Biology subjects

Song, E.

Publications and source records attributed to Song, E..

At least 19 recordsLinked to original sources

bioRxiv2026

Bacteriophage treatment of Pseudomonas aeruginosa PA14 infection does not alter the native microbiome of Caenorhabditis elegans

Bacteriophage therapeutics are alternatives to antibiotics for treating multi-drug-resistant (MDR) bacterial infections. Bacteriophages kill host bacteria species with targeted precision, unlike the broad-spectrum nature of antibiotics. While the precision and the natural occurrence of phages in the environment have drawn attention to phages as new "drugs" in the time of accelerated antibiotic resistance, it remains poorly understood how phage treatment impacts the community of organisms composing the microbiome. Before phage therapies can be more widespread in practice, this understanding is required. Caenorhabditis elegans lends itself as an excellent model organism to address this question, as worm populations are raised under sterile conditions and the gut microbiome can be populated experimentally by the worms natural bacterivore diet. Here we have established a C. elegans infection and phage treatment model using fluorescent Pseudomonas aeruginosa PA14 to quantify infection. We isolated and whole genome sequenced PA14-specific lytic phage from wastewater samples near West Point, New York. To characterize the impact of treatment on the microbiome, we populated the C. elegans gut microbiome with 11 strains of the native C. elegans microbiome (CeMbio) and used PacBio sequencing of the full length 16S rRNA gene to characterize the microbiome during PA14 infection in the presence and absence of phage treatment (n = 100 worms per sample, 4 replicates per condition). Taxonomic classification, phylogenetic analysis, and diversity analysis performed using a HiFi 16S bioinformatics pipeline revealed that phage treatment and infection level did not change the overall composition of the C. elegans gut microbiome. ImportanceMultidrug resistant infections are emerging faster than new antibiotic compounds can be synthesized. Bacteriophages are natural viruses of bacteria that seek out and kill only their host bacteria species. Bacteriophage therapeutics are a promising solution for drug resistant infections in patients where no other treatment exists. However, while phage treatment is effective, there is little understanding about what happens within the complex community of the microbiome when a phage treatment is employed. Here we establish a new model utilizing C. elegans to integrate a multidrug resistant infection, phage treatment, and the native microbiome of the C. elegans worm to address how the microbiome changes in response to phage treatment. We find that the microbiome remains unchanged after bacteriophage treatment, highlighting the targeted specificity of phage therapy and suggests fewer side effects for phage therapy than antibiotic treatment for the same infection.

microbiology↗

bioRxiv2026

MOTS-c Coordinates Inter-Organellar Proteostasis for Adaptation to Chronic Metabolic Stress

Mitochondrial communication coordinates adaptive responses across organelles to sustain cellular homeostasis, a network that declines with age and contributes to loss of proteostasis. Here, we identify MOTS-c, an exercise-induced mitochondrial-derived peptide (MDP) encoded within the 12S rRNA locus, as an inter-organellar arm of the mitochondrial stress response (MSR) that links mitochondrial signaling to endoplasmic reticulum (ER) proteostasis and enables adaptation to chronic stress. Using progressive stress media (PSM), a model of gradual and multifactorial metabolic stress, we show that MOTS-c enables adaptation through a biphasic program: acutely, a reversible, ATF4-independent suppression of protein synthesis; and chronically, an ATF6-biased ER unfolded protein response (UPRER) with tempered ATF4 engagement and coordinated metabolic remodeling. Whereas mitochondrial unfolded protein response (UPRmt) pathways have been extensively characterized in acute, genetic, and sustained models of mitochondrial perturbation, this work reveals how mitochondrial communication actively engages ER proteostasis during progressive and persistent metabolic stress. By expanding proteostatic capacity while tempering terminal stress signaling, MOTS-c enables cells to withstand chronic stress. Together, these findings define a MOTS-c-dependent arm of the MSR that integrates mitochondrial communication with ER proteostasis to promote chronic metabolic stress adaptation.

