Biology subjects

Rajesh, A.

Publications and source records attributed to Rajesh, A..

At least 19 recordsLinked to original sources

bioRxiv2026

NAMPT activation uncovers a senescence-specific vulnerability and promotes healthy aging in combination with NAM

Aging is driven by multiple interacting processes, suggesting that effective strategies to promote healthy aging may require simultaneous targeting of more than one underlying mechanism. Here we identify a strategy that couples restoration of nicotinamide adenine dinucleotide (NAD+) homeostasis with selective targeting of senescent cells, two mechanistically linked features of aging. Senescent cells express elevated intracellular levels of nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in the nicotinamide (NAM) salvage pathway for NAD+ biosynthesis. Despite increased NAMPT abundance, isotope-tracing studies revealed decreased NAD+ biosynthesis and consumption, indicating that elevated NAMPT abundance was not accompanied by a corresponding increase in NAD+ metabolic flux. Treatment with the NAMPT activator SBI-0802162 engaged the spare enzymatic capacity of NAMPT in senescent cells and produced a marked rise in intracellular NAD+ that, when sustained, disrupted their transcriptional program and selectively reduced the viability of senescent cells but not proliferating cells. In mice, SBI-0802162 reduced circulating NAM levels, suggesting that sustained NAMPT activation may be limited by substrate availability. This observation prompted the development of a combination approach using SBI-0802162 together with dietary NAM supplementation. Co-administration of SBI-0802162 and NAM robustly increased tissue NAD+, suppressed select age-associated inflammatory signatures and markers of cellular senescence in a tissue-specific manner. These molecular effects occurred alongside preserved physical performance in aged mice and reductions in food intake and body weight, which were observed whether SBI-0802162 was present in the chow or administered by oral gavage. Together, these findings establish a mechanistically integrated approach to target two convergent features of aging, NAD+ dysregulation and senescent cell accumulation, and support combined NAMPT activation and NAM supplementation as a strategy to promote healthy aging.

molecular biology↗

bioRxiv2026

Orthogonal CRISPR screens and human liver chimeric mice identify hepatitis B virus host factors

Hepatitis B virus (HBV) chronically infects approximately 250 million people worldwide, and reliable curative therapies are lacking. A broader understanding of viral-host interactions could accelerate efforts to find new host-centric therapeutic targets. However, inefficient cell culture systems and limited replication markers compatible with pooled screening have precluded the widespread use of genetic perturbation screens. Here, we performed the first pooled, genome-wide CRISPR-Cas9 knockout (KO) screen with authentic HBV infection and integrated these results with two orthogonal pooled screens to identify host factors. We selected 72 genes for a multi-step assessment that included arrayed validation assays using both HBV infection and pgRNA transfection. We then independently tested thirteen genes using high-efficiency bulk KO experiments to guide further investigations of both antiviral and proviral factors. In both KO and siRNA-mediated knockdown experiments, depletion of the top antiviral factor, EXOC1, enhanced multiple HBV replication markers, and transcriptomic analysis revealed activation of hypoxia- and HIF-1 gene signatures. Three proviral factors, IRF2, WDR48, and ZCCHC14, were investigated in vivo using a human liver chimeric mouse model, which demonstrated that ZCCHC14 KO greatly reduced HBV replication and spread. Together, these complementary in vitro and in vivo platforms expand the catalog of HBV host factors and provide a scalable framework for host target discovery.

microbiology↗

bioRxiv2026

Parallel processing chains span cytoarchitectures to organize association cortex

Task fMRI1 and electrophysiology2 have revealed distributed, linked cortical patches with shared category preferences (e.g., faces, objects, places)1,3-5, smaller than cytoarchitectonic areas. Resting-state functional connectivity (RSFC) similarly showed that somato-cognitive action network (SCAN) nodes interleave with effectors (foot, hand, mouth), subdividing the precentral gyrus6. Here, using multiple precision functional mapping (PFM) modalities (RSFC, task, lags), we discovered that most of association cortex is organized like face processing and SCAN, with small, discrete patches interconnected into chains. Such patch-chains densely tile prefrontal cortex but are largely absent from primary cortex. Cortico-striatal connectivity is organized such that patches of the same chain connect to the same striatal location. Within chains, infra-slow fMRI signals are ordered in time. RSFC-defined chains align with task fMRI localizers (e.g., visual, motor, pain). Chains are absent at birth and emerge in the first year of life, suggesting their formation is at least partially experience-driven. Cytoarchitectonic areas are subdivided by patches, and patches in the same chain are distributed across different cytoarchitectures. Chains represent parallel ordered processing streams that are separated by information domain and behavioral goals, not cytoarchitectonics. Functional subdivision of architectonics into smaller patches, interlinked to form cross-architecture chains, enable greater parallelization and flexible specialization of processing.

