scholarly journals The inherent mutational tolerance and antigenic evolvability of influenza hemagglutinin

2014 ◽  
Author(s):  
Bargavi Thyagarajan ◽  
Jesse D. Bloom
Keyword(s):  
Amino Acid ◽  
H1n1 Influenza ◽  
Influenza Hemagglutinin ◽  
Functional Variants ◽  
Viral Hemagglutinin ◽  
Before And After ◽  
Amino Acid Mutations ◽  
And Function ◽  
Phylogenetic Models ◽  
Better Than

AbstractInfluenza is notable for its evolutionary capacity to escape immunity targeting the viral hemagglutinin. We used deep mutational scanning to examine the extent to which a high inherent mutational tolerance contributes to this antigenic evolvability. We created mutant viruses that incorporate most of the ≈ 104 amino-acid mutations to hemagglutinin from A/WSN/1933 (H1N1) influenza. After passaging these viruses in tissue culture to select for functional variants, we used deep sequencing to quantify mutation frequencies before and after selection. These data enable us to infer the preference for each amino acid at each site in hemagglutinin. These inferences are consistent with existing knowledge about the protein’s structure and function, and can be used to create a model that describes hemagglutinin’s evolution far better than existing phylogenetic models. We show that hemagglutinin has a high inherent tolerance for mutations at antigenic sites, suggesting that this is one factor contributing to influenza’s antigenic evolution.

scholarly journals The inherent mutational tolerance and antigenic evolvability of influenza hemagglutinin

eLife ◽  
2014 ◽  
Vol 3 ◽  
Author(s):  
Bargavi Thyagarajan ◽  
Jesse D Bloom
Keyword(s):  
Amino Acid ◽  
H1n1 Influenza ◽  
Influenza Hemagglutinin ◽  
Functional Variants ◽  
Viral Hemagglutinin ◽  
Before And After ◽  
Amino Acid Mutations ◽  
And Function ◽  
Phylogenetic Models ◽  
Better Than

Influenza is notable for its evolutionary capacity to escape immunity targeting the viral hemagglutinin. We used deep mutational scanning to examine the extent to which a high inherent mutational tolerance contributes to this antigenic evolvability. We created mutant viruses that incorporate most of the ≈104 amino-acid mutations to hemagglutinin from A/WSN/1933 (H1N1) influenza. After passaging these viruses in tissue culture to select for functional variants, we used deep sequencing to quantify mutation frequencies before and after selection. These data enable us to infer the preference for each amino acid at each site in hemagglutinin. These inferences are consistent with existing knowledge about the protein's structure and function, and can be used to create a model that describes hemagglutinin's evolution far better than existing phylogenetic models. We show that hemagglutinin has a high inherent tolerance for mutations at antigenic sites, suggesting that this is one factor contributing to influenza's antigenic evolution.

scholarly journals Hemagglutination Inhibition (HAI) Antibody Landscapes after Vaccination with diverse H7 hemagglutinin (HA) proteins

2021 ◽  
Author(s):  
Hyesun Jang ◽  
Ted M Ross
Keyword(s):  
Amino Acid ◽  
Hemagglutination Inhibition ◽  
Lethal Dose ◽  
Antigenic Site ◽  
Glycosylation Site ◽  
Amino Acid Sequences ◽  
Serum Samples ◽  
Influenza Hemagglutinin ◽  
Amino Acid Mutations ◽  
Antigenic Profile

