrep.2023.113419 -
BMC Complementary Medicine and Therapies Nov 2023Malaria is a global health challenge with endemicity in sub-Saharan Africa, where there are multiple drug-resistant strains and limited access to modern health care...
Malaria is a global health challenge with endemicity in sub-Saharan Africa, where there are multiple drug-resistant strains and limited access to modern health care facilities, especially in rural areas. Studies indicate that African traditional medicine could make a substantial contribution to the reduction of malaria-related deaths and achievement of universal health coverage (UHC), particularly in these regions. Thus, this study evaluated the curative antimalarial effects of Chromolaena odorata leaf extract using mouse model. Forty-five (45) albino mice weighing between 18 and 22 g were grouped into nine groups of 5 animals each. Animals in groups 2-9 were infected with the chloroquine-resistant strain of Plasmodium berghei, while animals in groups 3-9 were subsequently treated with 10 mg/kg chloroquine, a combination of 1.4 mg/kg artemether and 8.75 mg/kg lumefantrine (Coartem), and varying concentrations of the fraction from the aqueous leaf extract of C. odorata at day 3 post-infection. The findings from this study indicate that treatment with 400 mg/kg of the ethanolic fraction of the crude extract resulted in a significant decrease in parasite load (97.6%), which was comparable to the activities of the conventional drugs chloroquine (98.6%) and Coartem (98.8%). The ethyl acetate and ethanolic fractions at 400 mg/kg also ameliorated the significant alterations in the red blood cells, white blood cells, and platelets of the infected animals. The high antimalarial activity displayed by the ethanolic fraction could be due to the presence of quercetin and kaempferol, as detected by high performance liquid chromatography (HPLC) analysis. The findings suggest that the fractions from C. odorata could serve as an alternative source of malaria therapy, particularly in sub-Saharan Africa.
Topics: Animals; Mice; Antimalarials; Chromolaena; Artemether, Lumefantrine Drug Combination; Plant Extracts; Malaria; Chloroquine
PubMed: 37946127
DOI: 10.1186/s12906-023-04200-8 -
Malaria Journal Nov 2023Acquired functional inhibitory antibodies are one of several humoral immune mechanisms used to neutralize foreign pathogens. In vitro bioassays are useful tools for...
BACKGROUND
Acquired functional inhibitory antibodies are one of several humoral immune mechanisms used to neutralize foreign pathogens. In vitro bioassays are useful tools for quantifying antibody-mediated inhibition and evaluating anti-parasite immune antibodies. However, a gap remains in understanding of how antibody-mediated inhibition in vitro translates to inhibition in vivo. In this study, two well-characterized transgenic Plasmodium berghei parasite lines, PbmCh-luc and Pb-PfCSP(r), and murine monoclonal antibodies (mAbs) specific to P. berghei and Plasmodium falciparum circumsporozoite protein (CSP), 3D11 and 2A10, respectively, were used to evaluate antibody-mediated inhibition of parasite development in both in vitro and in vivo functional assays.
METHODS
IC values of mAbs were determined using an established inhibition of liver-stage development assay (ILSDA). For the in vivo inhibition assay, mice were passively immunized by transfer of the mAbs and subsequently challenged with 5.0 × 10 sporozoites via tail vein injection. The infection burden in both assays was quantified by luminescence and qRT-PCR of P. berghei 18S rRNA normalized to host GAPDH.
RESULTS
The IC values quantified by relative luminescence of mAbs 3D11 and 2A10 were 0.396 µg/ml and 0.093 µg/ml, respectively, against transgenic lines in vitro. Using the highest (> 90%) inhibitory antibody concentrations in a passive transfer, an IC of 233.8 µg/ml and 181.5 µg/ml for mAbs 3D11 and 2A10, respectively, was observed in vivo. At 25 µg (250 µg/ml), the 2A10 antibody significantly inhibited liver burden in mice compared to control. Additionally, qRT-PCR of P. berghei 18S rRNA served as a secondary validation of liver burden quantification.
CONCLUSIONS
Results from both experimental models, ILSDA and in vivo challenge, demonstrated that increased concentrations of the homologous anti-CSP repeat mAbs increased parasite inhibition. However, differences in antibody IC values between parasite lines did not allow a direct correlation between the inhibition of sporozoite invasion in vitro by ILSDA and the inhibition of mouse liver stage burden. Further studies are needed to establish the conditions for confident predictions for the in vitro ILSDA to be a predictor of in vivo outcomes using this model system.
