Biology subjects

Arora, K.

Publications and source records attributed to Arora, K..

At least 19 recordsLinked to original sources

bioRxiv2026

Covert attentional tracking with invisible phase tagging

Attention forms a fundamental component of visual processing. The locus and spread of covert attention reveals how specific locations or features in the environment are preferentially processed, however, tracking this process in a time-resolved fashion is not easy. Rapid Invisible Frequency Tagging (RIFT) is a recent advance in localizing covert attention. This technique uses stimuli that flicker at unique frequencies to invisibly "tag" areas of the visual field. The frequency-specific response elicited offers a measure of visual processing (and covert attention) over time. However, the narrow frequency band compatible with RIFT restricts the number of distinct frequency tags that can be simultaneously used. This limitation can be addressed by using oscillatory phase as an additional tagging feature. Here, we conducted a RIFT-EEG experiment (n=24) with 8 unique tags based on both frequency and phase modulation. We show that modulations in visual processing can be measured at several tagged locations with identical frequency but different phases. This also allowed for the use of combined phase- and frequency- modulated RIFT to quantify the distribution of attention across the visual field. By integrating phase-modulation into invisible frequency tagging studies of attention, we bring the field a step closer towards fine-resolution attentional tracking continuously over time and space, allowing novel insights across various domains of visual cognition.

neuroscience↗

bioRxiv2026

Visual Attention doesnt Travel, it Teleports

Attention forms a key, yet elusive component of visual processing. We shift attention constantly across the visual field to enhance processing of relevant locations or stimuli in service of goal-directed behavior. Here, we investigate a fundamental property of attentional shifts: when covertly shifting from one location to another, does visual attention "travel" (enhance processing at intermediate locations) or "teleport" (not interact with intermediate locations)? While most shifts of information or movement "travel" (e.g., eye and body movements, neuronal signalling), for attentional shifts such intermediate processing enhancement might not be necessary, nor functional. To answer this question while tackling the difficulty of tracking covert attentional dynamics, we conducted an EEG-eyetracking experiment (n=24) paired with Rapid Invisible Frequency Tagging (RIFT). This let us track attentional enhancement during covert attentional shifts with high temporal and spatial precision. We successfully registered covert shifts, but found no evidence for any attentional modulation in-between the start and end-point of an attentional shift. Additional insilico modelling of attentional shifts confirmed that our method was sensitive enough to pick up on these modulations had they been present. Our results support a "teleporting" model of attention, suggesting that attention is implemented in a fundamentally different manner compared to overt visual behaviours such as eye movements.

neuroscience↗

bioRxiv2025

Independent Markers of Attentional Shifts

Visuospatial attention has been extensively studied using a wide variety of markers in the brain and in behaviour. We can broadly classify these markers into two distinct groups: reactive measures, where the presence and strength of attentional biases is inferred from the reaction to a probe stimulus, and proactive measures, which track attentional biases without (or before) the presentation of a probe stimulus. A difference in either type of measure (between two experimental conditions) is typically interpreted to reflect a difference in attentional resources. However, it is not a given that these various reactive and proactive measures of attention all read out the same construct; they may very well tap into independent processes. Here, we measure some of these proactive and reactive signatures of attending a location (changes in cortical excitability as measured by RIFT, alpha lateralization, gaze bias, probe-evoked ERPs, and behavioral reports) in an EEG-eyetracking task (n=23). Though all these metrics indeed correlate with our attentional manipulation, we show that they are not direct correlates of each other, and that of all the proactive measures only the gaze bias predicts subsequent behavioral responses. This demonstrates that existing markers of attention cannot be used interchangeably, and likely capture independent subprocesses of attention.