neuroscience↗

bioRxiv2026

HIRA-mediated H3.3 deposition preserves hepatocyte cell identity during liver aging

Age-associated functional decline is partly driven by progressive chromatin degeneration. Maintenance of chromatin integrity preserves cell identity and promotes healthy aging, but through different mechanisms in proliferating and non-proliferating cells. However, specific mechanisms of chromatin maintenance and their compensatory capacity in proliferating and non-proliferating cells are undefined. The histone chaperone HIRA deposits the histone variant H3.3 in a DNA replication-independent manner, leading to its accumulation in aging, non-proliferating cells. Here, we show that hepatocyte-specific loss of HIRA causes loss of cell identity, metabolic dysfunction, and accelerated fibrotic pathology with age. Transcriptomic and epigenomic analyses indicate that HIRA-H3.3 preserves chromatin integrity and sustains transcription of highly expressed genes, including cell identity genes. Partial hepatectomy, associated with induced proliferation, restores identity of HIRA knockout livers with compensatory deposition of canonical histones H3.1/2. Together, these results demonstrate that HIRA-mediated H3.3 deposition is essential for safeguarding cell identity and tissue function during aging of non-proliferating cells, but this function can be rescued by tissue regeneration and associated cell proliferation. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=124 SRC="FIGDIR/small/710643v1_ufig1.gif" ALT="Figure 1"> View larger version (29K): org.highwire.dtl.DTLVardef@a2a26aorg.highwire.dtl.DTLVardef@154e5aeorg.highwire.dtl.DTLVardef@b315a7org.highwire.dtl.DTLVardef@152bca4_HPS_FORMAT_FIGEXP M_FIG C_FIG

genomics↗

bioRxiv2026

Histone variant H2A.Z mutant suppresses the senescence-associated secretory phenotype

Cellular senescence features a durable cell-cycle arrest and a pro-inflammatory senescence-associated secretory phenotype (SASP) driven in part by chromatin remodeling. The histone variant H2A.Z plays an essential role in regulating gene expression through modulating nucleosome dynamics and is known to regulate the expression of cell cycle genes during the early stages of cellular senescence. However, how the intrinsic stability of H2A.Z-containing nucleosomes plays a role in the establishment of the senescent phenotype remains unexplored. To investigate this, we employed H2A.Z R80C, a H2A.Z mutant that destabilizes nucleosomes by disrupting histone-DNA interactions. We observed that expression of H2A.Z R80C causes suppression of SASP in senescent primary human fibroblasts, without affecting expression of cell cycle genes. H2A.Z knockdown did not suppress the SASP, demonstrating that SASP suppression is likely due to altered stability of H2A.Z-containing nucleosomes rather than loss of H2A.Z function. Mechanistically, SASP suppression is linked to decreased H3K27ac at SASP gene loci. These findings offer a novel avenue for understanding and manipulating the SASP during aging and other senescence-related pathologies.

molecular biology↗

bioRxiv2025

Thalamic hubs as early sources of global neuronal synchrony in absence epilepsy

Generalized seizures reflect a pathological state of sudden, global neuronal hypersynchrony. The mechanisms that support the initiation and maintenance of such synchrony remain unknown. Using simultaneous single-unit and electrocorticographic recordings in two mouse models of absence epilepsy, we evaluated the activity of approximately 2,000 individual neurons across 26 brain structures. By doing so, we resolved the temporal progression of single neuron activity prior to and during generalized seizures. Surprisingly, we observed that rhythmic, synchronized activity emerges early and gradually in both thalamus and cortex. Moreover, while we observe that individual neurons across most structures fire rhythmically and synchronously during seizures, a small subset of midline thalamic nuclei display activity that is strongly correlated across multiple regions. Finally, disturbing neuronal activity within the midline thalamus terminates seizures. Thus, our findings collectively highlight the possible role of the midline thalamus in emergence of neuronal hypersynchrony.

neuroscience↗

bioRxiv2025

Aging-induced hepatocyte CD44 drives IL6/STAT3 signaling and associates with impaired neighboring T cell function.

