scholarly journals Optimization of an in vivo model to study immunity to Plasmodium falciparum pre-erythrocytic stages

2019 ◽  
Vol 18 (1) ◽  
Author(s):  
Yevel Flores-Garcia ◽  
Sonia M. Herrera ◽  
Hugo Jhun ◽  
Daniel W. Pérez-Ramos ◽  
C. Richter King ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Plasmodium Falciparum ◽  
Genetically Engineered ◽  
In Vivo Model ◽  
Protective Capacity ◽  
Liver Stage ◽  
In Vivo Bioluminescence Imaging ◽  
Bioluminescence Assay ◽  
Stage Infection

Abstract Background The circumsporozoite protein (CSP) of Plasmodium is a key surface antigen that induces antibodies and T-cells, conferring immune protection in animal models and humans. However, much of the work on CSP and immunity has been developed based on studies using rodent or non-human primate CSP antigens, which may not be entirely translatable to CSP expressed by human malaria parasites, especially considering the host specificity of the different species. Methods Using a genetically engineered strain of Plasmodium berghei that expresses luciferase, GFP and the Plasmodium falciparum orthologue of CSP, the effect of laboratory preparation, mosquito treatment and mouse factors on sporozoite infectivity was assessed using an in vivo bioluminescence assay on mice. This assay was compared with a PCR-based protection assay using an already described monoclonal antibody that can provide sterile protection against sporozoite challenge. Results Bioluminescence assay demonstrated similar detection levels of the quantity and kinetics of liver-stage infection, compared to PCR-based detection. This assay was used to evaluate treatment of sporozoite and delivery method on mouse infectivity, as well as the effects of age, sex and strain of mice. Finally, this assay was used to test the protective capacity of monoclonal antibody AB317; results strongly recapitulate the findings of previous work on this antibody. Conclusions The PbGFP-Luc line and in vivo bioluminescence imaging provide highly sensitive read-outs of liver-stage infection in mice, and this method can be useful to reliably evaluate potency of pre-erythrocytic interventions.

scholarly journals Nme1 and Nme2 genes exert metastasis-suppressor activities in a genetically engineered mouse model of UV-induced melanoma

2020 ◽  
Vol 124 (1) ◽  
pp. 161-165
Author(s):  
Nidhi Pamidimukkala ◽  
Gemma S. Puts ◽  
M. Kathryn Leonard ◽  
Devin Snyder ◽  
Sandrine Dabernat ◽  
...  
Keyword(s):  
Mouse Model ◽  
Suppressor Gene ◽  
Genetically Engineered ◽  
In Vivo Model ◽  
Metastasis Suppressor ◽  
Specific Context ◽  
Genetically Engineered Mouse Model ◽  
Metastatic Activity ◽  
First Time

AbstractNME1 is a metastasis-suppressor gene (MSG), capable of suppressing metastatic activity in cell lines of melanoma, breast carcinoma and other cancer origins without affecting their growth in culture or as primary tumours. Herein, we selectively ablated the tandemly arranged Nme1 and Nme2 genes to assess their individual impacts on metastatic activity in a mouse model (HGF:p16−/−) of ultraviolet radiation (UVR)-induced melanoma. Metastatic activity was strongly enhanced in both genders of Nme1- and Nme2-null mice, with stronger activity in females across all genotypes. The study ascribes MSG activity to Nme2 for the first time in an in vivo model of spontaneous cancer, as well as a novel metastasis-suppressor function to Nme1 in the specific context of UVR-induced melanoma.

scholarly journals Metabolic Signature Profiling as a Diagnostic and Prognostic Tool in Pediatric Plasmodium falciparum Malaria

2015 ◽  
Vol 2 (2) ◽  
Author(s):  
Izabella Surowiec ◽  
Judy Orikiiriza ◽  
Elisabeth Karlsson ◽  
Maria Nelson ◽  
Mari Bonde ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Principal Component ◽  
Malaria Diagnosis ◽  
Plasmodium Falciparum Malaria ◽  
Metabolite Profile ◽  
Mass Spectrometry Analysis ◽  
Gas Chromatography Mass Spectrometry ◽  
In Vivo Model ◽  
Spectrometry Analysis

