scholarly journals SARS-CoV-2 Omicron: evasion of potent humoral responses and resistance to clinical immunotherapeutics relative to viral variants of concern

2022 ◽  
Author(s):  
Anupriya Aggarwal ◽  
Alberto Stella ◽  
Gregory Walker ◽  
Anouschka Akerman ◽  
Vanessa Milogiannakis ◽  
...  
Keyword(s):  
Mortality Rates ◽  
Clinical Effects ◽  
Human Igg ◽  
Gene Encoding ◽  
Virus Variant ◽  
Fold Reduction ◽  
Humoral Responses ◽  
The Impact ◽  
First World

Abstract Genetically distinct viral variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been recorded since January 2020. Over this time global vaccine programs have been introduced, contributing to lowered COVID-19 hospitalisation and mortality rates, particularly in the first world. In late 2021, the Omicron (B.1.1.529) virus variant emerged, with significant genetic differences and clinical effects from other variants of concern (VOC). This variant a demonstrated higher number of polymorphisms in the gene encoding the Spike (S) protein, and there has been displacement of the dominant Delta variant. We assessed the impact of Omicron infection on the ability of: serum from vaccinated and/or previously infected individuals; concentrated human IgG from plasma donors, and licensed monoclonal antibody therapies to neutralise the virus in vitro. There was a 17 to 27-fold reduction in neutralisation titres across all donors who had a detectable neutralising antibody titre to the Omicron variant. Concentrated pooled human IgG from convalescent and vaccinated donors had greater breadth of neutralisation, although the potency was still reduced 16-fold. Of all therapeutic antibodies tested, significant neutralisation of the Omicron variant was only observed for Sotrovimab, with other monoclonal antibodies unable to neutralise Omicron in vitro. These results have implications for ongoing therapy of individuals infected with the Omicron variant.

scholarly journals SARS-CoV-2 Omicron: reduction of potent humoral responses and resistance to clinical immunotherapeutics relative to viral variants of concern

2021 ◽  
Author(s):  
Anupriya Aggarwal ◽  
Alberto Ospina Stella ◽  
Gregory Walker ◽  
Anoushka Akerman ◽  
Vanessa Milogiannakis ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Mortality Rates ◽  
The Other ◽  
Therapeutic Antibodies ◽  
Human Igg ◽  
The World ◽  
Humoral Responses ◽  
Developed World ◽  
The Impact ◽  
Rapid Emergence

From late 2020 the world observed the rapid emergence of many distinct SARS-CoV-2 variants. At the same time, pandemic responses resulted in significant global vaccine rollouts that have now significantly lowered Covid-19 hospitalisation and mortality rates in the developed world. Unfortunately, in late 2021, the variant Omicron (B.1.1.529) emerged and it eclipsed the other variants of concern (VOC) in its number of Spike polymorphisms, and its ability to compete with and displacement of the dominant VOC Delta. Herein we accessed the impact of Omicron to humoral neutralisation in vaccinated, convalescent cohorts, in concentrated human IgG from thousands of plasma donors and also alongside many clinically used monoclonal antibodies. Overall, we observed a 17 to 22 fold drop in neutralisation titres across all donors that reached a titre to Omicron. Concentrated pooled human IgG from convalescent and vaccinated donors had greater breadth but was still reduced by 16-fold. In all therapeutic antibodies tested, significant neutralization was only observed for Sotrovimab, with other monoclonals unable to neutralize B.1.1.529.

scholarly journals Influence of Ferroportin Disease Mutations on Manganese Accumulation and Toxicity (P24-060-19)

2019 ◽  
Vol 3 (Supplement_1) ◽  
Author(s):  
Eun-kyung Choi ◽  
Young-Ah Seo
Keyword(s):  
Genetic Disorder ◽  
Functional Results ◽  
Site Directed Mutagenesis ◽  
Loss Of Function ◽  
Gene Encoding ◽  
Excess Iron ◽  
Funding Sources ◽  
Disease Mutations ◽  
The Impact