Cell Biology↗

bioRxiv2026

Pore-Resolved High-Throughput Quantification of Amyloid Aggregation and Amplification

Amyloid fibrils are implicated in a wide spectrum of neurodegenerative and systemic disorders, yet their biological consequences are governed not only by total fibril content but also by how fibrillar species are organized, clustered, and amplified within heterogeneous populations. Conventional thioflavin T (ThT)-based assays provide sensitive sample-level readouts of {beta}-sheet-rich material but offer limited access to the local population structure underlying amyloid aggregation and amplification. Here, we introduce the Amyloid Pore Quantification (APQ) chip, a pore-resolved geometric partitioning platform that converts heterogeneous amyloid assembly states into fluorescence intensity distributions across thousands of defined pore-level units. Using hen egg-white lysozyme as a model amyloid-forming protein, we combine length-controlled truncated amyloid nanofibrils with vacuum-assisted ThT infiltration to establish a reproducible pore fluorescence intensity reference. APQ provided quantitative concentration-dependent calibration across a 50-fold concentration range, enabling bulk-comparable quantification while preserving pore-level distribution information. Deviations from this reference resolved pH-dependent fibril clustering near the isoelectric point as pore-signal suppression and accessibility loss, captured pepsin-associated fibrillar amplification as a population-wide increase in pore intensity, and distinguished monomer- and oligomer-driven fibril processing through coupled amplification-aggregation fingerprints. When benchmarked against ensemble fluorescence measurements and AFM morphological analysis, APQ revealed assembly-state changes that were not fully represented by sample-level ThT intensity alone. These results establish APQ as a high-throughput, distribution-aware analytical framework for translating amyloid aggregation and amplification into quantitative pore-resolved fingerprints.

bioengineering↗

bioRxiv2026

Mechanochemically Programmed, Oligomer-Selective Amyloid Assembly via Axial Rotation

Amyloid oligomers have been widely implicated as primary cytotoxic intermediates; however, their selective and scalable production remains challenging due to rapid fibril amplification. Here, we demonstrated that sustained axial rotation enables programmable mechanochemical control over amyloid pathway selection without the use of chemical additives. Using a thermal axial rotator, native monomeric hen egg-white lysozyme was incubated at 60 {degrees}C under quantitatively tunable rotational speeds, imposing defined centrifugal forces and wall-associated shear that restructured the hydrodynamic boundary conditions. A discrete transition emerged near 600 RPM, separating the two distinct assembly regimes. Below this threshold, aggregation followed a fibril-amplifying pathway characterized by elevated {beta}-sheet content and elongated fibrillar morphologies. Above this threshold, fibrillar growth was strongly attenuated and oligomer-dominant assemblies predominated. Spectroscopic analyses and atomic force microscopy revealed that axial rotation redistributes the amyloid assembly states rather than simply suppressing aggregation. Functionally, the RPM-defined assemblies exhibited kinetically distinct seeding behaviors and induced divergent cytotoxic phenotypes in SH-SY5Y neuroblastoma cells. These findings establish axial rotation-mediated hydrodynamic boundary control as a scalable, chemical-free strategy for reprogramming amyloid assembly pathways and producing oligomer-rich assemblies with well-defined structural and functional properties.

bioengineering↗

bioRxiv2026

RIG-I RNA agonist activates immunostimulatory macrophages to enhance checkpoint immunotherapy for glioblastoma

Glioblastoma (GBM), the most frequent and aggressive primary brain tumor, remains refractory to all current therapies including surgical resection, chemotherapy, radiotherapy and immunotherapy. Immunosuppressive mechanisms in the GBM tumor microenvironment contribute to the lack of anti-tumor adaptive immunity. We found that a subset of tumor associated macrophages (TAMs) can be repolarized into an anti-tumor phenotype via agonist stimulation of the retinoic acid-inducible gene I (RIGI), a cytosolic double-stranded RNA pattern recognition receptor (PRR). In silico analysis of adult GBM datasets available in the public domain revealed that RIGI expression by a subset of activated TAMs positively correlated with patient survival. Studies in syngeneic mouse models of GBM showed that intratumoral delivery of stem-loop RNA 14 (SLR14), a RIG-I agonist, improved the efficacy of chemotherapy, radiotherapy and immunotherapy treatments, beyond the effects of other nuclei acid sensor agonists. We found that RIGI+ macrophages are the main drivers of SLR14 effect, combining activation of TAMs and priming of functional cytotoxic CD8+ T lymphocytes and NK cells. The anti-GBM effect of SLR14 is opening a significant new avenue for adult GBM treatment.

cancer biology↗

bioRxiv2025

Allele Specific Expression Quality Control Fills Critical Gap in Transcriptome Assisted Rare Variant Interpretation

