Single-cell BCR and transcriptome analysis after influenza infection reveals spatiotemporal dynamics of antigen-specific B cells

Mathew, Nimitha R.; Jayanthan, Jayalal K; Смирнов, И. В.; Robinson, Jonathan L.; Axelsson, Hannes; Nakka, Sravya Sowdamini; Emmanouilidi, Aikaterini; Czarnewski, Paulo; Yewdell, William T.; Schön, Karin; Lebrero‐Fernández, Cristina; Bernasconi, Valentina; Rodin, William; Harandi, Ali M.; Lycke, Nils; Borcherding, Nicholas; Yewdell, Jonathan W.; Greiff, Victor; Bemark, Mats; Angeletti, Davide

doi:10.1016/j.celrep.2022.111764

Cited by 8 publications

(12 citation statements)

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“…With B cell activation after COVID-19 infection initially consisting of recalled seasonal CoV-specific B cells, it could be that such B cells, in combination with pre-existing serum Abs, could promote the diversity of the ongoing GC. A more diverse GC would favor novel responses and the ability of the B cells to adapt to existing and future viral variants (15,17,61).…”

Section: Discussionmentioning

confidence: 99%

“…With the emergence of viral variants, there has been great emphasis in studying MBC. Early studies with influenza, dengue and other viral infections in animal models suggested that the MBC pool has greater breadth of antigenic binding, as compared to the plasmablast response (15)(16)(17)(18). This led to the hypothesis that while plasma cells and the serum Abs they produce protect against reinfection with the same strain, the MBC pool represents a diverse reservoir which is able to protect against possible emerging variants.…”

Section: Introductionmentioning

confidence: 99%

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Longitudinal single-cell analysis of SARS-CoV-2–reactive B cells uncovers persistence of early-formed, antigen-specific clones

Scharf¹,

Axelsson²,

Emmanouilidi³

et al. 2023

JCI Insight

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Understanding persistence and evolution of B cell clones after COVID-19 infection and vaccination is crucial for predicting responses against emerging viral variants and optimizing vaccines. Here, we collected longitudinal samples from severe COVID-19 patients every third to seventh day during hospitalization and every third month after recovery. We profiled their antigen-specific immune cell dynamics by combining single cell RNA-Seq, Cellular Indexing of Transcriptomes and Epitopes by Sequencing (CITE)-Seq, B cell receptor (BCR)-Seq with oligotagged antigen baits. While the proportion of Spike Receptor Binding Domain-specific memory B cells (MBC) increased from 3 months after infection, the other Spike-and Nucleocapsid-specific B cells remained constant. All patients showed ongoing class switching and sustained affinity maturation of antigen specific cells, which was not significantly increased early after vaccine. B cell analysis revealed a polyclonal response with limited clonal expansion; nevertheless, some clones detected during hospitalization, as plasmablasts, persisted for up to one year, as MBC. Monoclonal antibodies derived from persistent B cell families increased their binding and neutralization breadth and started recognizing viral variants by 3 months after infection. Overall, our findings provide important insights into the clonal evolution and dynamics of antigen specific B cell responses in longitudinally sampled COVID-19 infected patients.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Longitudinal single-cell analysis of SARS-CoV-2–reactive B cells uncovers persistence of early-formed, antigen-specific clones

Scharf¹,

Axelsson²,

Emmanouilidi³

et al. 2023

JCI Insight

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“…When performing B cell subset assignment we observed that cluster 4 was assigned the marginal zone (MZ) module. MZ B cells have been reported as precursors of PCs with additional evidence demonstrating that CD9, the main determinant of the MZmodule [49], is acquired by PCs during immune responses in a T cell-dependent fashion [78,82]. Cells from GFAP:GP Fig.…”