Liver cancer incidences increase dramatically beyond 55 years of age, suggesting that age-associated changes contribute critically to tumor initiation. However, the mechanisms linking liver aging and cancer initiation are not well defined. This study investigates the role of CD44, a marker of liver tumor-initiating cells (TIC), in age-associated liver pathophysiology. Aged livers showed accumulation of CD44-expressing hepatocytes exhibiting enrichment of immune modulatory genes and activation of the immunosuppressive IL6/JAK/STAT3 pathway. Indeed, in adoptive transfer assays, antigen-exposed CD8+ T cells mounted a lower IFN-{gamma} response in aged livers than in young livers, indicating an immunosuppressive aged milieu. Concordantly, spatial analyses showed that the proximal neighbourhoods of Cd44-expressing hepatocytes are enriched in T cells exhibiting reduced cytokine and chemokine gene expression. Finally, hepatocyte-specific knock out of Cd44 mitigated the IL6/JAK/STAT3 gene signature in aged livers. Overall, these findings suggest that CD44 expression in aged hepatocytes promotes activation of the immunosuppressive IL6/JAK/STAT3 pathway and this is associated with impaired T cell effector function.

cell biology↗

bioRxiv2025

Nucleosome stability safeguards cell identity, stress resilience and healthy aging

Nucleosomes are the minimal repeating units of chromatin. Their dynamic assembly and disassembly underpins chromatin organization and genome regulation. However, it remains unclear how intrinsic nucleosome stability contributes to higher-level yet fundamental cellular and organismal properties--such as preservation of cell identity, lineage specification, stress resilience and ultimately healthy aging. To address this, we tested the impact of decreased intrinsic nucleosome stability across multiple cell, tissue and organismal models by introducing histone mutants that weaken histone-histone interactions. While nucleosome instability did not broadly alter global chromatin accessibility, DNA damage, cell proliferation or viability, it impaired lineage-specific gene expression programs, altered lineage specification and activated intrinsic inflammatory and stress pathways in a manner reminiscent of aging in mouse tissues and human cells. Consistently, nucleosome instability accelerated the onset of age-associated transcriptional alterations and functional decline in Caenorhabditis elegans and Drosophila melanogaster, and reduced cellular resilience to exogenous perturbations-- including environmental, epigenetic and mitotic stress--in human cells and Saccharomyces cerevisiae. These cross-species findings identify nucleosome stability as an evolutionarily conserved epigenetic safeguard that preserves cell identity and stress resilience and supports organismal function and healthy aging.

genomics↗

bioRxiv2025

Targeting CyclinD1-CDK6 to Mitigate Senescence-Driven Inflammation and Age-Associated Functional Decline

Cellular senescence contributes to aging and age-related diseases by driving chronic inflammation through the Senescence Associated Secretory Phenotype (SASP) and interferon-stimulated genes (ISGs). Cyclin D1 (CCND1), a key cell cycle regulator, is paradoxically upregulated in these non-proliferating cells. We show that CCND1 and its kinase partner CDK6 drive SASP and ISG expression in senescent cells by promoting DNA damage accumulation. This leads to the formation of cytoplasmic chromatin fragments (CCFs) that activate pro-inflammatory CGAS-STING signaling. The tumor suppressor p53 (TP53) and its target p21 (CDKN2A) antagonize this CCND1-CDK6-dependent DNA damage accumulation pathway to suppress the SASP. In aged mouse livers, senescent hepatocytes show increased Ccnd1 expression. Hepatocyte-specific Ccnd1 knockout or treatment with the Cdk4/6 inhibitor Palbociclib reduces DNA damage and ISGs in aged mouse liver. Notably, Palbociclib also suppresses frailty and improves physical performance of aged mice. These findings reveal a novel role for CCND1/CDK6 in regulating DNA damage and inflammation in senescence and aging, highlighting it as a promising therapeutic target.

cell biology↗

bioRxiv2025

Rapamycin Reverses the Hepatic Response to Diet-Induced Metabolic Stress That Is Amplified by Aging.