Allele-specific expression (ASE) captures the functional impact of genetic variation on transcription, offering a high-resolution view of cis-regulatory effects, but its quality can be diminished by technical, biological, and analysis artifacts. We introduce aseQC, a statistical framework that quantifies sample-level ASE quality in terms of the overall expected extra-binomial variation to exclude uncharacteristically noisy samples in a cohort to improve robustness of downstream analyses. Applying aseQC to a dataset of rare mendelian muscular disorders, successfully identified previously annotated low-quality cases demonstrating clinical genomic utility. When applied to 15,253 samples in extensively quality controlled GTEx project data, aseQC uncovered 563 low-quality samples that exhibit excessive allelic imbalance. We identify these to be associated with specific processing dates but not otherwise described adequately by any other quality control measures and metadata available in GTEx data. We show that these low-quality samples lead to 23.6 and 31.6 -fold increased ASE, and splicing outliers, degrading the performance of transcriptome analysis for rare variant interpretation. In contrast, we did not observe any adverse effect associated with inclusion of these samples in common-variant analysis using quantitative traits loci mapping. By enabling quick and reliable assessment of sample quality, aseQC presents a critical step for identifying subtle quality issues that remain critical for a successful analysis of rare variant effects using transcriptome data.

bioinformatics↗

bioRxiv2025

Th1 cells express Tfh effector molecules and associate with B cells at the T-B borderfollowing viral infection

Antibodies protect the host from pathogens by neutralizing viruses, targeting pathogens for phagocytosis and complement deposition, and by activating innate immune cells. Most studies on the cellular mechanisms of antibody induction focus on the role of germinal centers (GCs) - areas within lymph nodes (LNs) and spleen where activated B cells undergo mutation and then selection by T follicular helper (Tfh) cells to produce high affinity antibodies. However, specific and long-lived antibodies can be produced in the absence of GCs and Tfh cells, sometimes referred to as "extrafollicular" (EF) responses. However, EF responses are typically assumed to be short-lived and low affinity. We characterized the CD4+ T cells present in wild type and Tfh cell-deficient mice in lung draining LNs following influenza A virus or SARS-CoV-2 infection to compare the nature of T cell help for activated B cells. We found that a population of helper Th1 cells remains in LNs seven days following viral infection and interacts with IgG2c+ B cells at the T-B border in both WT and Tfh-deficient mice. We propose that Th1 cells promote virus-specific antibody production in parallel with Tfh cells in the GC and that such a response is contiguous with the T-B border and therefore is not an EF response as classically defined.

immunology↗

bioRxiv2024

SARS-CoV-2 infection activates inflammatory macrophages in vascular immune organoids

SARS-CoV-2 provokes devastating tissue damage by cytokine release syndrome and leads to multi-organ failure. Modeling the process of immune cell activation and subsequent tissue damage is a significant task. Organoids from human tissues advanced our understanding of SARS-CoV-2 infection mechanisms though, they are missing crucial components: immune cells and endothelial cells. This study aims to generate organoids with these components. We established vascular immune organoids from human pluripotent stem cells and examined the effect of SARS-CoV-2 infection. We demonstrated that infections activated inflammatory macrophages. Notably, the upregulation of interferon signaling supports macrophages role in cytokine release syndrome. We propose vascular immune organoids are a useful platform to model and discover factors that ameliorate SARS-CoV-2-mediated cytokine release syndrome.

immunology↗

bioRxiv2023

Maternal H3.3-Mediated Paternal Genome Reprogramming Contributes to Minor Zygotic Genome Activation

In mice, zygotic genome activation (ZGA) is initiated at the late-one-cell stage, accompanied by an extensive incorporation of the histone variant H3.3 into the parental genomes. However, it is unclear how H3.3 engages in the onset of ZGA. Here, using the H3.3B-HA-tagged mouse model, we found that the paternal and maternal genomes are activated asynchronously. Paternally expressed H3.3 begins deposition on the zygotic genome at the early two-cell stage, whereas the deposition of maternally expressed H3.3 is delayed until the four-cell stage. Oocyte-stored maternal H3.3 (mH3.3) is crucial for cleavage development and minor ZGA. Deposition of mH3.3 on the paternal genome occurs globally during the protamine-to-histone transition but shows preferential enrichment at CpG-rich TSSs after the initial round of DNA replication. Depletion of mH3.3 can lead to a loss of H3K27ac, resulting in minor ZGA failure and early embryonic arrest. Mechanistically, mH3.3 deposition on the sperm genome removes repressive histone modifications, promotes the establishment of active histone modifications, and in turn enables the initiation of minor ZGA from the paternal genome. Our study highlights the pivotal role of mH3.3 in paternal genome reprogramming and minor ZGA initiation.

