scholarly journals Severe malarial anemia of low parasite burden in rodent models results from accelerated clearance of uninfected erythrocytes

Blood ◽  
2006 ◽  
Vol 107 (3) ◽  
pp. 1192-1199 ◽  
Author(s):  
Krystal J. Evans ◽  
Diana S. Hansen ◽  
Nico van Rooijen ◽  
Lynn A. Buckingham ◽  
Louis Schofield
Keyword(s):  
Parasite Burden ◽  
Rodent Models ◽  
Phagocytic Cells ◽  
Severe Malarial Anemia ◽  
Blood Compartment ◽  
Circulating Cells ◽  
Life Threatening ◽  
Patent Infection ◽  
Malarial Anemia

AbstractSevere malarial anemia (SMA) is the most frequent life-threatening complication of malaria and may contribute to the majority of malarial deaths worldwide. To explore the mechanisms of pathogenesis, we developed a novel murine model of SMA in which parasitemias peaked around 1.0% of circulating red blood cells (RBCs) and yet hemoglobin levels fell to 47% to 56% of baseline. The severity of anemia was independent of the level of peak or cumulative parasitemia, but was linked kinetically to the duration of patent infection. In vivo biotinylation analysis of the circulating blood compartment revealed that anemia arose from accelerated RBC turnover. Labeled RBCs were reduced to 1% of circulating cells by 8 days after labeling, indicating that the entire blood compartment had been turned over in approximately one week. The survival rate of freshly transfused RBCs was also markedly reduced in SMA animals, but was not altered when RBCs from SMA donors were transferred into naive recipients, suggesting few functional modifications to target RBCs. Anemia was significantly alleviated by depletion of either phagocytic cells or CD4+ T lymphocytes. This study demonstrates that immunologic mechanisms may contribute to SMA by promoting the accelerated turnover of uninfected RBCs.

scholarly journals Developing a novel risk prediction model for severe malarial anemia

2017 ◽  
Vol 2 ◽  
Author(s):  
E. B. Brickley ◽  
E. Kabyemela ◽  
J. D. Kurtis ◽  
M. Fried ◽  
A. M. Wood ◽  
...  
Keyword(s):  
Prediction Model ◽  
Prediction Models ◽  
Blood Levels ◽  
Transmission Season ◽  
Severe Malarial Anemia ◽  
Screening Programs ◽  
Life Threatening ◽  
Larger Sample ◽  
Related Mortality ◽  
Malarial Anemia

AbstractAs a pilot study to investigate whether personalized medicine approaches could have value for the reduction of malaria-related mortality in young children, we evaluated questionnaire and biomarker data collected from the Mother Offspring Malaria Study Project birth cohort (Muheza, Tanzania, 2002–2006) at the time of delivery as potential prognostic markers for pediatric severe malarial anemia. Severe malarial anemia, defined here as aPlasmodium falciparuminfection accompanied by hemoglobin levels below 50 g/L, is a key manifestation of life-threatening malaria in high transmission regions. For this study sample, a prediction model incorporating cord blood levels of interleukin-1β provided the strongest discrimination of severe malarial anemia risk with a C-index of 0.77 (95% CI 0.70–0.84), whereas a pragmatic model based on sex, gravidity, transmission season at delivery, and bed net possession yielded a more modest C-index of 0.63 (95% CI 0.54–0.71). Although additional studies, ideally incorporating larger sample sizes and higher event per predictor ratios, are needed to externally validate these prediction models, the findings provide proof of concept that risk score-based screening programs could be developed to avert severe malaria cases in early childhood.

scholarly journals Sequential Plasmodium chabaudi and Plasmodium berghei Infections Provide a Novel Model of Severe Malarial Anemia

2012 ◽  
Vol 80 (9) ◽  
pp. 2997-3007 ◽  
Author(s):  
Juliana V. Harris ◽  
Tiffany M. Bohr ◽  
Catherine Stracener ◽  
Mary E. Landmesser ◽  
Vladimir Torres ◽  
...  
Keyword(s):  
Ex Vivo ◽  
Interleukin 10 ◽  
Red Cells ◽  
Second Phase ◽  
Necrosis Factor Alpha ◽  
Content Type ◽  
Severe Malarial Anemia ◽  
Antibody Levels ◽  
Malarial Anemia