Abstract Objectives Hemochromatosis is a frequent genetic disorder characterized by the accumulation of excess iron across tissues. Mutations in the FPN1 gene, encoding a cell-surface iron exporter ferroportin (Fpn), are responsible for hemochromatosis type 4, also known as ferroportin disease. Recently, Fpn has been implicated in the regulation of manganese (Mn), another essential nutrient required for numerous cellular enzymes. However, the roles of Fpn in Mn regulation remain ill defined, and the impact of disease mutations on cellular Mn levels is unknown. Thus, this study aimed to define the role of Fpn in Mn regulation and determine the functional consequences of ferroportin disease mutations in cellular Mn levels. Methods Thus far, over 50 mutations in Fpn have been identified in hemochromatosis type 4/ferroportin disease. To test whether these mutations alter cellular Mn metabolism, we constructed an expression vector encoding human Fpn with a C-terminal HA epitope tag and introduced nine clinically relevant mutations by site-directed mutagenesis. Based on previously reported in vitro functional results, we selected five ferroportin disease mutations from each of the two groups: five loss-of-function (LOF) mutations (G80S, R88G, D157G, D157Y, and V162Δ) and four gain-of-function (GOF) mutations (N144H, N144T, C326S, and and S338R). Results Here, we provide evidence that Fpn can export Mn from cells into extracellular space. Fpn appears to play protective roles in Mn-induced cellular toxicity and oxidative stress. Finally, disease mutations interfere with Fpn's role in controlling Mn levels as well as the stability of Fpn. Conclusions These results define the function of Fpn as an exporter of both iron and Mn and highlight the potential involvement of Mn dysregulation in ferroportin disease. Funding Sources National Institutes of Health (NIH) to Y.A.S. (K99/R00 ES024340).

Metallo-β-lactamase resistance in Enterobacteriaceae is an artefact of currently utilized antimicrobial susceptibility testing methods

2020 ◽  
Vol 75 (4) ◽  
pp. 997-1005 ◽  
Author(s):  
Tomefa E Asempa ◽  
Kamilia Abdelraouf ◽  
David P Nicolau
Keyword(s):  
Susceptibility Testing ◽  
Bacterial Killing ◽  
Phenotypic Profile ◽  
Fold Reduction ◽  
Pharmacodynamic Profile ◽  
Zinc Depletion ◽  
Zinc Concentrations ◽  
The Impact

Abstract Background MBLs are a major contributor to β-lactam resistance when tested using CAMHB. Despite in vitro resistance, positive outcomes have been reported in MBL-infected patients following carbapenem treatment. The impact of physiological zinc concentrations on this in vitro–in vivo MBL discordance warrants investigation. Objectives To evaluate meropenem in vitro activity against MBL-producing Enterobacteriaceae in zinc-depleted broth (Chelex-CAMHB, EDTA-CAMHB) and assess meropenem efficacy in murine infection models. Methods Neutropenic mice received a meropenem human-simulated regimen of 2 g q8h or levofloxacin 750 mg q24h (for model validation). Zinc concentrations were determined in conventional CAMHB, zinc-depleted CAMHB and epithelial lining fluid (ELF) of lung-infected mice. Results All MBL-producing isolates (NDM, n = 25; VIM, n = 3; IMP, n = 2) examined were meropenem resistant in CAMHB and susceptible in zinc-depleted CAMHB (5- to 11-fold reduction), with zinc depletion having no impact on levofloxacin MICs. Zinc concentrations (mean ± SD) in CAMHB were 0.959 ± 0.038 mg/L and in both zinc-depleted CAMHB and ELF were <0.002 mg/L. In vivo, levofloxacin displayed predictable efficacy consistent with its phenotypic profile, while meropenem produced >1 log unit bacterial killing despite in vitro resistance in conventional CAMHB. Conclusions Results indicate that meropenem in vivo efficacy is best represented by the pharmacodynamic profile generated using MICs determined in zinc-depleted media for MBL-producing Enterobacteriaceae. These translational data suggest that the use of conventional CAMHB for MBL susceptibility testing is inappropriate in distinguishing meaningful in vivo resistance given that zinc concentrations are supraphysiological in conventional CAMHB and negligible at infection sites.