genetics↗

bioRxiv2023

Setdb1-loss induces type-I interferons and immune clearance of melanoma

Despite recent advances in the treatment of melanoma, many patients with metastatic disease still succumb to their disease. To identify tumor-intrinsic modulators of immunity to melanoma, we performed a whole-genome CRISPR screen in melanoma and identified multiple components of the HUSH complex, including Setdb1, as hits. We found that loss of Setdb1 leads to increased immunogenicity and complete tumor clearance in a CD8+ T-cell dependent manner. Mechanistically, loss of Setdb1 causes de-repression of endogenous retroviruses (ERVs) in melanoma cells and triggers tumor-cell intrinsic type-I interferon signaling, upregulation of MHC-I expression, and increased CD8+ T-cell infiltration. Furthermore, spontaneous immune clearance observed in Setdb1-/- tumors results in subsequent protection from other ERV-expressing tumor lines, supporting the functional anti-tumor role of ERV-specific CD8+ T-cells found in the Setdb1-/- microenvironment. Blocking the type-I interferon receptor in mice grafted with Setdb1-/- tumors decreases immunogenicity by decreasing MHC-I expression, leading to decreased T-cell infiltration and increased melanoma growth comparable to Setdb1wt tumors. Together, these results indicate a critical role for Setdb1 and type-I interferons in generating an inflamed tumor microenvironment, and potentiating tumor-cell intrinsic immunogenicity in melanoma. This study further emphasizes regulators of ERV expression and type-I interferon expression as potential therapeutic targets for augmenting anti-cancer immune responses.

cancer biology↗

bioRxiv2023

Cell Type-Specific Regulation by a Heptad of Transcription Factors in Human Hematopoietic Stem and Progenitor Cells

Hematopoietic stem and progenitor cells (HSPCs) rely on a complex interplay of transcription factors (TFs) to regulate differentiation into mature blood cells. A heptad of TFs - FLI1, ERG, GATA2, RUNX1, TAL1, LYL1, LMO2 - bind regulatory elements in bulk CD34+ HSPCs. However, whether specific heptad-TF combinations have distinct roles in regulating hematopoietic differentiation remained unknown. We mapped genome-wide chromatin contacts and TF binding profiles in HSPC subsets (HSC, CMP, GMP, MEP) and found that heptad occupancy and enhancer-promoter interactions varied significantly across cell types and were associated with cell-type-specific gene expression. Distinct regulatory elements were enriched with specific heptad-TF combinations, including stem-cell-specific elements with ERG, and myeloid- and erythroid-specific elements with combinations of FLI1, RUNX1, GATA2, TAL1, LYL1, and LMO2. These findings suggest that specific heptad-TF combinations play critical roles in regulating hematopoietic differentiation and provide a valuable resource for development of targeted therapies to manipulate specific HSPC subsets.

developmental biology↗

bioRxiv2022

Effects of hydroxychloroquine on atrial electrophysiology in in silico wild-type and PITX2+/- atrial cardiomyocytes

Hydroxychloroquine (HCQ) is commonly used in the treatment of autoimmune diseases and increases the risk of QT interval prolongation. We quantitatively examined the potential atrial arrhythmogenic effects of HCQ on atrial fibrillation (AF) using a computational model of human atrial cardiomyocytes. We measured atrial electrophysiological markers after systematically varying HCQ concentrations. HCQ concentrations were positively correlated with the action potential duration (APD), resting membrane potential, refractory period, APD alternans threshold, and calcium transient alternans threshold (P<0.05). In contrast, HCQ concentrations were inversely correlated with the maximum upstroke velocity and calcium transient amplitude (P<0.05). When the therapeutic concentration (Cmax) of HCQ was applied, HCQ increased APD90 by 1.4% in normal sinus rhythm, 1.8% in wild-type AF, and 2.6% in PITX2+/- AF, but did not affect the alternans thresholds. The overall in silico results suggest no significant atrial arrhythmogenic effects of HCQ at Cmax, rather implying a potential antiarrhythmic role of low-dose HCQ in AF. However, at HCQ of 4-fold Cmax, a rapid pacing rate of 4 Hz could induce prominent APD alternans, particularly in the PITX2+/- AF model. Concomitant PITX2 mutations and HCQ treatments may increase the risk of AF, and this potential arrhythmogenic effect of HCQ should be further investigated.