Aging is associated with increased susceptibility to metabolic stress and chronic liver disease, yet the interactions between age and metabolic stressors and the potential for ameliorating interventions remain incompletely understood. Here, we examined the hepatic response of young (7-month-old) and old (25-month-old) C57BL/6 male mice to a 9-week high-fat diet (HFD) and assessed whether rapamycin, a well-established pro-longevity intervention, could mitigate age-exacerbated effects. While both age groups developed metabolic-associated steatohepatitis (MASH), older mice displayed more severe hepatic steatosis, inflammation, and transcriptional dysregulation. Transcriptomic profiling of whole livers and purified hepatocytes revealed that aging amplifies HFD-induced inflammatory and metabolic gene expression changes, including activation of immune pathways and suppression of metabolic pathways. Notably, treatment of aging mice with rapamycin reversed the majority of HFD-driven transcriptional alterations, including upregulation of pro-inflammatory regulators such as Stat1, and dysregulation of metabolic gene networks. Rapamycin also reduced hepatosteatosis, total body weight, and a tumorigenic transcriptomic signature associated with hepatocellular carcinoma risk. These findings demonstrate that aging intensifies hepatic sensitivity to metabolic stress and identify rapamycin as a promising therapeutic to counteract age-related liver dysfunction and MAFLD progression.

cell biology↗

bioRxiv2025

Stimulant medications affect arousal and reward, not attention

Prescription stimulants such as methylphenidate are being used by an increasing portion of the population, primarily children. These potent norepinephrine and dopamine reuptake inhibitors promote wakefulness, suppress appetite, enhance physical performance, and are purported to increase attentional abilities. Prior functional magnetic resonance imaging (fMRI) studies have yielded conflicting results about the effects of stimulants on the brains attention, action/motor, and salience regions that are difficult to reconcile with their proposed attentional effects. Here, we utilized resting-state fMRI (rs-fMRI) data from the large Adolescent Brain Cognitive Development (ABCD) Study to understand the effects of stimulants on brain functional connectivity (FC) in children (n = 11,875; 8-11 years old) using network level analysis (NLA). We validated these brain-wide association study (BWAS) findings in a controlled, precision imaging drug trial (PIDT) with highly-sampled (165-210 minutes) healthy adults receiving high-dose methylphenidate (Ritalin, 40 mg). In both studies, stimulants were associated with altered FC in action and motor regions, matching patterns of norepinephrine transporter expression. Connectivity was also changed in the salience (SAL) and parietal memory networks (PMN), which are important for reward-motivated learning and closely linked to dopamine, but not the brains attention systems (e.g. dorsal attention network, DAN). Stimulant-related differences in FC closely matched the rs-fMRI pattern of getting enough sleep, as well as EEG- and respiration-derived brain maps of arousal. Taking stimulants rescued the effects of sleep deprivation on brain connectivity and school grades. The combined noradrenergic and dopaminergic effects of stimulants may drive brain organization towards a more wakeful and rewarded configuration, explaining improved task effort and persistence without direct effects on attention networks.

neuroscience↗

bioRxiv2025

Dense Longitudinal Precision Neuroimaging of Recovery from Traumatic Brain Injury

Traumatic brain injury (TBI) disrupts white matter tracts essential for cognition and emotion. Diffusion tensor imaging (DTI) can noninvasively measure white matter integrity. However, DTI has been inconsistent in predicting patient recovery from TBI, possibly due to the complex, dynamic, and individual-specific process of post-TBI white matter remodeling. Here, we employed dense longitudinal neuroimaging to track white matter recovery weekly over six months after a TBI within a single patient and a control in a similar age group (21 vs. 24 y.o.). In the patient, but not in the control, DTI metrics precisely tracked parabolic trajectories across time, with early structural alterations continuing for more than 15 weeks before reversing direction. The extent of alteration in each tract was correlated with the time until reversal. These continuous DTI changes also mediated recovery of cognitive and emotional function, suggesting they are not passive markers of damage but dynamic processes underlying functional improvement. Complementary diffusion basis spectrum imaging (DBSI) revealed an initial phase of cellular loss followed by inflammatory remodeling, vascular adaptations, and persistent metabolic activity. Our findings indicate that recovery does not follow predefined phases but rather individualized transition points, which could define optimal windows for rehabilitation. Identifying these inflection points may enable personalized interventions aligned with biologically relevant structural shifts, rather than broad recovery periods.