ABSTRACTLack of an adequate animal model ofPlasmodium falciparumsevere malarial anemia (SMA) has hampered the understanding of this highly lethal condition. We developed a model of SMA by infecting C57BL/6 mice withP. chabaudifollowed after recovery byP. bergheiinfection.P. chabaudi/P. berghei-infected mice had an initial 9- to 10-day phase of relatively low parasitemia and severe anemia, followed by a second phase of hyperparasitemia, more profound anemia, reticulocytosis, and death 14 to 21 days after infection.P. chabaudi/P. berghei-infected animals had more intense splenic hematopoiesis, higher interleukin-10 (IL-10)/tumor necrosis factor alpha and IL-12/gamma interferon (IFN-γ) ratios, and higher antibody levels againstP. bergheiandP. chabaudiantigens thanP. berghei-infected orP. chabaudi-recovered animals. Early treatment with chloroquine or artesunate did not prevent the anemia, suggesting that the bulk of red cell destruction was not due to the parasite. Red cells fromP. chabaudi/P. berghei-infected animals had increased surface IgG and C3 by flow cytometry. However, C3−/−mice still developed anemia. Tracking of red cells labeledex vivoandin vivoand analysis of frozen tissue sections by immunofluorescence microscopy showed that red cells fromP. chabaudi/P. berghei-infected animals were removed at an accelerated rate in the liver by erythrophagocytosis. This model is practical and reproducible, and its similarities withP. falciparumSMA in humans makes it an appealing system with which to study the pathogenesis of this condition and explore potential immunomodulatory interventions.

scholarly journals Acquisition of Hemozoin by Monocytes Down-Regulates Interleukin-12 p40 (IL-12p40) Transcripts and Circulating IL-12p70 through an IL-10-Dependent Mechanism: In Vivo and In Vitro Findings in Severe Malarial Anemia

2006 ◽  
Vol 74 (9) ◽  
pp. 5249-5260 ◽  
Author(s):  
Christopher C. Keller ◽  
Ouma Yamo ◽  
Collins Ouma ◽  
John Michael Ong'echa ◽  
David Ounah ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Mononuclear Cells ◽  
Interleukin 12 ◽  
Peripheral Blood Mononuclear ◽  
Necrosis Factor Alpha ◽  
Severe Malarial Anemia ◽  
Tnf Α ◽  
Malarial Anemia

ABSTRACT Severe malarial anemia (SMA) is a primary cause of morbidity and mortality in immune-naïve infants and young children residing in areas of holoendemic Plasmodium falciparum transmission. Although the immunopathogenesis of SMA is largely undefined, we have previously shown that systemic interleukin-12 (IL-12) production is suppressed during childhood blood-stage malaria. Since IL-10 and tumor necrosis factor alpha (TNF-α) are known to decrease IL-12 synthesis in a number of infectious diseases, altered transcriptional regulation of these inflammatory mediators was investigated as a potential mechanism for IL-12 down-regulation. Ingestion of naturally acquired malarial pigment (hemozoin [PfHz]) by monocytes promoted the overproduction of IL-10 and TNF-α relative to the production of IL-12, which correlated with an enhanced severity of malarial anemia. Experiments with cultured peripheral blood mononuclear cells (PBMC) and CD14+ cells from malaria-naïve donors revealed that physiological concentrations of PfHz suppressed IL-12 and augmented IL-10 and TNF-α by altering the transcriptional kinetics of IL-12p40, IL-10, and TNF-α, respectively. IL-10 neutralizing antibodies, but not TNF-α antibodies, restored PfHz-induced suppression of IL-12. Blockade of IL-10 and the addition of recombinant IL-10 to cultured PBMC from children with SMA confirmed that IL-10 was responsible for malaria-induced suppression of IL-12. Taken together, these results demonstrate that PfHz-induced up-regulation of IL-10 is responsible for the suppression of IL-12 during malaria.