physiology↗

bioRxiv2022

A novel pathway of functional microRNA uptake and mitochondria delivery

Extracellular miRNAs serve as signal molecules in the recipient cells. Uptake of extracellular miRNAs by the recipient cells and their intracellular transport, however, remains elusive. Here we show RNA phase separation as a novel pathway of miRNA uptake. In the presence of serum, synthetic miRNAs rapidly self-assembly into [~]110nm discrete nanoparticles which enable miRNAs entry into different cells. Depleting serum cationic proteins prevents the formation of such nanoparticles and thus blocks miRNA uptake. Different from lipofectamine-mediated miRNA transfection in which the majority of miRNAs are in lysosomes of transfected cells, nanoparticles-mediated miRNA uptake predominantly delivers miRNAs into mitochondria in a polyribonucleotide nucleotidyltransferase 1-dependent manner. Functional assays further show that the internalized miR-21 via miRNA phase separation enhances mitochondrial translation of Cytochrome b, leading to increase in ATP and ROS reduction in HEK293T cells. Our findings reveal a previously unrecognized mechanism for uptaking and delivering functional extracellular miRNAs into mitochondria. Synopsis O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=122 SRC="FIGDIR/small/515397v1_ufig1.gif" ALT="Figure 1"> View larger version (26K): org.highwire.dtl.DTLVardef@1b83cd8org.highwire.dtl.DTLVardef@a29f54org.highwire.dtl.DTLVardef@8a6b1aorg.highwire.dtl.DTLVardef@17d9d2a_HPS_FORMAT_FIGEXP M_FIG C_FIG RNA phase separation-based extracellular miRNA uptake and PNPT1-mediated mitochondrial delivery of internalized miRNAs O_LImiRNAs can self-assembly into [~]110nm nanoparticles to enter various cells in the presence of serum C_LIO_LImiRNA phase separation is mediated by serum cationic proteins C_LIO_LIInternalized miRNAs via this nanoparticle pathway are predominantly delivered to mitochondria C_LIO_LIMitochondrial delivery of the internalized miRNAs is mediated by PNPT1 C_LI

cell biology↗

bioRxiv2022

Haplotype-aware modeling of cis-regulatory effects highlights the gaps remaining in eQTL data

Expression Quantitative Trait Loci (eQTLs) are critical to understanding the mechanisms underlying disease-associated genomic loci. Nearly all protein-coding genes in the human genome have been associated with one or more eQTLs. Here we introduce a multi-variant generalization of allelic Fold Change (aFC), aFC-n, to enable accurate quantification of the cis-regulatory effects in genes with multiple conditionally independent eQTLs. Applying aFC-n to 458,465 eQTLs in the Genotype-Tissue Expression (GTEx) project data, we demonstrate significant improvement in accuracy over the current tools for estimating the eQTL effect size and predicting genetically regulated gene expression. We characterize some of the empirical properties of the eQTL data and use this framework to assess the current state of eQTL data in terms of characterizing cis-regulatory landscape in individual genomes. Notably, we show that 77.4% of the genes with an allelic imbalance in a sample show 0.5 log2 fold or more of residual imbalance after accounting for the eQTL data underlining the remaining gap in characterizing regulatory landscape in individual genomes. We further contrast this gap across tissue types, and ancestry backgrounds to identify its correlates and guide future studies.

genetics↗

bioRxiv2022

Mild respiratory SARS-CoV-2 infection can cause multi-lineage cellular dysregulation and myelin loss in the brain

Survivors of Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) infection frequently experience lingering neurological symptoms, including impairment in attention, concentration, speed of information processing and memory. This long-COVID cognitive syndrome shares many features with the syndrome of cancer therapy-related cognitive impairment (CRCI). Neuroinflammation, particularly microglial reactivity and consequent dysregulation of hippocampal neurogenesis and oligodendrocyte lineage cells, is central to CRCI. We hypothesized that similar cellular mechanisms may contribute to the persistent neurological symptoms associated with even mild SARS-CoV-2 respiratory infection. Here, we explored neuroinflammation caused by mild respiratory SARS-CoV-2 infection - without neuroinvasion - and effects on hippocampal neurogenesis and the oligodendroglial lineage. Using a mouse model of mild respiratory SARS-CoV-2 infection induced by intranasal SARS-CoV-2 delivery, we found white matter-selective microglial reactivity, a pattern observed in CRCI. Human brain tissue from 9 individuals with COVID-19 or SARS-CoV-2 infection exhibits the same pattern of prominent white matter-selective microglial reactivity. In mice, pro-inflammatory CSF cytokines/chemokines were elevated for at least 7-weeks post-infection; among the chemokines demonstrating persistent elevation is CCL11, which is associated with impairments in neurogenesis and cognitive function. Humans experiencing long-COVID with cognitive symptoms (48 subjects) similarly demonstrate elevated CCL11 levels compared to those with long-COVID who lack cognitive symptoms (15 subjects). Impaired hippocampal neurogenesis, decreased oligodendrocytes and myelin loss in subcortical white matter were evident at 1 week, and persisted until at least 7 weeks, following mild respiratory SARS-CoV-2 infection in mice. Taken together, the findings presented here illustrate striking similarities between neuropathophysiology after cancer therapy and after SARS-CoV-2 infection, and elucidate cellular deficits that may contribute to lasting neurological symptoms following even mild SARS-CoV-2 infection.