Abstract Background.  Accuracy in malaria diagnosis and staging is vital to reduce mortality and post infectious sequelae. In this study, we present a metabolomics approach to diagnostic staging of malaria infection, specifically Plasmodium falciparum infection in children. Methods.  A group of 421 patients between 6 months and 6 years of age with mild and severe states of malaria with age-matched controls were included in the study, 107, 192, and 122, individuals, respectively. A multivariate design was used as basis for representative selection of 20 patients in each category. Patient plasma was subjected to gas chromatography-mass spectrometry analysis, and a full metabolite profile was produced from each patient. In addition, a proof-of-concept model was tested in a Plasmodium berghei in vivo model where metabolic profiles were discernible over time of infection. Results.  A 2-component principal component analysis revealed that the patients could be separated into disease categories according to metabolite profiles, independently of any clinical information. Furthermore, 2 subgroups could be ide.jpegied in the mild malaria cohort who we believe represent patients with divergent prognoses. Conclusions.  Metabolite signature profiling could be used both for decision support in disease staging and prognostication.

SYNCHRONY-BREAKING HOPF BIFURCATION IN A MODEL OF ANTIGENIC VARIATION

2013 ◽  
Vol 23 (02) ◽  
pp. 1350021 ◽  
Author(s):  
BERNARD S. CHAN ◽  
PEI YU
Keyword(s):  
Plasmodium Falciparum ◽  
Hopf Bifurcation ◽  
Numerical Simulations ◽  
Antigenic Variation ◽  
Cross Reactivity ◽  
In Vivo Model ◽  
Main Attention ◽  
Cell Systems ◽  
Coupled Cell Systems

In this paper, we will analyze the bifurcation dynamics of an in vivo model of Plasmodium falciparum. The main attention of this model is focused on the dynamics of cross-reactivity from antigenic variation. We apply the techniques of coupled cell systems to study this model. It is shown that synchrony-breaking Hopf bifurcation occurs from a nontrivial synchronous equilibrium. In proving the existence of a Hopf bifurcation, we also discover the condition under which possible 2-color synchrony patterns arise from the bifurcation. The dynamics resulting from the bifurcation are qualitatively similar to known behavior of antigenic variation. These results are discussed and illustrated with specific examples and numerical simulations.

scholarly journals In VitroandIn VivoAntimalarial Activities of T-2307, a Novel Arylamidine

2012 ◽  
Vol 56 (4) ◽  
pp. 2191-2193 ◽  
Author(s):  
Akiko Kimura ◽  
Hiroshi Nishikawa ◽  
Nobuhiko Nomura ◽  
Junichi Mitsuyama ◽  
Shinya Fukumoto ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Body Weight ◽  
Broad Spectrum ◽  
Antimalarial Activity ◽  
Liver Stage ◽  
Rodent Malaria ◽  
Content Type ◽  
Clinically Significant

ABSTRACTT-2307, a novel arylamidine, has been shown to exhibit broad-spectrum antifungal activities against clinically significant pathogens. Here, we evaluated thein vitroandin vivoantimalarial activity of T-2307. The 50% inhibitory concentrations (IC50s) of T-2307 againstPlasmodium falciparumFCR-3 and K-1 strains were 0.47 and 0.17 μM, respectively. T-2307 at 2.5 to 10 mg/kg of body weight/day exhibited activity against blood stage and liver stage parasites in rodent malaria models. In conclusion, T-2307 exhibitedin vitroandin vivoantimalarial activity.

scholarly journals Nonspecific CD8+ T Cells and Dendritic Cells/Macrophages Participate in Formation of CD8+ T Cell-Mediated Clusters against Malaria Liver-Stage Infection

2018 ◽  
Vol 86 (4) ◽  
pp. e00717-17 ◽  
Author(s):  
Masoud Akbari ◽  
Kazumi Kimura ◽  
Ganchimeg Bayarsaikhan ◽  
Daisuke Kimura ◽  
Mana Miyakoda ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Protective Immunity ◽  
Cluster Formation ◽  
Dependent Manner ◽  
Liver Stage ◽  
Content Type ◽  
Stage Infection