Erk1 Plays Critical Role in Macrophage Development

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 517-517 ◽  
Author(s):  
Yongzheng He ◽  
Karl Staser ◽  
Steven D Rhodes ◽  
Xiaohua Wu ◽  
Ping Zhang ◽  
...  
Keyword(s):  
Bone Mineral Density ◽  
Bone Marrow ◽  
Bone Mineral ◽  
Type I ◽  
Mineral Density ◽  
Macrophage Differentiation ◽  
Fold Reduction ◽  
The Impact

Abstract Abstract 517 Extracellular signal-regulated kinase (ERK 1 and 2) are widely expressed and are involved in the regulation of meiosis, mitosis, and postmitotic functions in multiple cell lineages, including T cells, B cells and osteoblasts. Macrophages are capable of differentiating into osteoclasts, which resorb bone. Abnormal osteoclast development and functions underlie certain diseases, especially skeletal defects. Altered ERK1/2 signaling has been found in several genetic diseases with skeletal phenotypes, including Noonan syndrome, polycystic kidney disease and serious developmental disorders such as cardio-facio-cutaneous syndrome. These clinical findings suggest the importance of the ERK MAPK pathway in human skeletal development. In the present study, we examined the consequence of Erk1 and Erk2 disruption in modulating macrophage development in the murine system. We found that deletion of Erk1 reduced macrophage progenitor numbers. Erk1−/− bone marrow mononuclear cells (BMMNCs) had significant reduction in osteoclast formation as compared to wildtype BMMNCs. In addition, Erk1−/− macrophages; the osteoclast progenitors, had a two-three fold reduction in migration and a two-fold reduction in αv ß3 mediated adhesion as compared to WT macrophages as evaluated by transwell and adhesion assay, respectively. These in vitro data demonstrate that Erk1 positively regulates macrophage differentiation into osteoclasts. To evaluate the impact of deficiency of Erk1 in vivo, we examined bone mineral density and trabecular microarchitecture in the distal femoral metaphysis by dual-energy X-ray absorptiometry (DEXA) with a Lunar Piximus densitometer and a high-resolution desktop microcomputed tomography imaging system (μCT-20; Scanco Medical AG, Basserdorf, Switzerland), respectively. Erk1−/− mice displayed elevated bone mineral density and increased trabecular bone formation as compared to WT mice. Histomorphometric analysis indicated that the Erk1−/− femur had significant reduction in osteoclast numbers as determined by tartrate resistant acid phosphatase staining, an osteoclast specific staining, as compared to femur of wildtype and Erk2−/− mice. Most importantly, Erk1−/− plasma had reduced C-terminal telopeptide of type I collagen, indicating less bone resorption in vivo. These data suggest that the impaired macrophage differentiation and osteoclast bone resorptive activity play an important role in increased bone mass in Erk1−/− mice. Finally, to verify that the macrophage-osteoclast lineage is a key cell lineage for the phenotypic changes in vivo in Erk1−/− mice, we performed bone marrow transplantation. WT mice reconstituted long-term with Erk1−/− hematopoietic stem cells demonstrated increased bone mineral density as compared to WT and Erk2−/− stem cell recipients, implicating marrow autonomous, Erk1-dependent macrophage differentiation and osteoclast bioactivity in vivo. Collectively, our in vitro and in vivo data demonstrate isoform-specific Erk function in macrophage while providing rationale for the development of a specific inhibitor for Erk1 that might be used for the treatment of dysplastic and erosive bone diseases. Disclosures: No relevant conflicts of interest to declare.

Mutations in Both env and gag genes are required for HIV-1 resistance to the polysulfonic dendrimer SPL2923, as corroborated by chimeric virus technology

2005 ◽  
Vol 16 (4) ◽  
pp. 253-266 ◽  
Author(s):  
Anke Hantson ◽  
Valery Fikkert ◽  
Barbara Van Remoortel ◽  
Chistophe Pannecouque ◽  
Peter Cherepanov ◽  
...  
Keyword(s):  
Matrix Protein ◽  
In Vitro Selection ◽  
Chimeric Virus ◽  
Cross Resistance ◽  
Phenotypic Analysis ◽  
Gene Encoding ◽  
The Cross ◽  
The Impact ◽  
Hiv 1