neuroscience↗

bioRxiv2025

Tracking attention using RIFT with a consumer-monitor setup

Rapid Invisible Frequency Tagging (RIFT) is a recent technique that extends the traditional frequency tagging approach by modulating the luminance of distinct locations on a screen at frequencies beyond the threshold of perception ([≥]60Hz). Retrieving the corresponding frequencies from M/EEG recordings provides a time-resolved and location-specific measure of early visual processing, without the confounding effect of introducing visible stimuli. This method is most frequently harnessed as a tracker of covert attention in experimental paradigms across various disciplines in cognitive neuroscience. However, almost all existing RIFT work so far has made use of expensive display hardware limited in its accessibility. Recent work has shown that a RIFT response elicited by a 480Hz refresh-rate consumer monitor can be retrieved from the EEG, but it is not yet clear whether such a setup can be utilized to track the locus of attention. Here, using a spatial cueing paradigm (n=24) while simultaneously tagging two locations (60.0Hz and 65.5Hz), we show that covert attention can be reliably measured with RIFT on a 360Hz refresh rate consumer monitor. We hope that this study will facilitate the widespread application of using consumer-grade high refresh-rate gaming monitors with RIFT for future scientific and applied research.

neuroscience↗

bioRxiv2025

Dynamic competition between bottom-up saliency and top-down goals in early visual cortex

Task-irrelevant yet salient stimuli can elicit automatic, bottom-up attentional capture and compete with top-down, goal-directed processes for neural representation. However, the temporal dynamics underlying this competition, and how they influence early visual processing, remain poorly understood. Here, we combined electroencephalography (EEG) with Rapid Invisible Frequency Tagging (RIFT) to non-invasively and simultaneously track early visual cortex responses to target and distractor. Both target and distractor evoked stronger initial RIFT responses than nontargets, reflecting top-down and bottom-up attentional effects on early visual processing. Importantly, the presence of a distractor attenuated the initial RIFT response to the target, reflecting competition during the initial stages of visual processing and predicting subsequent behavioral performance. RIFT responses to the distractor eventually even decreased below responses to the target and nontarget, representing active suppression of task-irrelevant but salient stimuli. We show that the dynamic interplay between top-down control and bottom-up saliency directly impacts early visual responses, thereby illuminating a complete timeline of attentional competition in visual cortex.

neuroscience↗

bioRxiv2025

Anticipated Relevance Prepares Visual Processing for Efficient Memory-Guided Selection

Finding an object typically involves using working memory to select relevant visual information at the right time. Using EEG, we investigated how predictable changes in stimulus relevance influence top-down visual selection. Participants memorized an oriented grating, followed by a cue indicating which of two sequentially presented probes was relevant for a memory-match/-mismatch judgment. Consistent with earlier work, relevant probes evoked stronger univariate responses than irrelevant probes. Furthermore, responses to (memory-matching and memory-mismatching) probes were more distinct when they were relevant compared to irrelevant. Crucially, using rapid invisible frequency tagging (RIFT), we found that visual responses to the (empty) probe location were enhanced even before the presentation of relevant (compared to irrelevant) probes. Predictable changes in stimulus relevance, therefore, induce both pro-active and re-active changes in visual processing. We conclude that anticipating the (ir)relevance of upcoming visual events enables the visual system to prepare for efficient memory-guided visual selection.

neuroscience↗

bioRxiv2025

Differential Expression and Microsystem Physiology Reveal Predominant and Drug Reversible CFTR-Related Defects in Idiopathic Pancreatitis