scholarly journals Low plasma haptoglobin is a risk factor for life-threatening childhood severe malarial anemia and not an exclusive consequence of hemolysis

2018 ◽  
Vol 8 (1) ◽  
Author(s):  
Samuel Eneọjọ Abah ◽  
Florence Burté ◽  
Sandrine Marquet ◽  
Biobele J. Brown ◽  
Francis Akinkunmi ◽  
...  
Keyword(s):  
Risk Factor ◽  
Severe Malarial Anemia ◽  
Life Threatening ◽  
Plasma Haptoglobin ◽  
Malarial Anemia

In Silico Identification of a Potent Arsenic Based Approved Drug Darinaparsin against SARS-CoV-2: Inhibitor of RNA Dependent RNA polymerase (RdRp) and Essential Proteases

2020 ◽  
Vol 20 ◽  
Author(s):  
Trinath Chowdhury ◽  
Gourisankar Roymahapatra ◽  
Santi M. Mandal
Keyword(s):  
Rna Polymerase ◽  
Viral Entry ◽  
In Silico ◽  
Rna Dependent Rna Polymerase ◽  
Replication Complex ◽  
In Silico Study ◽  
Life Threatening ◽  
In Vivo Analysis ◽  
3Cl Protease

Background: COVID-19 is a life threatening novel corona viral infection to our civilization and spreading rapidly. Terrific efforts are generous by the researchers to search for a drug to control SARS-CoV-2. Methods: Here, a series of arsenical derivatives were optimized and analyzed with in silico study to search the inhibitor of RNA dependent RNA polymerase (RdRp), the major replication factor of SARS-CoV-2. All the optimized derivatives were blindly docked with RdRp of SARS-CoV-2 using iGEMDOCK v2.1. Results: Based on the lower idock score in the catalytic pocket of RdRp, darinaparsin (-82.52 kcal/mol) revealed most effective among them. Darinaparsin strongly binds with both Nsp9 replicase protein (-8.77 kcal/mol) and Nsp15 endoribonuclease (-8.3 kcal/mol) of SARS-CoV-2 as confirmed from the AutoDock analysis. During infection, the ssRNA of SARS-CoV2 is translated into large polyproteins forming viral replication complex by specific proteases like 3CL protease and papain protease. This is also another target to control the virus infection where darinaparsin also perform the inhibitory role to proteases of 3CL protease (-7.69 kcal/mol) and papain protease (-8.43 kcal/mol). Conclusion: In host cell, the furin protease serves as a gateway to the viral entry and darinaparsin docked with furin protease which revealed a strong binding affinity. Thus, screening of potential arsenic drugs would help in providing the fast invitro to in-vivo analysis towards development of therapeutics against SARS-CoV-2.

scholarly journals In vivo multi-parametric manganese-enhanced MRI for detecting amyloid plaques in rodent models of Alzheimer’s disease

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Eugene Kim ◽  
Davide Di Censo ◽  
Mattia Baraldo ◽  
Camilla Simmons ◽  
Ilaria Rosa ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Plaques ◽  
Transgenic Animals ◽  
Surrounding Tissue ◽  
Rodent Models ◽  
Enhanced Mri ◽  
5Xfad Mice ◽  
Manganese Enhanced Mri