A drug-resistant NL4.3.SPL2923 strain has previously been generated by in vitro selection of HIV-1(NL4.3) in the presence of the polysulfonic dendrimer SPL2923 and mutations were reported in its gp120 gene (Witvrouw et al., 2000). Here, we further analysed the (cross) resistance profile of NL4.3/SPL2923. NL4.3.SPL2923 was found to contain additional mutations in gp41 and showed reduced susceptibility to SPL2923, dextran sulfate (DS) and enfuvirtide. To delineate to what extent the mutations in each env gene were accountable for the phenotypic (cross) resistance of NL4.3.SPL2923, the gp120-, gp41- and gp160-sequences derived from this strain were placed into a wild-type background using env chimeric virus technology (CVT). The cross resistance of NL4.3.SPL2923 towards DS was fully reproduced following gp160recombination, while it was only partially reproduced following gp120- or gp41-recombination. The mutations in gp41 of NL4.3/SPL2923 were sufficient to reproduce the cross resistance to enfuvirtide. Unexpectedly, the reduced sensitivity towards SPL2923 was not fully reproduced after gp160-recombination. The search for mutations in NL4.3.SPL2923 in viral genes other than env revealed several mutations in the gene encoding the HIV p17 matrix protein (MA) and one mutation in the gene encoding the p24 capsid protein (CA). In order to analyse the impact of the gag mutations alone and in combination with the mutations in env on the phenotypic resistance towards SPL2923, we developed a novel p17- and p17.gp160-CVT. Phenotypic analysis of the NL4.3.SPL2923 p17- and p17.gp160-recombined strains indicated that the mutations in both env and gag have to be present to fully reproduce the resistance of NL4.3.SPL2923 towards SPL2923.

scholarly journals Restructuring citrus endophytic diversity through potential indigenous endophytes could eliminate huanglongbing pathogen Candidatus Liberibacter asiaticus

2020 ◽  
Author(s):  
Shahzad Munir ◽  
Yongmei Li ◽  
Pengfei He ◽  
Pengbo He ◽  
Pengjie He ◽  
...  
Keyword(s):  
Large Scale ◽  
Pathogen Resistance ◽  
Candidatus Liberibacter Asiaticus ◽  
Citrus Grove ◽  
Fold Reduction ◽  
Candidatus Liberibacter ◽  
Liberibacter Asiaticus ◽  
The Impact ◽  
Leaf Midrib

Abstract Background Huanglongbing (HLB) is a major botanical pandemic of citrus crops caused by Candidatus Liberibacter asiaticus (Clas). It is important to understand the different mechanisms involved in interaction of pathogen with plants to develop novel management strategy against HLB. However, until now there has been no control strategy to manage this disease in vitro and on large scale in citrus grove. We found that, indigenous endophyte Bacillus subtilis L1-21, a patented strain isolated from healthy citrus tree, may have the potential to reduce the impact of pathogen through restructuring of core endophytes. Results A novel half-leaf method was developed to test the efficacy of B. subtilis L1-21 against Clas. Concentration of B. subtilis L1-21 at 104 cfu ml− 1 resulted in a 1000-fold reduction in Clas copy densities per gram of leaf midrib (107 to 104) by 4 d after treatment. With endophytes, where HLB incidence was reduced to < 3% and Clas copy density was reduced from 109 to 104 pathogen g− 1 of diseased leaf midrib. We found that 16 of 93 tree samples became Clas-free and functional pathways and pathogen resistance genes were regulated in diseased citrus trees after treatment. Conclusions This is the first large-scale study using an indigenous endophyte and shows its potential utility in sustainable disease management through strengthening the citrus microbiome.

scholarly journals CdpA Is a Burkholderia pseudomallei Cyclic di-GMP Phosphodiesterase Involved in Autoaggregation, Flagellum Synthesis, Motility, Biofilm Formation, Cell Invasion, and Cytotoxicity

2010 ◽  
Vol 78 (5) ◽  
pp. 1832-1840 ◽  
Author(s):  
Hwee Siang Lee ◽  
Feiyu Gu ◽  
Shi Min Ching ◽  
Yulin Lam ◽  
Kim Lee Chua
Keyword(s):  
Intracellular Signaling ◽  
Biofilm Formation ◽  
Burkholderia Pseudomallei ◽  
Cell Aggregation ◽  
Lung Epithelial Cells ◽  
Human Macrophage ◽  
Null Mutant ◽  
Gene Encoding ◽  
Fold Reduction