Pancreatitis is a potentially fatal and difficult to control exocrine-tissue defect with no FDA approved therapies. Variants of a chloride/bicarbonate transporter cystic fibrosis transmembrane conductance regulator (CFTR) pose multi-fold increased risk of pancreatitis accounting for up to 40% of the patients with idiopathic pancreatitis. However, the relationship between the duct-restricted CFTR-function and total exocrine tissue defect during pancreatitis remains less known and animal models do not translate well to human disease. To overcome this challenge, we developed a robust and highly durable iPSC-derived model system of pancreatic ductal tissues from an idiopathic pancreatitis patient with a common pancreatitis-associated CFTR variant. In the patient line termed PANx, we found deficient CFTR function and a distinct gene expression signature for ductal tissue pancreatitis marked by aberrant mucin production, inflammatory cytokines and cystic neoplasms. By applying clinically used CFTR-modulator drug ivacaftor, we observed a remarkable restoration of deficient CFTR-mediated fluid secretion as well as upto 40% reversal of the differential gene signature for PANx including the reduction in mucinous neoplasms and immunogenic cytokines such as IL-11, CCL20 and CXCL8. We further employed a microsystem device to model hyperamylasemia, a diagnostic feature of acute pancreatitis attack, due to a ductal reaction causing acinar injury. The key mucinous signature was validated in primary pancreatitis ductal tissues with a CFTR variant. Overall, we unraveled new layers of CFTR-related pathology in pancreatitis to help us better understand the early course of this debilitating condition. The test methods and model systems discovered in this study will significantly expedite the discovery of diagnostic and therapeutic tools for treating idiopathic pancreatitis. For the first time, we provided molecular and physiologic evidence supporting the benefit of CFTR modulator drug ivacaftor in human CFTR-related pancreatitis.

pathology↗

bioRxiv2025

Macromolecular Diamidobenzimidazole Conjugates Activate STING

Pharmacologic activation of the stimulator of interferon genes (STING) pathway has broad potential applications, including the treatment of cancer and viral infections, which has motivated the synthesis and testing of a diversity of STING agonists as next generation immunotherapeutics. A promising class of STING agonists are the non-nucleotide, small molecule, dimeric-amidobenzimidazoles (diABZI), which have been recently used in the synthesis of polymer- and antibody-drug conjugates to improve pharmacokinetics, modulate biodistribution, and to confer other favorable properties for specific disease applications. These approaches have leveraged diABZI variants functionalized with reactive handles and enzyme-cleavable linkers at the 7-position of the benzimidazole for conjugation to and tunable drug release from carriers. However, since this position does not interact with STING and is exposed from the binding pocket when bound in an "open lid" configuration, we sought to evaluate the activity of macromolecular diABZI conjugates that lack enzymatic release and are instead conjugated to polymers via a stable linker. By covalently ligating diABZI to 5 or 20 kDa mPEG chains via an amide bond, we surprisingly found that these conjugates could activate STING in vitro. To further evaluate this phenomenon, we designed a diABZI-functionalized RAFT chain transfer agent that provided an enabling tool for synthesis of large, hydrophilic, dimethylacrylamide (DMA) polymers directly from a single agonist and we found that these conjugates also elicited STING activation in vitro with similar kinetics to highly potent small molecule analogs. We further demonstrated the in vivo activity of these macromolecular diABZI platforms, which inhibited tumor growth to a similar extent as small molecule variants. Using flow cytometry and fluorescence microscopy to evaluate intracellular uptake and distribution of Cy5-labeled analogs, our data indicate that although diABZI-DMA conjugates enter cells via endocytosis, they can still colocalize with the ER, suggesting that intracellular trafficking processes can promote delivery of endocytosed macromolecular diABZI compounds to STING. In conclusion, we have described new chemical strategies for the synthesis of stable macromolecular diABZI conjugates with unexpectedly high immunostimulatory potency, findings with potential implications for the design of polymer-drug conjugates for STING agonist delivery that also further motivate investigation of endosomal and intracellular trafficking as an alternative route for achieving STING activation.

bioengineering↗

bioRxiv2024

Fragment-based development of small molecule inhibitors targeting Mycobacterium tuberculosis cholesterol metabolism