neuroscience↗

bioRxiv2024

Activated Interferon Signaling Suppresses Age-Dependent Liver Cancer

Age is a major risk factor for liver cancer, as is the case for most adult human cancers. However, the underlying mechanisms are not well defined. A better understanding of the role of aging in liver and other cancers can facilitate approaches for risk assessment, early detection and prevention. We hypothesize that age-driven changes render aged liver more sensitive to oncogenic stress and hence tumorigenesis. To investigate how the liver changes with age, we documented the immune profile, transcriptome and epigenome of healthy livers from both young and aged mice, revealing pronounced alterations with aging. Notably, in aged hepatocytes, we identified heightened interferon (IFN) signaling, as well as simultaneous tumor suppressor and oncogene signaling at both bulk and single cell level, suggestive of an aged liver that is poised for neoplasia. To challenge this seemingly poised state, we employed adeno-associated virus (AAV)-mediated expression of a c-Myc oncogene in young and aged mouse liver hepatocytes in vivo. Analysis of aged hepatocytes expressing c-Myc revealed further elevated expression of IFN Stimulated Genes (ISGs). This ISG upregulation was evident in multiple models of oncogenic stress and transformation in older mice and also observed in aged humans with Metabolic dysfunction-Associated Steatohepatitis (MASH). We determined that Stat1 is both necessary and sufficient for the age specific elevated ISG expression in old wild type mice. Remarkably, inhibiting Jak/Stat signaling alongside ectopic c-Myc expression led to high-grade hepatocyte dysplasia and tumor formation, selectively in aged mice. Together, these results suggest that an aged liver is in a state of "precarious balance", due to concurrent activation of oncogenic and tumor suppressor pathways, but protected against neoplastic progression by IFN-signaling. Age-dependent activation of IFN signaling has been observed in many tissues and recent studies have demonstrated its detrimental consequences on aging, raising the question as to why IFN-signaling is activated during aging. We propose that aged tissues are intrinsically at higher risk of cancer and age-dependent activation of IFN-signaling is an adaptive process to protect from tumorigenesis, but one that also has maladaptive consequences.

cancer biology↗

bioRxiv2024

PROTGOAT : Improved automated protein function predictions using Protein Language Models

Accurate prediction of protein function is crucial for understanding biological processes and various disease mechanisms. Current methods for protein function prediction relies primarily on sequence similarities and often misses out on important aspects of protein function. New developments in protein function prediction methods have recently shown exciting progress via the use of large transformer-based Protein Language Models (PLMs) that allow for the capture of nuanced relationships between amino acids in protein sequences which are crucial for understanding their function. This has enabled an unprecedented level of accuracy in predicting the functions of previously little understood proteins. We here developed an ensemble method called PROTGOAT based on embeddings extracted from multiple and diverse pre-trained PLMs and existing text information about the protein in published literature. PROTGOAT outperforms most current state-of-the-art methods, ranking fourth in the Critical Assessment of Functional Annotation (CAFA 5), a global competition benchmarking such developments among 1600 methods tested. The high performance of our method demonstrates how protein function prediction can be improved through the use of an ensemble of diverse PLMs. PROTGOAT is publicly available for academic use and can be accessed here: https://github.com/zongmingchua/cafa5

bioinformatics↗

bioRxiv2023

Framewise multi-echo distortion correction for superior functional MRI

Functional MRI (fMRI) data are severely distorted by magnetic field (B0) inhomogeneities which currently must be corrected using separately acquired field map data. However, changes in the head position of a scanning participant across fMRI frames can cause changes in the B0 field, preventing accurate correction of geometric distortions. Additionally, field maps can be corrupted by movement during their acquisition, preventing distortion correction altogether. In this study, we use phase information from multi-echo (ME) fMRI data to dynamically sample distortion due to fluctuating B0 field inhomogeneity across frames by acquiring multiple echoes during a single EPI readout. Our distortion correction approach, MEDIC (Multi-Echo DIstortion Correction), accurately estimates B0 related distortions for each frame of multi-echo fMRI data. Here, we demonstrate that MEDICs framewise distortion correction produces improved alignment to anatomy and decreases the impact of head motion on resting-state functional connectivity (RSFC) maps, in higher motion data, when compared to the prior gold standard approach (i.e., TOPUP). Enhanced framewise distortion correction with MEDIC, without the requirement for field map collection, furthers the advantage of multi-echo over single-echo fMRI.