ABSTRACT Cyclic diguanylic acid (c-di-GMP) is an intracellular signaling molecule involved in regulation of cellular functions such as motility, biofilm formation and virulence. Intracellular level of c-di-GMP is controlled through opposing diguanylate cyclase (DGC) and phosphodiesterase (PDE) activities of GGDEF and EAL domain proteins, respectively. We report the identification and characterization of cdpA, a gene encoding a protein containing an EAL domain in the Gram-negative soil bacillus and human pathogen Burkholderia pseudomallei KHW. Purified recombinant CdpA protein exhibited PDE activity in vitro. Evidence that CdpA is a major c-di-GMP-specific PDE in B. pseudomallei KHW was shown by an 8-fold-higher c-di-GMP level in the cdpA-null mutant as compared to the wild type and the complemented cdpA mutant. The presence of higher intracellular c-di-GMP levels in the cdpA-null mutant was associated with increased production of exopolysaccharides, increased cell-to-cell aggregation, absence of flagella and swimming motility, and increased biofilm formation. The relevance of CdpA in B. pseudomallei virulence was demonstrated by a 3-fold reduction in invasion of human lung epithelial cells and a 6-fold reduction in cytotoxicity on human macrophage cells infected with the cdpA mutant.

Biophysical groundwork as a hinge to unravel the biology of α-synuclein aggregation and toxicity

2014 ◽  
Vol 47 (1) ◽  
pp. 1-48 ◽  
Author(s):  
Nicoletta Plotegher ◽  
Elisa Greggio ◽  
Marco Bisaglia ◽  
Luigi Bubacco
Keyword(s):  
Point Mutations ◽  
Alpha Synuclein ◽  
Aggregation Process ◽  
Gene Encoding ◽  
Cellular Models ◽  
Transient Complex ◽  
Biophysical Studies ◽  
Heterogeneous Ensemble ◽  
The Impact

AbstractAlpha-synuclein (aS) and its aggregation properties are central in the development and spread of Parkinson's disease. Point mutations and multiplications of the SNCA gene encoding aS cause autosomal dominant forms of the disorder. Moreover, protein inclusions found in the surviving neurons of parkinsonian brains consist mainly of a fibrillar form of aS. Aggregates of aS, which form a transient, complex and heterogeneous ensemble, participate in a wide variety of toxic mechanisms that may be amplified by aS spreading among neighbouring neurons. Recently, significant effort has been directed into the study of the aS aggregation process and the impact of aS aggregates on neuron survival. In this review, we present state-of-the-art biophysical studies on the aS aggregation process in vitro and in cellular models. We comprehensively review the new insights generated by the recent biophysical investigations, which could provide a solid basis from which to design future biomedical studies. The diverse cellular models of aS toxicity and their potential use in the biophysical investigation are also discussed.

scholarly journals Neutralization of SARS-CoV-2 Variants by Serum from BNT162b2 Vaccine Recipients

Viruses ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 2011
Author(s):  
Fabrizia Valleriani ◽  
Elisa Mancuso ◽  
Giacomo Vincifori ◽  
Liana Teodori ◽  
Lisa Di Marcantonio ◽  
...  
Keyword(s):  
Reference Strain ◽  
Vaccine Dose ◽  
Humoral Response ◽  
Serum Samples ◽  
Fold Reduction ◽  
Long Term Follow Up ◽  
The Impact

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has evolved rapidly, leading to viral lineages characterized by multiple mutations in the spike protein, which could potentially confer to the virus the ability to avoid the vaccine-induced immune response, making the vaccines less effective or ineffective. Here, we initially evaluated the neutralization capabilities in vitro by serum neutralization (SN) of six serum samples collected from recipients of the BNT162b2 vaccine against 11 SARS-CoV-2 isolates belonging to the major SARS-CoV-2 lineages that had been circulating in Italy. Then, we considered 30 additional serum samples by SN assay against the dominant B.1.617.2 (Delta) variant. A B.1 lineage isolate was used as a reference. In the first analysis, significant differences when compared with the reference strain (p > 0.05) were not evidenced; instead, when the panel of 30 sera was tested against the B.1.617.2 (Delta) variant, a significant (p = 0.0015) 2.38-fold reduction in neutralizing titres compared with the reference after the first vaccine dose was demonstrated. After the second vaccine dose, the reduction was not significant (p = 0.1835). This study highlights that the BNT162b2 vaccine stimulates a humoral response able to neutralize all tested SARS-CoV-2 variants, thus suggesting a prominent role in mitigating the impact of the SARS-CoV-2 pandemic in real-world conditions. Long-term follow-up is currently ongoing.

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