neuroscience↗

bioRxiv2021

LINE-1 activation in the cerebellum drives ataxia

Previous studies have revealed that dysregulation of long interspersed nuclear element 1 (LINE-1), a dominant class of transposable elements in the human genome, correlates with neurodegeneration1-3. Yet whether LINE-1 dysregulation is causal to disease pathogenesis has not been proven directly. Here, we demonstrate that expression of evolutionarily younger LINE-1 families is elevated in the cerebella of ataxia telangiectasia (AT) patients, which was correlated with extensive downregulation of epigenetic silencers. To examine whether LINE-1 activation causes neurologic disease, we established an approach to directly target and activate the promoter of a young family of LINE-1 in mice. LINE-1 activation in the cerebellum was sufficient to lead to robust progressive ataxia. Purkinje cells in the diseased mice exhibited marked electrophysiological dysfunctions and degeneration with a significant accumulation of cytoplasmic ribonucleoprotein LINE-1Orf1p aggregates, endoplasmic reticulum (ER) stress, and DNA damage. Treatment with lamivudine, a nucleoside reverse transcriptase inhibitor, blunted the disease progression by reducing DNA damage, attenuating gliosis and interferon gene signature, and recovering the loss of key functional molecules for calcium homeostasis in Purkinje cells. This study provides direct evidence that young LINE-1 activation drives ataxia phenotype, and points to its pleiotropic effects leading to DNA damage, inflammation, and dysfunction and degeneration of neurons.

neuroscience↗

bioRxiv2021

The evolutionary trajectory of drosophilid walking

Neural circuits must both execute the behavioral repertoire of individuals and account for behavioral variation across species. Understanding how this variation emerges over evolutionary time requires large-scale phylogenetic comparisons of behavioral repertoires. Here, we describe the evolution of walking in fruit flies by capturing high-resolution, unconstrained movement from 13 species and 15 strains of drosophilids. We find that walking can be captured in a universal behavior space, the structure of which is evolutionarily conserved. However, the occurrence of, and transitions between, specific movements have evolved rapidly, resulting in repeated convergent evolution in the temporal structure of locomotion. Moreover, a meta-analysis demonstrates that many behaviors evolve more rapidly than other traits. Thus, the architecture and physiology of locomotor circuits can both execute precise individual movements in one species and simultaneously support rapid evolutionary changes in the temporal ordering of these modular elements across clades.

animal behavior and cognition↗

bioRxiv2021

High-affinity, neutralizing antibodies to SARS-CoV-2 can be made in the absence of T follicular helper cells

T follicular helper (Tfh) cells are the conventional drivers of protective, germinal center (GC)-based antiviral antibody responses. However, loss of Tfh cells and GCs has been observed in patients with severe COVID-19. As T cell-B cell interactions and immunoglobulin class switching still occur in these patients, non-canonical pathways of antibody production may be operative during SARS-CoV-2 infection. We found that both Tfh-dependent and -independent antibodies were induced against SARS-CoV-2 as well as influenza A virus. Tfh-independent responses were mediated by a population we call lymph node (LN)-Th1 cells, which remain in the LN and interact with B cells outside of GCs to promote high-affinity but broad-spectrum antibodies. Strikingly, antibodies generated in the presence and absence of Tfh cells displayed similar neutralization potency against homologous SARS-CoV-2 as well as the B.1.351 variant of concern. These data support a new paradigm for the induction of B cell responses during viral infection that enables effective, neutralizing antibody production to complement traditional GCs and even compensate for GCs damaged by viral inflammation. One-Sentence SummaryComplementary pathways of antibody production mediate neutralizing responses to SARS-CoV-2.

immunology↗