AbstractAmyloid plaques are a hallmark of Alzheimer’s disease (AD) that develop in its earliest stages. Thus, non-invasive detection of these plaques would be invaluable for diagnosis and the development and monitoring of treatments, but this remains a challenge due to their small size. Here, we investigated the utility of manganese-enhanced MRI (MEMRI) for visualizing plaques in transgenic rodent models of AD across two species: 5xFAD mice and TgF344-AD rats. Animals were given subcutaneous injections of MnCl2 and imaged in vivo using a 9.4 T Bruker scanner. MnCl2 improved signal-to-noise ratio but was not necessary to detect plaques in high-resolution images. Plaques were visible in all transgenic animals and no wild-types, and quantitative susceptibility mapping showed that they were more paramagnetic than the surrounding tissue. This, combined with beta-amyloid and iron staining, indicate that plaque MR visibility in both animal models was driven by plaque size and iron load. Longitudinal relaxation rate mapping revealed increased manganese uptake in brain regions of high plaque burden in transgenic animals compared to their wild-type littermates. This was limited to the rhinencephalon in the TgF344-AD rats, while it was most significantly increased in the cortex of the 5xFAD mice. Alizarin Red staining suggests that manganese bound to plaques in 5xFAD mice but not in TgF344-AD rats. Multi-parametric MEMRI is a simple, viable method for detecting amyloid plaques in rodent models of AD. Manganese-induced signal enhancement can enable higher-resolution imaging, which is key to visualizing these small amyloid deposits. We also present the first in vivo evidence of manganese as a potential targeted contrast agent for imaging plaques in the 5xFAD model of AD.

scholarly journals Characterization of Distinctive In Vivo Metabolism between Enhancing and Non-Enhancing Gliomas Using Hyperpolarized Carbon-13 MRI

Metabolites ◽  
2021 ◽  
Vol 11 (8) ◽  
pp. 504
Author(s):  
Seunggwi Park ◽  
Hashizume Rintaro ◽  
Seul Kee Kim ◽  
Ilwoo Park
Keyword(s):  
Metabolic Imaging ◽  
Metabolic Profiles ◽  
Rodent Models ◽  
In Vivo Metabolism ◽  
Hyperpolarized 13C ◽  
Noninvasive Assessment ◽  
Diffuse Midline Glioma ◽  
Mr Spectroscopic Imaging

The development of hyperpolarized carbon-13 (13C) metabolic MRI has enabled the sensitive and noninvasive assessment of real-time in vivo metabolism in tumors. Although several studies have explored the feasibility of using hyperpolarized 13C metabolic imaging for neuro-oncology applications, most of these studies utilized high-grade enhancing tumors, and little is known about hyperpolarized 13C metabolic features of a non-enhancing tumor. In this study, 13C MR spectroscopic imaging with hyperpolarized [1-13C]pyruvate was applied for the differential characterization of metabolic profiles between enhancing and non-enhancing gliomas using rodent models of glioblastoma and a diffuse midline glioma. Distinct metabolic profiles were found between the enhancing and non-enhancing tumors, as well as their contralateral normal-appearing brain tissues. The preliminary results from this study suggest that the characterization of metabolic patterns from hyperpolarized 13C imaging between non-enhancing and enhancing tumors may be beneficial not only for understanding distinct metabolic features between the two lesions, but also for providing a basis for understanding 13C metabolic processes in ongoing clinical trials with neuro-oncology patients using this technology.

scholarly journals Fibrosis after Myocardial Infarction: An Overview on Cellular Processes, Molecular Pathways, Clinical Evaluation and Prognostic Value

2021 ◽  
Vol 9 (1) ◽  
pp. 16
Author(s):  
Renato Francesco Maria Scalise ◽  
Rosalba De Sarro ◽  
Alessandro Caracciolo ◽  
Rita Lauro ◽  
Francesco Squadrito ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Signaling Pathways ◽  
Ventricular Dysfunction ◽  
Healing Process ◽  
Molecular Signaling ◽  
Cellular Processes ◽  
Molecular Signaling Pathways ◽  
Fibrotic Scar ◽  
Life Threatening

The ischemic injury caused by myocardial infarction activates a complex healing process wherein a powerful inflammatory response and a reparative phase follow and balance each other. An intricate network of mediators finely orchestrate a large variety of cellular subtypes throughout molecular signaling pathways that determine the intensity and duration of each phase. At the end of this process, the necrotic tissue is replaced with a fibrotic scar whose quality strictly depends on the delicate balance resulting from the interaction between multiple actors involved in fibrogenesis. An inflammatory or reparative dysregulation, both in term of excess and deficiency, may cause ventricular dysfunction and life-threatening arrhythmias that heavily affect clinical outcome. This review discusses cellular process and molecular signaling pathways that determine fibrosis and the imaging technique that can characterize the clinical impact of this process in-vivo.