AbstractBackgroundA systemic evaluation of the antigenic differences of the H7 influenza hemagglutinin (HA) proteins, especially for the viruses isolated after 2016, are limited. The purpose of this study was to investigate the antigenic differences of major H7 strains with an ultimate aim to discover H7 HA proteins that can elicit protective receptor-blocking antibodies against co-circulating H7 influenza strains.MethodA panel of nine H7 influenza strains were selected from 3,633 H7 HA amino acid sequences identified over the past two decades (2000-2018). The sequences were expressed on the surface of virus like particles (VLPs) and used to vaccinate C57BL/6 mice. Serum samples were collected and tested for hemagglutination-inhibition (HAI) activity. The vaccinated mice were challenged with lethal dose of H7N9 virus, A/Anhui/1/2013.ResultsVLPs expressing the H7 HA antigens elicited broadly reactive antibodies each of the selected H7 HAs, except the A/Turkey/Italy/589/2000 (Italy/00) H7 HA. A putative glycosylation due to an A169T substitution in antigenic site B was identified as a unique antigenic profile of Italy/00. Introduction of the putative glycosylation site (H7 HA-A169T) significantly altered the antigenic profile of HA of the A/Anhui/1/2013 (H7N9) strain.ConclusionThis study identified key amino acid mutations that result in severe vaccine mismatches for future H7 epidemics. Future universal influenza vaccine candidates will need to focus on viral variants with these key mutations.

scholarly journals Ten emerging SARS-CoV-2 spike variants exhibit variable infectivity, animal tropism, and antibody neutralization

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Li Zhang ◽  
Zhimin Cui ◽  
Qianqian Li ◽  
Bo Wang ◽  
Yuanling Yu ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Amino Acid ◽  
Receptor Binding ◽  
Immune Escape ◽  
Cathepsin L ◽  
Single Amino Acid ◽  
Receptor Binding Domain ◽  
Therapeutic Antibodies ◽  
Amino Acid Mutations ◽  
Better Than

AbstractEmerging mutations in SARS-CoV-2 cause several waves of COVID-19 pandemic. Here we investigate the infectivity and antigenicity of ten emerging SARS-CoV-2 variants—B.1.1.298, B.1.1.7(Alpha), B.1.351(Beta), P.1(Gamma), P.2(Zeta), B.1.429(Epsilon), B.1.525(Eta), B.1.526-1(Iota), B.1.526-2(Iota), B.1.1.318—and seven corresponding single amino acid mutations in the receptor-binding domain using SARS-CoV-2 pseudovirus. The results indicate that the pseudovirus of most of the SARS-CoV-2 variants (except B.1.1.298) display slightly increased infectivity in human and monkey cell lines, especially B.1.351, B.1.525 and B.1.526 in Calu-3 cells. The K417N/T, N501Y, or E484K-carrying variants exhibit significantly increased abilities to infect mouse ACE2-overexpressing cells. The activities of furin, TMPRSS2, and cathepsin L are increased against most of the variants. RBD amino acid mutations comprising K417T/N, L452R, Y453F, S477N, E484K, and N501Y cause significant immune escape from 11 of 13 monoclonal antibodies. However, the resistance to neutralization by convalescent serum or vaccines elicited serum is mainly caused by the E484K mutation. The convalescent serum from B.1.1.7- and B.1.351-infected patients neutralized the variants themselves better than other SARS-CoV-2 variants. Our study provides insights regarding therapeutic antibodies and vaccines, and highlights the importance of E484K mutation.

scholarly journals Interaction between FliE and FlgB, a Proximal Rod Component of the Flagellar Basal Body ofSalmonella

2000 ◽  
Vol 182 (11) ◽  
pp. 3029-3036 ◽  
Author(s):  
Tohru Minamino ◽  
Shigeru Yamaguchi ◽  
Robert M. Macnab
Keyword(s):  
Amino Acid ◽  
Amino Acid Sequence ◽  
Basal Body ◽  
Strong Interactions ◽  
Wild Type ◽  
Body Protein ◽  
C Terminus ◽  
Genes Encoding ◽  
And Function ◽  
Better Than