Mycobacterium tuberculosis (Mtb) is the worlds most deadly infectious pathogen and new drugs are urgently required to combat the emergence of multi-(MDR) and extensively-(XDR) drug resistant strains. The bacterium specifically upregulates sterol uptake pathways in infected macrophages and the metabolism of host-derived cholesterol is essential for Mtbs long-term survival in vivo. Here, we report the development of antitubercular small molecules that inhibit the Mtb cholesterol oxidases CYP125 and CYP142, which catalyze the initial step of cholesterol metabolism. An efficient biophysical fragment screen was used to characterize the structure-activity relationships of CYP125 and CYP142, and identify a non-azole small molecule 1a that can bind to the heme cofactor of both enzymes. A structure-guided fragment-linking strategy was used to optimize the binding affinity of 1a, yielding a potent dual CYP125/142 inhibitor 5m (KD CYP125/CYP142 = 0.04/0.16 {micro}M). Compound 5m potently inhibits the catalytic activity of CYP125 and CYP142 in vitro (KI values < 0.1 {micro}M), and rapidly depletes Mtb intracellular ATP (IC50 = 0.15 {micro}M). The compound has antimicrobial activity against both drug susceptible and MDR Mtb (MIC99 values 0.4 - 1.5 {micro}M) in extracellular assays, and inhibits the growth of Mtb in human macrophages (MIC = 1.7 {micro}M) with good selectivity over mammalian cytotoxicity (LD50 [≥] 50 {micro}M). The combination of small molecule inhibitors and structural data reported here provide useful tools to study the role of cholesterol metabolism in Mtb and are a promising step towards novel antibiotics targeting bioenergetic pathways, which could be used to help combat MDR-TB.

pharmacology and toxicology↗

bioRxiv2024

Gaze biases can reflect task-specific spatial memorization strategies

Previous work has suggested that small directional eye movements not only reveal the focus of external spatial attention towards visible stimuli, but also accompany shifts of internal attention to stimuli in visual working memory (VWM)(van Ede et al., 2019). When the orientations of two bars are memorized and a subsequent retro-cue indicates which orientation needs to be reported, participants gaze is systematically biased towards the former location of the cued item (Figure 1AB). This finding was interpreted as evidence that the oculomotor system indexes internal attention; that is, attention directed at the location of stimuli that are no longer presented but are maintained in VWM. Importantly, as the location of the bars is presumably not relevant to the memory report, the authors concluded that orientation features in VWM are automatically associated with locations, suggesting that VWM is inherently spatially organized. This conclusion depends on the key assumption that participants indeed memorize and subsequently attend orientation features. Here we re-analyse Experiment 1 by van Ede et al. (2019) and demonstrate that this assumption does not hold. Instead of memorizing orientation features, participants deployed an alternative spatial strategy by memorizing bar endpoints. Although we do not call into question the conclusion that internal attention is inherently spatially organized, our results do imply that directional gaze biases might also reflect attention directed at task-relevant stimulus endpoints, rather than internal attention directed at memorized orientations. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=161 SRC="FIGDIR/small/610231v2_fig1.gif" ALT="Figure 1"> View larger version (43K): org.highwire.dtl.DTLVardef@940e51org.highwire.dtl.DTLVardef@37ec3dorg.highwire.dtl.DTLVardef@176b186org.highwire.dtl.DTLVardef@180e8a7_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOFigure 1.C_FLOATNO Gaze density maps from Experiment 1 by van Ede et al. (2019) (N = 23, trials included = 20.864, 400 to 1000 ms). AB. Original reported effect of cued item location on gaze bias. Calculated by subtracting cued-item-left and cued-item-right gaze density maps. Rectangles indicate used stimulus positions and orientation ranges (min: 20{degrees}, mean: 45{degrees}, max: 70{degrees}; min: 110{degrees}, mean: 135{degrees}, max: 160{degrees}) of bar stimuli. C. Normalized Gaze bias vectors per condition (red dotted lines), horizontal vectors (dotted black lines) and average vectors pointing towards most foveal bar endpoints (solid black lines). Gaze bias vector endpoints were calculated from the centre of mass of each condition, ignoring negative values. Circular t-tests revealed that individual gaze bias vector angles (red dotted lines) were significantly different from horizontal vectors (dotted black lines) but not significantly different from endpoint vectors (solid black lines). FI. Vertical gaze bias revealed by separating trials based on bar orientations. Red dotted lines depict group average gaze bias vectors. F. Both bar endpoints "upwards" (left: 20{degrees} to 70{degrees} right: 110{degrees} to 160{degrees}) minus both bars endpoints "downwards" (left: 110{degrees} to 160{degrees}, right: 20{degrees} to 70{degrees}). I. Both "downwards" minus both "upwards". DEGH. Individual gaze density maps for each attention (left versus right) and bar endpoint direction (upwards versus downwards) separately. Solid black Lines show average vector pointing towards closest 45{degrees}/135{degrees} bar endpoint (i.e., average optimal gaze location for solving the memory task through memory maintenance of a spatial location). Red dotted lines depict group average gaze bias vectors (calculated from the centre of mass of each condition, ignoring negative values). C_FIG