bioengineering↗

bioRxiv2023

Structure-Function Coupling in Highly Sampled Individual Brains

Structural connections (SC) between distant regions of the brain support synchronized function known as functional connectivity (FC) and give rise to the large-scale brain networks that enable cognition and behavior. Understanding how SC enables FC is important to understand how injuries to structural connections may alter brain function and cognition. Previous work evaluating whole-brain SC-FC relationships showed that SC explained FC well in unimodal visual and motor areas, but only weakly in association areas, suggesting a unimodal-heteromodal gradient organization of SC-FC coupling. However, this work was conducted in group-averaged SC/FC data. Thus, it could not account for inter-individual variability in the locations of cortical areas and white matter tracts. We evaluated the correspondence of SC and FC within three highly sampled healthy participants. For each participant, we collected 78 minutes of diffusion-weighted MRI for SC and 360 minutes of resting state fMRI for FC. We found that FC was best explained by SC in visual and motor systems, as well as in anterior and posterior cingulate regions. A unimodal-to-heteromodal gradient could not fully explain SC-FC coupling. We conclude that the SC-FC coupling of the anterior-posterior cingulate circuit is more similar to unimodal areas than to heteromodal areas. SIGNIFICANCE STATEMENTStructural connections between distant regions of the human brain support networked function that enables cognition and behavior. Improving our understanding of how structure enables function could allow better insight into how brain disconnection injuries impair brain function. Previous work using neuroimaging suggested that structure-function relationships vary systematically across the brain, with structure better explaining function in basic visual/motor areas than in higher-order areas. However, this work was conducted in group-averaged data, which may obscure details of individual-specific structure-function relationships. Using individual-specific densely sampled neuroimaging data, we found that in addition to visual/motor regions, structure strongly predicts function in specific circuits of the higher-order cingulate gyrus. The cingulates structure-function relationship suggests that its organization may be unique among higher-order cortical regions.

neuroscience↗

bioRxiv2023

Histone chaperone HIRA, Promyelocytic Leukemia (PML) protein and p62/SQSTM1 coordinate to regulate inflammation during cell senescence and aging.

Cellular senescence, a stress-induced stable proliferation arrest associated with an inflammatory Senescence-Associated Secretory Phenotype (SASP), is a cause of aging. In senescent cells, Cytoplasmic Chromatin Fragments (CCFs) activate SASP via the anti-viral cGAS/STING pathway. PML protein organizes PML nuclear bodies (NBs), also involved in senescence and anti-viral immunity. The HIRA histone H3.3 chaperone localizes to PML NBs in senescent cells. Here, we show that HIRA and PML are essential for SASP expression, tightly linked to HIRAs localization to PML NBs. Inactivation of HIRA does not directly block expression of NF-{kappa}B target genes. Instead, an H3.3-independent HIRA function activates SASP through a CCF-cGAS-STING-TBK1-NF-{kappa}B pathway. HIRA physically interacts with p62/SQSTM1, an autophagy regulator and negative SASP regulator. HIRA and p62 co-localize in PML NBs, linked to their antagonistic regulation of SASP, with PML NBs controlling their spatial configuration. These results outline a role for HIRA and PML in regulation of SASP.

cell biology↗

bioRxiv2023

Therapeutic and vaccine-induced cross-reactive antibodies with effector function against emerging Omicron variants

Currently circulating SARS-CoV-2 variants acquired convergent mutations at receptor-binding domain (RBD) hot spots1. Their impact on viral infection, transmission, and efficacy of vaccines and therapeutics remains poorly understood. Here, we demonstrate that recently emerged BQ.1.1. and XBB.1 variants bind ACE2 with high affinity and promote membrane fusion more efficiently than earlier Omicron variants. Structures of the BQ.1.1 and XBB.1 RBDs bound to human ACE2 and S309 Fab (sotrovimab parent) explain the altered ACE2 recognition and preserved antibody binding through conformational selection. We show that sotrovimab binds avidly to all Omicron variants, promotes Fc-dependent effector functions and protects mice challenged with BQ.1.1, the variant displaying the greatest loss of neutralization. Moreover, in several donors vaccine-elicited plasma antibodies cross-react with and trigger effector functions against Omicron variants despite reduced neutralizing activity. Cross-reactive RBD-directed human memory B cells remained dominant even after two exposures to Omicron spikes, underscoring persistent immune imprinting. Our findings suggest that this previously overlooked class of cross-reactive antibodies, exemplified by S309, may contribute to protection against disease caused by emerging variants through elicitation of effector functions.

immunology↗