ABSTRACT FliE is a flagellar basal body protein of Salmonellawhose detailed location and function have not been established. A mutant allele of fliE, which caused extremely poor flagellation and swarming, generated extragenic suppressors, all of which mapped to flgB, one of four genes encoding the basal body rod; the fliE flgB pseudorevertants were better flagellated and swarmed better than the fliE parent, especially when the temperature was reduced from 37 to 30°C. Motility of the pseudorevertants in liquid culture was markedly better than motility on swarm plates; we interpret this to mean that reduced flagellation is less deleterious at low viscous loads. Overproduction of the mutant FliE protein improved the motility of the parentalfliE mutant and its pseudorevertants, though not to wild-type levels. Overproduction of suppressor FlgB (but not wild-type FlgB) in the fliE mutant also resulted in improved motility. The second-site FlgB mutation by itself had no phenotype; cells swarmed as well as wild-type cells. When overproduced, wild-type FliE was dominant over FliE-V99G, but the reverse was not true; that is, overproduced FliE-V99G was not negatively dominant over wild-type FliE. We conclude that the mutant protein has reduced probability of assembly but, if assembled, functions relatively well. Export of the flagellar protein FlgD, which is known to be FliE dependent, was severely impaired by the FliE-V99G mutation but was significantly improved in the suppressor strains. The FliE mutation, V99G, was close to the C terminus of the 104-amino-acid sequence; the suppressing mutations in FlgB were all either G119E or G129D, close to the C terminus of its 138-amino-acid sequence. Affinity blotting experiments between FliE as probe and various basal body proteins as targets and vice versa revealed strong interactions between FliE and FlgB; much weaker interactions between FliE and other rod proteins were observed and probably derive from the known similarities among these proteins. We suggest that FliE subunits constitute a junction zone between the MS ring and the rod and also that the proximal rod structure consists of FlgB subunits.

scholarly journals Effectiveness of combined chain exercises on pain and function in patients with knee osteoarthritis

2016 ◽  
Vol 15 (2) ◽  
pp. 178-188 ◽  
Author(s):  
Oladapo Michael Olagbegi ◽  
Babatunde Olusola Adeleke Adegoke ◽  
Adesola C Odole
Keyword(s):  
Controlled Trial ◽  
Medical Science ◽  
Hip Osteoarthritis ◽  
Kinetic Chain ◽  
Knee Oa ◽  
Randomized Controlled ◽  
Dependent Variables ◽  
Before And After ◽  
And Function ◽  
Better Than

Objective: This randomized controlled trial was designed to investigate and compare the effectiveness of twelve-week open, closed and combined kinetic-chain exercises (OKCEs, CKCEs and CCEs) on pain and physical function (PF) in the management of knee osteoarthritis.Method: Ninety-six consecutive patients with knee OA were randomly assigned to one of OKCE, CKCE and CCE groups. Participants’ average daily pain (ADP), pain before and after walking (PBW and PAW), were evaluated using Visual Analogue Scale while PF was assessed using Ibadan Knee/Hip Osteoarthritis Outcome Measure.Results: Seventy-nine participants completed the study but data of another 4 participants who completed only 8-week treatment were included in data analysis (total=83; mean age = 61.10±13.75 years). The groups’ demographic and dependent variables were comparable at baseline but CCE group demonstrated significantly more reductions (p < 0.05) in ADP, PBW and PAW than OKCE and CKCE groups at weeks 4, 8 and 12 of the study. However, there were significant within group improvements (p < 0.05) in all four variables for the three groups. Conclusion: CCEs are better than OKCEs and CKCEs for pain reduction in though all three exercise regimens are singly effective. CCEs are recommended for improving treatment outcome for pain in patients with knee osteoarthritis.Bangladesh Journal of Medical Science Vol.15(2) 2016 p.178-188

scholarly journals 18F-FACBC PET/MRI in the evaluation of human brain metastases: a case report

2021 ◽  
Vol 5 (1) ◽  
Author(s):  
Knut Johannessen ◽  
Erik Magnus Berntsen ◽  
Håkon Johansen ◽  
Tora S. Solheim ◽  
Anna Karlberg ◽  
...  
Keyword(s):  
Case Report ◽  
Clinical Practice ◽  
Amino Acid ◽  
Brain Metastases ◽  
Metastatic Cancer ◽  
Low Grade ◽  
Pet Tracer ◽  
Before And After ◽  
Amino Acid Pet ◽  
And Function