ABSTRACT CD8+ T cells are the major effector cells that protect against malaria liver-stage infection, forming clusters around Plasmodium-infected hepatocytes and eliminating parasites after a prolonged interaction with these hepatocytes. We aimed to investigate the roles of specific and nonspecific CD8+ T cells in cluster formation and protective immunity. To this end, we used Plasmodium berghei ANKA expressing ovalbumin as well as CD8+ T cells from transgenic mice expressing a T cell receptor specific for ovalbumin (OT-I) and CD8+ T cells specific for an unrelated antigen, respectively. While antigen-specific CD8+ T cells were essential for cluster formation, both antigen-specific and nonspecific CD8+ T cells joined the clusters. However, nonspecific CD8+ T cells did not significantly contribute to protective immunity. In the livers of infected mice, specific CD8+ T cells expressed high levels of CD25, compatible with a local, activated effector phenotype. In vivo imaging of the liver revealed that specific CD8+ T cells interact with CD11c+ cells around infected hepatocytes. The depletion of CD11c+ cells virtually eliminated the clusters in the liver, leading to a significant decrease in protection. These experiments reveal an essential role of hepatic CD11c+ dendritic cells and presumably macrophages in the formation of CD8+ T cell clusters around Plasmodium-infected hepatocytes. Once cluster formation is triggered by parasite-specific CD8+ T cells, specific and unrelated activated CD8+ T cells join the clusters in a chemokine- and dendritic cell-dependent manner. Nonspecific CD8+ T cells seem to play a limited role in protective immunity against Plasmodium parasites.

scholarly journals Chemical Attenuation of Plasmodium berghei Sporozoites Induces Sterile Immunity in Mice

2008 ◽  
Vol 76 (3) ◽  
pp. 1193-1199 ◽  
Author(s):  
Lisa A. Purcell ◽  
Stephanie K. Yanow ◽  
Moses Lee ◽  
Terry W. Spithill ◽  
Ana Rodriguez
Keyword(s):  
Plasmodium Falciparum ◽  
Plasmodium Berghei ◽  
Alkylating Agent ◽  
Blood Stage ◽  
Wild Type ◽  
Vaccine Strategy ◽  
Liver Stage ◽  
Stage Development

ABSTRACT Radiation and genetic attenuation of Plasmodium sporozoites are two approaches for whole-organism vaccines that protect against malaria. We evaluated chemical attenuation of sporozoites as an alternative vaccine strategy. Sporozoites were treated with the DNA sequence-specific alkylating agent centanamycin, a compound that significantly affects blood stage parasitemia and transmission of murine malaria and also inhibits Plasmodium falciparum growth in vitro. Here we show that treatment of Plasmodium berghei sporozoites with centanamycin impaired parasite function both in vitro and in vivo. The infection of hepatocytes by sporozoites in vitro was significantly reduced, and treated parasites showed arrested liver stage development. Inoculation of mice with sporozoites that were treated in vitro with centanamycin failed to produce blood stage infections. Furthermore, BALB/c and C57BL/6 mice vaccinated with treated sporozoites were protected against subsequent challenge with wild-type sporozoites. Our findings demonstrate that chemically attenuated sporozoites could be a viable alternative for the production of an effective liver stage vaccine for malaria.

scholarly journals Identification of Plasmodium falciparum proteoforms from liver stage models

2020 ◽  
Vol 19 (1) ◽  
Author(s):  
Benjamin Winer ◽  
Kimberly A. Edgel ◽  
Xiaoyan Zou ◽  
Julie Sellau ◽  
Sri Hadiwidjojo ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Plasmodium Falciparum ◽  
Vaccine Development ◽  
Strongly Correlated ◽  
T Cell Epitopes ◽  
Liver Stage ◽  
Stage Models ◽  
Erythrocyte Antigen

Abstract Background Immunization with attenuated malaria sporozoites protects humans from experimental malaria challenge by mosquito bite. Protection in humans is strongly correlated with the production of T cells targeting a heterogeneous population of pre-erythrocyte antigen proteoforms, including liver stage antigens. Currently, few T cell epitopes derived from Plasmodium falciparum, the major aetiologic agent of malaria in humans are known. Methods In this study both in vitro and in vivo malaria liver stage models were used to sequence host and pathogen proteoforms. Proteoforms from these diverse models were subjected to mild acid elution (of soluble forms), multi-dimensional fractionation, tandem mass spectrometry, and top-down bioinformatics analysis to identify proteoforms in their intact state. Results These results identify a group of host and malaria liver stage proteoforms that meet a 5% false discovery rate threshold. Conclusions This work provides proof-of-concept for the validity of this mass spectrometry/bioinformatic approach for future studies seeking to reveal malaria liver stage antigens towards vaccine development.

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