neuroscience↗

bioRxiv2024

Dissociating External and Internal Attentional Selection

Visual Working Memory (VWM) stores visual information for upcoming actions. Just as attention can shift externally towards relevant objects in the visual environment, attention can shift internally towards (i.e., prioritize) VWM content that is relevant for upcoming tasks. Internal and external attentional selection share a number of key neural and functional characteristics, which include their spatial organization: recent work has shown that spatial attention is directed towards the previous location of a prioritized memory item, similar to how a perceived stimulus is prioritized. Attending stimuli that are physically present is useful, as it enhances processing of the relevant visual input. When prioritizing items in memory, however, attending the prior stimulus location cannot serve this purpose, as there is no visual input to enhance. Here, we address this apparent contradiction which highlights the gaps in our understanding of the mechanisms underlying external and internal visual attention. In two EEG experiments, we compare location-specific sensory enhancement during the attentional selection of external (perceived) as compared to internal (memorized) stimuli. During both internal and external selection we observed a lateralization of alpha oscillations and gaze position bias toward the previous locations of prioritized items, confirming earlier findings that suggested an inherent spatial organization within VWM. Critically, using Rapid Invisible Frequency Tagging (RIFT), we show that sensory enhancement at the attended location is only observed during external attentional selection of (perceived) stimuli. No such location-specific sensory enhancement was observed during attentional selection of items in VWM. Furthermore, we found no clear relationship across trials between alpha lateralization and sensory enhancement (measured through RIFT) during external attention, suggesting that these two metrics indeed reflect distinct cognitive mechanisms. In sum, using a novel combination of EEG and RIFT, we demonstrate a fundamental distinction between the neural mechanisms underlying the selection of perceived and memorized objects. Both types of selection operate within a spatial reference frame, but only external selection modulates early sensory processing. Our findings suggest that the visual system is not vestigially recruiting existing mechanisms of external attention for prioritization in VWM, but is instead using space as an organizational principle to store and select items in VWM.

neuroscience↗

bioRxiv2024

T2R14 mediated antimicrobial responses through interactions with CFTR

Bitter taste receptors (T2Rs), are a subset of G protein-coupled receptors (GPCRs) that play a key role in responding to microbial presence at epithelial surfaces. In epithelia, the activities of ion channels and transporters, and of T2Rs, mutually affect each other. The normal function of one such anion channel, cystic fibrosis transmembrane conductance regulator (CFTR), is essential for the maintenance of healthy epithelia, not just in the respiratory but in the digestive and reproductive system as well. Based on evidence that T2R14 activity is affected upon mutations in CFTR, we explored the possibility that T2R14 and CFTR directly interact in cell membranes. The biophysical interaction between these proteins was mapped to specific regions of the CFTR, and was dependent on agonist stimulation of T2R14. Further, T2R14 was found to couple to Gq, in addition to the canonical Gi, in response to bacterial and fungal quorum sensing molecules. Whether the interaction with CFTR affects T2R14 driven responses to microbial signals is under investigation.