Topics: Mice; Animals; Antibodies, Monoclonal; Plasmodium berghei; Plasmodium falciparum; RNA, Ribosomal, 18S; Protozoan Proteins; Animals, Genetically Modified; Antibodies, Protozoan; Malaria Vaccines
PubMed: 37936181
DOI: 10.1186/s12936-023-04765-2 -
Parasites & Vectors Nov 2023Safe and effective vaccines are crucial for the control and eventual elimination of malaria. Novel approaches to optimize and improve vaccine efficacy are urgently...
BACKGROUND
Safe and effective vaccines are crucial for the control and eventual elimination of malaria. Novel approaches to optimize and improve vaccine efficacy are urgently required. Nanoparticle-based delivery platforms are considered potent and powerful tools for vaccine development.
METHODS
In this study, we developed a transmission-blocking vaccine against malaria by conjugating the ookinete surface antigen PSOP25 to the Acinetobacter phage coat protein AP205, forming virus-like particles (VLPs) using the SpyTag/SpyCatcher adaptor system. The combination of AP205-2*SpyTag with PSOP25-SpyCatcher resulted in the formation of AP205-PSOP25 complexes (VLP-PSOP25). The antibody titers and avidity of serum from each immunization group were assessed by ELISA. Western blot and IFA were performed to confirm the specific reactivity of the elicit antisera to the native PSOP25 in Plasmodium berghei ookinetes. Both in vitro and in vivo assays were conducted to evaluate the transmission-blocking activity of VLP-PSOP25 vaccine.
RESULTS
Immunization of mice with VLP-PSOP25 could induced higher levels of high-affinity antibodies than the recombinant PSOP25 (rPSOP25) alone or mixtures of untagged AP205 and rPSOP25 but was comparable to rPSOP25 formulated with alum. Additionally, the VLP-PSOP25 vaccine enhanced Th1-type immune response with remarkably increased levels of IgG2a subclass. The antiserum generated by VLP-PSOP25 specifically recognizes the native PSOP25 antigen in P. berghei ookinetes. Importantly, antisera generated by inoculation with the VLP-PSOP25 could inhibit ookinete development in vitro and reduce the prevalence of infected mosquitoes or oocyst intensity in direct mosquito feeding assays.
CONCLUSIONS
Antisera elicited by immunization with the VLP-PSOP25 vaccine confer moderate transmission-reducing activity and transmission-blocking activity. Our results support the utilization of the AP205-SpyTag/SpyCatcher platform for next-generation TBVs development.
Topics: Animals; Mice; Protozoan Proteins; Malaria Vaccines; Plasmodium berghei; Antibody Formation; Malaria; Immune Sera; Antibodies, Protozoan; Mice, Inbred BALB C
PubMed: 37932796
DOI: 10.1186/s13071-023-06020-8 -
Parasites & Vectors Nov 2023The extrinsic incubation period (EIP), defined as the time it takes for malaria parasites in a mosquito to become infectious to a vertebrate host, is one of the most...
BACKGROUND
The extrinsic incubation period (EIP), defined as the time it takes for malaria parasites in a mosquito to become infectious to a vertebrate host, is one of the most influential parameters for malaria transmission but remains poorly understood. The EIP is usually estimated by quantifying salivary gland sporozoites in subsets of mosquitoes, which requires terminal sampling. However, assays that allow repeated sampling of individual mosquitoes over time could provide better resolution of the EIP.
METHODS
We tested a non-destructive assay to quantify sporozoites of two rodent malaria species, Plasmodium chabaudi and Plasmodium berghei, expelled throughout 24-h windows, from sugar-soaked feeding substrates using quantitative-PCR.
RESULTS
The assay is able to quantify sporozoites from sugar-soaked feeding substrates, but the prevalence of parasite-positive substrates was low. Various methods were attempted to increase the detection of expelled parasites (e.g. running additional technical replicates; using groups rather than individual mosquitoes), but these did not increase the detection rate, suggesting that expulsion of sporozoites is variable and infrequent.
CONCLUSIONS
We reveal successful detection of expelled sporozoites from sugar-soaked feeding substrates. However, investigations of the biological causes underlying the low detection rate of sporozoites (e.g. mosquito feeding behaviour, frequency of sporozoite expulsion or sporozoite clumping) are needed to maximise the utility of using non-destructive assays to quantify sporozoite dynamics. Increasing detection rates will facilitate the detailed investigation on infection dynamics within mosquitoes, which is necessary to explain the highly variable EIP of Plasmodium and to improve understanding of malaria transmission dynamics.
Topics: Animals; Sporozoites; Anopheles; Plasmodium; Malaria; Plasmodium berghei; Sugars
PubMed: 37925480
DOI: 10.1186/s13071-023-06015-5