scholarly journals A sand fly salivary protein acts as a neutrophil chemoattractant

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Anderson B. Guimaraes-Costa ◽  
John P. Shannon ◽  
Ingrid Waclawiak ◽  
Jullyanna Oliveira ◽  
Claudio Meneses ◽  
...  
Keyword(s):  
Inflammatory Responses ◽  
Calcium Influx ◽  
Parasite Burden ◽  
Salivary Protein ◽  
Sand Fly ◽  
Human Neutrophils ◽  
Chemotactic Protein ◽  
The Impact

AbstractApart from bacterial formyl peptides or viral chemokine mimicry, a non-vertebrate or insect protein that directly attracts mammalian innate cells such as neutrophils has not been molecularly characterized. Here, we show that members of sand fly yellow salivary proteins induce in vitro chemotaxis of mouse, canine and human neutrophils in transwell migration or EZ-TAXIScan assays. We demonstrate murine neutrophil recruitment in vivo using flow cytometry and two-photon intravital microscopy in Lysozyme-M-eGFP transgenic mice. We establish that the structure of this ~ 45 kDa neutrophil chemotactic protein does not resemble that of known chemokines. This chemoattractant acts through a G-protein-coupled receptor and is dependent on calcium influx. Of significance, this chemoattractant protein enhances lesion pathology (P < 0.0001) and increases parasite burden (P < 0.001) in mice upon co-injection with Leishmania parasites, underlining the impact of the sand fly salivary yellow proteins on disease outcome. These findings show that some arthropod vector-derived factors, such as this chemotactic salivary protein, activate rather than inhibit the host innate immune response, and that pathogens take advantage of these inflammatory responses to establish in the host.

scholarly journals Suppression of a Novel Hematopoietic Mediator in Children with Severe Malarial Anemia

2009 ◽  
Vol 77 (9) ◽  
pp. 3864-3871 ◽  
Author(s):  
Christopher C. Keller ◽  
Collins Ouma ◽  
Yamo Ouma ◽  
Gordon A. Awandare ◽  
Gregory C. Davenport ◽  
...  
Keyword(s):  
Growth Factor ◽  
Mononuclear Cells ◽  
Dependent Manner ◽  
Peripheral Blood Mononuclear ◽  
Severe Malarial Anemia ◽  
Lectin Domain ◽  
Stem Cell Growth Factor ◽  
Reticulocyte Production ◽  
Pediatric Morbidity ◽  
Malarial Anemia

ABSTRACT In areas of holoendemic Plasmodium falciparum transmission, severe malarial anemia (SMA) is a leading cause of pediatric morbidity and mortality. Although many soluble mediators regulate erythropoiesis, it is unclear how these factors contribute to development of SMA. Investigation of novel genes dysregulated in response to malarial pigment (hemozoin [PfHz]) revealed that stem cell growth factor (SCGF; also called C-type lectin domain family member 11A [CLEC11A]), a hematopoietic growth factor important for development of erythroid and myeloid progenitors, was one of the most differentially expressed genes. Additional experiments with cultured peripheral blood mononuclear cells (PBMCs) demonstrated that PfHz decreased SCGF/CLEC11A transcriptional expression in a time-dependent manner. Circulating SCGF levels were then determined for Kenyan children (n = 90; aged 3 to 36 months) presenting at a rural hospital with various severities of malarial anemia. SCGF levels in circulation (P = 0.001) and in cultured PBMCs (P = 0.004) were suppressed in children with SMA. Circulating SCGF also correlated positively with hemoglobin levels (r = 0.241; P = 0.022) and the reticulocyte production index (RPI) (r = 0.280; P = 0.029). In addition, SCGF was decreased in children with reduced erythropoiesis (RPI of <2) (P < 0.001) and in children with elevated levels of naturally acquired monocytic PfHz (P = 0.019). Thus, phagocytosis of PfHz promotes a decrease in SCGF gene products, which may contribute to reduced erythropoiesis in children with SMA.

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