Quantitative and Qualitative Analysis of Humoral Immunity Reveals Continued and Personalized Evolution in Chronic Viral Infection

Kräutler, Nike Julia; Yermanos, Alexander; Pedrioli, Alessandro; Welten, Suzanne P. M.; Lorgé, Dominique; Greczmiel, Ute; Bartsch, Ilka; Scheuermann, Jörg; Kiefer, Jonathan D.; Eyer, Klaus; Menzel, Ulrike; Greiff, Victor; Neri, Dario; Stadler, Tanja; Reddy, Sai T.; Oxenius, Annette

doi:10.1016/j.celrep.2019.12.088

Cited by 34 publications

(76 citation statements)

References 62 publications

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“…We therefore quantified the proportion of sequences from each time point within the public clonal lineages shared between the acutely and chronically infected cohorts ( Figure 4F). Our analysis revealed that the public clonal lineages, on average, contain a higher number of sequences from each time point before the terminal sacrifice ( Figure 4F), consistent with previous findings (Kräutler et al, 2020).…”

Section: Different Strategies Impact the Inferred Public Clonal Lineagessupporting

confidence: 91%

“…While different germline aligner tools have been previously compared (Marcou et al, 2018), how the aligner tools impact the repertoire fingerprint remains less characterized. We therefore compared the influence of various clonal lineage assignment pipelines following identical germline assignment of when analyzing recently published time-resolved Ig-Seq data (Kräutler et al, 2020). This sequencing data set consists of bulk heavy chain sequencing from 15 mice of the three different previously mentioned cohorts (uninfected, acute LCMV and chronic LCMV infection) and provides a unique opportunity to compare the influence of the bioinformatics processing pipeline across both multiple individuals and cohorts ( Figure 1A).…”

Section: Rooting Strategy Influences Number Size and Time-resolutionmentioning

confidence: 99%

“…For each mouse (excluding one acute mouse), blood samples at 10, 20, 50, 60 and 70 days post infection (dpi) and bone marrow PCs (a subset of antibody secreting B cells) 70 dpi were collected, in all samples the heavy chain repertoires were subjected to Ig-seq (Kräutler et al, 2020).…”

Section: Rooting Strategy Influences Number Size and Time-resolutionmentioning

confidence: 99%

“…Ig-seq data from accession number E-MTAB-8585 (Kräutler et al, 2020) was aligned using MiXCR (v2.1.2) to the built in murine reference germline segments under default parameters (Bolotin et al, 2015). The alignments were subsequently clonotyped by the full length VDJ region on the nucleotide level and exported using exportClones function with presets set to full.…”

Section: Repertoire Processingmentioning

confidence: 99%

“…Here, we explored how various bioinformatics pipelines shape evolutionary conclusions arising from Ig-Seq experiments. Using previously published timeresolved Ig-Seq experiments from blood-derived B cell and bone marrow (BM) PC (PC) repertoires (Kräutler et al, 2020), we analyzed the robustness of multiple conclusions based on phylogenetic analyses for three cohorts: uninfected mice, mice infected with low dose (acute) lymphocytic choriomeningitis virus (LCMV), and mice infected with high dose (chronic) LCMV. This unique experimental model provides a system in which a viral infection is either cleared within two weeks (in the case of the low-dose, acute infection) in a primarily CD8 T+ cell dependent manner or over the course of months in the case of mice receiving the high dose infection.…”

Section: Introductionmentioning

confidence: 99%

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The influence of the phylogenetic inference pipeline on murine antibody repertoire sequencing data following viral infection

Yermanos

Greiff

Stadler

et al. 2020

Preprint

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Understanding B cell evolution following vaccination or infection is crucial for instructing targeted immunotherapies when searching for potential therapeutic or virus-neutralizing antibodies. Antibody phylogenetics holds the potential to quantify both clonal selection and somatic hypermutation, two key players shaping B cell evolution. A wide range of bioinformatic pipelines and phylogenetic inference methods have been utilized on antibody repertoire sequencing datasets to delineate B cell evolution. Although the majority of B cell repertoire studies incorporate some aspect of antibody evolution, how the chosen computational methods affect the results is largely ignored. Therefore, we performed an extensive computational analysis on time-resolved antibody repertoire sequencing data to better characterize how commonly employed bioinformatic practices influence conclusions regarding antibody selection and evolution. Our findings reveal that different combinations of clonal lineage assignment strategies, phylogenetic inference methods, and biological sampling affect the inferred size, mutation rates, and topologies of B cell lineages in response to virus infection.

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Section: Different Strategies Impact the Inferred Public Clonal Lineagessupporting

confidence: 91%

Section: Rooting Strategy Influences Number Size and Time-resolutionmentioning

confidence: 99%

Section: Rooting Strategy Influences Number Size and Time-resolutionmentioning

confidence: 99%

Section: Repertoire Processingmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

The influence of the phylogenetic inference pipeline on murine antibody repertoire sequencing data following viral infection

Yermanos

Greiff

Stadler

et al. 2020

Preprint

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Profiling the specificity of clonally expanded plasma cells during chronic viral infection by single‐cell analysis

et al. 2021

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Plasma cells and their secreted antibodies play a central role in the long-term protection against chronic viral infection. However, due to experimental limitations, a comprehensive description of linked genotypic, phenotypic, and antibody repertoire features of plasma cells (gene expression, clonal frequency, virus specificity, and affinity) has been challenging to obtain. To address this, we performed single-cell transcriptome and antibody repertoire sequencing of the murine BM plasma cell population following chronic lymphocytic choriomeningitis virus infection. Our single-cell sequencing approach recovered full-length and paired heavy-and light-chain sequence information for thousands of plasma cells and enabled us to perform recombinant antibody expression and specificity screening. Antibody repertoire analysis revealed that, relative to protein immunization, chronic infection led to increased levels of clonal expansion, class-switching, and somatic variants. Furthermore, antibodies from the highly expanded and class-switched (IgG) plasma cells were found to be specific for multiple viral antigens and a subset of clones exhibited cross-reactivity to nonviral and autoantigens. Integrating single-cell transcriptome data with antibody specificity suggested that plasma cell transcriptional phenotype was correlated to viral antigen specificity. Our findings demonstrate that chronic viral infection can induce and sustain plasma cell clonal expansion, combined with significant somatic hypermutation, and can generate cross-reactive antibodies.

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Chronic Viral Infection Promotes Efficient Germinal Center B Cell Responses

et al. 2020

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Quantitative and Qualitative Analysis of Humoral Immunity Reveals Continued and Personalized Evolution in Chronic Viral Infection

Cited by 34 publications

References 62 publications

The influence of the phylogenetic inference pipeline on murine antibody repertoire sequencing data following viral infection

The influence of the phylogenetic inference pipeline on murine antibody repertoire sequencing data following viral infection

Profiling the specificity of clonally expanded plasma cells during chronic viral infection by single‐cell analysis

Chronic Viral Infection Promotes Efficient Germinal Center B Cell Responses

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