Abstract Background Patients with metastatic cancer to the brain have a poor prognosis. In clinical practice, MRI is used to delineate, diagnose and plan treatment of brain metastases. However, MRI alone is limited in detecting micro-metastases, delineating lesions and discriminating progression from pseudo-progression. Combined PET/MRI utilises superior soft tissue images from MRI and metabolic data from PET to evaluate tumour structure and function. The amino acid PET tracer 18F-FACBC has shown promising results in discriminating high- and low-grade gliomas, but there are currently no reports on its use on brain metastases. This is the first study to evaluate the use of 18F-FACBC on brain metastases. Case presentation A middle-aged female patient with brain metastases was evaluated using hybrid PET/MRI with 18F-FACBC before and after stereotactic radiotherapy, and at suspicion of recurrence. Static/dynamic PET and contrast-enhanced T1 MRI data were acquired and analysed. This case report includes the analysis of four 18F-FACBC PET/MRI examinations, investigating their utility in evaluating functional and structural metastasis properties. Conclusion Analysis showed high tumour-to-background ratios in brain metastases compared to other amino acid PET tracers, including high uptake in a very small cerebellar metastasis, suggesting that 18F-FACBC PET can provide early detection of otherwise overlooked metastases. Further studies to determine a threshold for 18F-FACBC brain tumour boundaries and explore its utility in clinical practice should be performed.

scholarly journals Visualizing Deep Mutational Scan Data

2018 ◽  
Author(s):  
C. K. Sruthi ◽  
Hemalatha Balaram ◽  
Meher K. Prakash
Keyword(s):  
Amino Acid ◽  
Single Point ◽  
Point Mutations ◽  
Random Mutagenesis ◽  
Opportunity To Learn ◽  
Single Point Mutations ◽  
The Rich ◽  
Amino Acid Mutations ◽  
Rich Data ◽  
And Function

AbstractSite-directed and random mutagenesis are biochemical tools to obtain insights into the structure and function of proteins. Recent advances such as deep mutational scan have allowed a complete scan of all the amino acid positions in a protein with each of the 19 possible alternatives. Mapping out the phenotypic consequences of thousands of single point mutations in the same protein is now possible. Visualizing and analysing the rich data offers an opportunity to learn more about the effects of mutations, for a better understanding and engineering of proteins. This work focuses on such visualization analyses applied to the mutational data of TEM-1 β-lactamase. The data is examined in the light of the expected biochemical effects of single point mutations, with the goal of reinforcing or retraining the intuitions. Individual attributes of the amino acid mutations such as the solvent accessible area, charge type change, and distance from the catalytic center capture most of the relevant functional effects. Visualizing the data suggests how combinations of these attributes can be used for a better classification of the effects of mutations, when independently they do not offer a high predictability.

scholarly journals Accurate measurement of the effects of all amino-acid mutations to influenza hemagglutinin

2016 ◽  
Author(s):  
Michael B. Doud ◽  
Jesse D. Bloom
Keyword(s):  
Amino Acid ◽  
Neutralizing Antibodies ◽  
Viral Evolution ◽  
Point Mutations ◽  
Helper Virus ◽  
Broadly Neutralizing Antibodies ◽  
Amino Acid Mutation ◽  
Influenza Hemagglutinin ◽  
Amino Acid Mutations ◽  
Evolutionary Paths

AbstractInfluenza genes evolve mostly via point mutations, and so knowing the effect of every amino-acid mutation provides information about evolutionary paths available to the virus. We previously used high-throughput mutagenesis and deep sequencing to estimate the effects of all mutations to an H1 influenza hemagglutinin on viral replication in cell culture (Thyagarajan and Bloom, 2014); however, these measurements suffered from sub-stantial noise. Here we describe advances that greatly improve the accuracy and reproducibility of our measurements. The largest improvements come from using a helper virus to reduce bottlenecks when generating viruses from plasmids. Our measurements confirm that antigenic sites on the globular head of hemagglutinin are highly tolerant of mutations. However, other regions – including stalk epitopes targeted by broadly neutralizing antibodies – have a limited capacity to evolve. The ability to accurately measure the effects of all influenza mutations should enhance efforts to understand and predict viral evolution.

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