Section: Cns Infection Generates Long-lived Brain-infiltrating Ascs T...mentioning

confidence: 99%

Persistent virus-specific and clonally expanded antibody-secreting cells respond to induced self-antigen in the CNS

et al. 2023

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B cells contribute to the pathogenesis of both cellular- and humoral-mediated central nervous system (CNS) inflammatory diseases through a variety of mechanisms. In such conditions, B cells may enter the CNS parenchyma and contribute to local tissue destruction. It remains unexplored, however, how infection and autoimmunity drive transcriptional phenotypes, repertoire features, and antibody functionality. Here, we profiled B cells from the CNS of murine models of intracranial (i.c.) viral infections and autoimmunity. We identified a population of clonally expanded, antibody-secreting cells (ASCs) that had undergone class-switch recombination and extensive somatic hypermutation following i.c. infection with attenuated lymphocytic choriomeningitis virus (rLCMV). Recombinant expression and characterisation of these antibodies revealed specificity to viral antigens (LCMV glycoprotein GP), correlating with ASC persistence in the brain weeks after resolved infection. Furthermore, these virus-specific ASCs upregulated proliferation and expansion programs in response to the conditional and transient induction of the LCMV GP as a neo-self antigen by astrocytes. This class-switched, clonally expanded, and mutated population persisted and was even more pronounced when peripheral B cells were depleted prior to autoantigen induction in the CNS. In contrast, the most expanded B cell clones in mice with persistent expression of LCMV GP in the CNS did not exhibit neo-self antigen specificity, potentially a consequence of local tolerance induction. Finally, a comparable population of clonally expanded, class-switched, and proliferating ASCs was detected in the cerebrospinal fluid of relapsing multiple sclerosis (RMS) patients. Taken together, our findings support the existence of B cells that populate the CNS and are capable of responding to locally encountered autoantigens.

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“…This method is most commonly used in conjunction with microfluidics-based platforms such as those offered by 10X Genomics, though similar methods have now been developed for compatibility with well-based platforms, including BD Rhapsody and Seq-Well, which use a unique 3' approach to capture TCR sequences [59]. The advent of techniques that allow for simultaneous study of the whole transcriptome and TCR/BCR sequences provides the opportunity to analyze the transcriptomes of cells with specific TCR or BCRs, for example, clonally expanded populations [60][61][62][63][64].…”

Section: Single-cell Tcr/bcr Sequencingmentioning

confidence: 99%

Single-cell RNA-seq methods to interrogate virus-host interactions

et al. 2022

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The twenty-first century has seen the emergence of many epidemic and pandemic viruses, with the most recent being the SARS-CoV-2-driven COVID-19 pandemic. As obligate intracellular parasites, viruses rely on host cells to replicate and produce progeny, resulting in complex virus and host dynamics during an infection. Single-cell RNA sequencing (scRNA-seq), by enabling broad and simultaneous profiling of both host and virus transcripts, represents a powerful technology to unravel the delicate balance between host and virus. In this review, we summarize technological and methodological advances in scRNA-seq and their applications to antiviral immunity. We highlight key scRNA-seq applications that have enabled the understanding of viral genomic and host response heterogeneity, differential responses of infected versus bystander cells, and intercellular communication networks. We expect further development of scRNA-seq technologies and analytical methods, combined with measurements of additional multi-omic modalities and increased availability of publicly accessible scRNA-seq datasets, to enable a better understanding of viral pathogenesis and enhance the development of antiviral therapeutics strategies.

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Single-cell BCR and transcriptome analysis after influenza infection reveals spatiotemporal dynamics of antigen-specific B cells

Cited by 8 publications

References 0 publications

Longitudinal single-cell analysis of SARS-CoV-2–reactive B cells uncovers persistence of early-formed, antigen-specific clones

Longitudinal single-cell analysis of SARS-CoV-2–reactive B cells uncovers persistence of early-formed, antigen-specific clones

Persistent virus-specific and clonally expanded antibody-secreting cells respond to induced self-antigen in the CNS

Single-cell RNA-seq methods to interrogate virus-host interactions

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