biochemistry↗

bioRxiv2024

STING-Activating Polymer-Drug Conjugates for Cancer Immunotherapy

The stimulator of interferon genes (STING) pathway links innate and adaptive antitumor immunity and therefore plays an important role in cancer immune surveillance. This has prompted widespread development of STING agonists for cancer immunotherapy, but pharmacological barriers continue to limit the clinical impact of STING agonists and motivate the development of drug delivery systems to improve their efficacy and/or safety. To address these challenges, we developed SAPCon, a STING-activating polymer-drug conjugate platform based on strain-promoted azide-alkyne cycloaddition of dimeric-amidobenzimidazole (diABZI) STING agonists to hydrophilic polymer chains through an enzyme-responsive chemical linker. To synthesize a first-generation SAPCon, we designed a diABZI prodrug modified with a DBCO reactive handle with a cathepsin B-cleavable spacer for intracellular drug release and conjugated this to pendant azide groups on a 100kDa poly(dimethyla acrylamide-co-azide methacrylate) copolymer backbone to increase circulation time and enable passive tumor accumulation. We found that intravenously administered SAPCon accumulated at tumor sites, where it was endocytosed by tumor-associated myeloid cells, resulting in increased STING activation in tumor tissue. Consequently, SAPCon promoted an immunogenic tumor microenvironment, characterized by increased frequency of activated macrophages and dendritic cells and improved infiltration of CD8+ T cells, resulting in inhibition of tumor growth, prolonged survival, and enhanced response to anti-PD-1 immune checkpoint blockade in orthotopic breast cancer models. Collectively, these studies position SAPCon as a modular and programmable platform for improving the efficacy of systemically administered STING agonists for cancer immunotherapy.

bioengineering↗

bioRxiv2024

Rapid Invisible Frequency Tagging (RIFT) in a novel setup with EEG

Steady-State Visual Evoked Potentials (SSVEPs) provide a report-free and continuous measure of neural processing. Recent progress in display technology has allowed for the tagging of multiple stimuli simultaneously at >60Hz frequencies - high enough to evade perceptibility, while still evoking an oscillatory neural response. Known as Rapid Invisible Frequency Tagging (RIFT), this technique has currently only been used in combination with Magnetoencephalography (MEG), which is less accessible compared to Electroencephalography (EEG). Although responses to LEDs flickering at similar frequencies have been shown in EEG, it is currently unclear whether RIFT, using a more conventional stimulus display, can sufficiently evoke a response in EEG, and therefore whether it is worth adding the RIFT-EEG pairing to the cognitive neuroscientists toolkit. Here, we successfully implement the first RIFT-EEG setup. We show that the oscillatory input is measurable in the EEG trace, what its topographical spread is, a rough range of applicable frequencies, and that this response is comparable to that evoked in MEG.

neuroscience↗

bioRxiv2023

A potential acoustic role for CFTR ion channel in conductive hearing loss

Loss-of-function mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene cause cystic fibrosis (CF). The middle ear and eustachian tube could be adversely affected in CF. In this study, we provide evidence of the role of CFTR function in conductive hearing. We developed an in-situ model to determine CFTR dependent fluid secretion in the middle ear using native mouse auditory capsule. A unique middle ear-on-a-chip was developed to address the functional and molecular basis of conductive hearing impairment. Using single-cell transcriptomics, middle ear cell composition and the associated transcriptomic signature were compared between CF and WT groups. A specialized subset of epithelial cells expressed CFTR with an overlapping signature with secretory epithelial cells. Genes related to ciliogenesis, hearing and ossification were significantly altered in CF mice middle ear. Our data suggest that CF middle ear may be at higher risk for conductive hearing loss.

cell biology↗

bioRxiv2022

A Simplified Model of Motor Control

In general, control of movement is considered to be either cortical, spinal, or purely biomechanical and is studied separately at these levels. To achieve this separation when studying a particular level, variations that may be introduced by the other levels are generally either ignored or restricted. This restriction misrepresents the way movements occur in realistic scenarios and limits the ability to model movements in a biologically inspired manner. In this work, we propose a heuristic model for motor control that conceptually and mathematically accounts for the entire motor process, from target to endpoint. It simulates human arm motion and is able to represent functionally different motion properties by flexibly choosing more or less complex motion paths without built-in optimization or joint constraints. With a novel implementation of hierarchical control, this model successfully overcomes the problem of degrees of freedom in robotics. It can serve as a template for neurocomputational work that currently uses control architectures that do not mirror the human motor control process. The model itself also suggests a maximum threshold for delays in position feedback for effective movement, and that the primary role of position feedback in movement is to overcome the effects of environmental perturbations at the joint level. These findings can inform future efforts to develop biologically inspired motor control techniques for prosthetic devices.

neuroscience↗

bioRxiv2022

Nucleoid-Associated Proteins Undergo Liquid-Liquid Phase Separation with DNA into Multiphasic Condensates Resembling Bacterial Nucleoids

Liquid-liquid phase separation offers unique spatiotemporal control over myriad complex intracellular biochemical processes through compartmentalization of biomolecules into highly dynamic, liquid-like condensates known as membrane-less organelles. The bacterial nucleoid is thought to be one such phase-separated condensate; however, its formation, regulation, and biophysical characteristics are poorly understood. Our super-resolution imaging data suggests that nucleoids are dynamic assemblages of sub-micron-sized liquid-like droplets. We demonstrate that non-sequence-specific Nucleoid-Associated Proteins (NAPs) such as HU-A, HU-B and Dps, accrete nucleic acids and spontaneously condense with them into liquid-like, multicomponent, multiphasic, heterotypic phase-separated droplets. Upon mixing of HU-B, DNA and Dps, HU-B-enriched droplets are seen to contain demixed Dps-enriched droplets. Our findings indicate scope for the possible existence of multiphasic liquid-like compartments within nucleoids, providing insights into bacterial growth phase-dependent variations in the levels of different NAPs.

biophysics↗

bioRxiv2022

Differential pathogenesis of SARS-CoV-2 variants of concern in human ACE2-expressing mice

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a pandemic resulting in millions of deaths worldwide. Increasingly contagious variants of concern (VoC) have fueled recurring global infection waves. A major question is the relative severity of disease caused by the previous and currently circulating variants of SARS-CoV-2. In this study, we evaluated the pathogenesis of SARS-CoV-2 variants in human ACE-2-expressing (K18-hACE2) mice. Eight-week-old K18-hACE2 mice were inoculated intranasally with a representative virus from the original B.1 lineage, or the emerging B.1.1.7 (alpha), B.1.351 (beta), B.1.617.2 (delta) or B.1.1.529 (omicron) lineages. We also infected a group of mice with the mouse-adapted SARS-CoV-2 (MA10). Our results demonstrate that B.1.1.7, B.1.351 and B.1.617.2 viruses are significantly more lethal than B.1 strain in K18-hACE2 mice. Infection with B.1.1.7, B.1.351 and B.1.617.2 variants resulted in significantly higher virus titers in the lungs and brain of mice compared to the B.1 virus. Interestingly, mice infected with the B.1.1.529 variant exhibited less severe clinical signs and high survival rate. We found that B.1.1.529 replication was significantly lower in the lungs and brain of infected mice in comparison to other VoC. Transcription levels of cytokines and chemokines in the lungs of the B.1.1.529-infected mice were significantly less when compared to those challenged with the B.1.1.7 virus. Together, our data provide insights into the pathogenesis of the previous and circulating SARS-CoV-2 VoC in mice.

microbiology↗