Biology subjects

Kim, A. H.

Publications and source records attributed to Kim, A. H..

At least 19 recordsLinked to original sources

bioRxiv2026

Quantitative dissection of the metastatic cascade at single colony resolution

Metastasis is the leading cause of cancer-related deaths. However, the core determinants and mechanistic principles underlying the metastatic cascade remain elusive. Small cell lung cancer (SCLC) is a highly aggressive malignancy with exceptional metastatic potential and limited therapeutic options. Here, we present Metastasis Originated Barcode Sequencing (MOBA-seq), a high-throughput in vivo platform that systematically maps genetic regulators across the metastatic cascade at single-colony resolution. MOBA-seq integrates scalable barcode-based lineage tracing with a computational pipeline that quantitatively deconvolutes genotype-specific effects on metastatic seeding, dormancy, and clonal expansion across hundreds of thousands of metastatic events. Applying this approach to more than 400 candidate regulators of SCLC, we uncovered tissue-specific metastatic suppressors and universal metastatic essential genes. We identified metastatic seeding as the predominant determinant of metastasis. Comparative analysis across recipient mice of distinct genetic backgrounds further revealed that innate immune surveillance constrains metastatic progression by reducing metastatic seeding and enforcing dormancy, with additional modulation by sex and tissue context. We validated the frequently mutated gene CREBBP as a key metastasis suppressor whose loss enhances SCLC metastasis through both tumor-intrinsic and immune-modulatory mechanisms. This work establishes a scalable and quantitative platform for mapping the metastatic fitness landscape at single-colony resolution across hundreds of thousands of in vivo data points. Our approach offers a broadly applicable framework for dissecting the interactions between cancer-intrinsic and microenvironmental factors governing tumor initiation, progression, and therapeutic response.

cancer biology↗

bioRxiv2025

Cerebellum metastasis model of HER2-positive breast cancer unveils key role of IL34-induced Arg1+ macrophages.

Brain metastases occur in up to 40% of Stage IV breast cancer patients. The cerebellum is a frequent location for metastases in HER2-positive breast cancer patients, but the mechanisms for this are unknown. Here, we developed a syngeneic, immunocompetent mouse model for breast cancer brain metastases by stereotactically injecting mouse HER2-overexpressing breast cancer organoids into the cerebellum. Growth of these cerebellar metastases was monitored by MRI and trastuzumab optical imaging using a near-infrared fluorophore conjugated to trastuzumab. Spatial transcriptomics identified interleukin-34 production by breast cancer cells inducing ARG1+ macrophages at the invading edge of the metastasis. Treatment with a blocking antibody to interleukin-34s receptor, CSF1R, produced tumor shrinkage. These findings have immediate translation potential as a CSF1R-blocking antibody is FDA-approved. Further, it demonstrates that cancer-associated inflammation bordering the brain metastasis promotes metastatic growth and offers a molecularly targeted strategy to treat inflammation in brain metastasis. Graphical summary O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/660224v1_ufig1.gif" ALT="Figure 1"> View larger version (38K): org.highwire.dtl.DTLVardef@9f1a50org.highwire.dtl.DTLVardef@178acc5org.highwire.dtl.DTLVardef@196d803org.highwire.dtl.DTLVardef@3fe631_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2025

Disentangling objects' contextual associations from perceptual and conceptual attributes using time-resolved neural decoding

Humans effortlessly relate what they see to what they know, drawing on existing knowledge of objects perceptual, conceptual, and contextual attributes while searching for and recognising objects. While prior studies have investigated the temporal dynamics of perceptual and conceptual object properties in the neural signal, it remains unclear whether and when contextual associations are uniquely represented. In this study, we used representational similarity analysis on electroencephalography (EEG) data to explore how the brain processes the perceptual, conceptual, and contextual dimensions of object knowledge over time. Using human similarity judgments of 190 naturalistic object concepts presented as either as images or words, we constructed separate behavioural models of objects perceptual, conceptual, and contextual properties. We correlated these models with neural patterns from two EEG datasets, one publicly available and one newly collected, both recorded while participants passively viewed the same object stimuli. Across both datasets, we found that perceptual features dominated the early EEG response to object images, while conceptual features emerged later. Contextual associations were also reflected in neural patterns, but their explanatory power largely overlapped with that of conceptual models, suggesting limited unique representation of objects contextual attributes under passive viewing conditions. These results highlight the brains integration of perceptual and conceptual information when processing visual objects. By combining high temporal resolution EEG with behaviourally derived models, this study advances our understanding of how distinct dimensions of object knowledge are encoded in the human brain.

neuroscience↗

bioRxiv2025

Single-Cell Analysis of Meningiomas Reveals Mutation-Associated Tumor and Immune Cell Gene Expression Programs

Genomic and epigenetic profiling, particularly DNA methylation analysis, have refined the molecular classification of meningiomas and revealed marked intratumoral heterogeneity. To further characterize heterogeneity within and between patients, we analyzed meningiomas using single-cell RNA sequencing (n=11), whole-exome sequencing (n=9), and spatial transcriptomics (n=3). Single-cell analysis revealed six transcriptionally distinct tumor cell states that corresponded to unique biological processes. Integration of the single-cell data with published exome and bulk RNA sequencing data from a large cohort revealed significant associations among somatic variants, tumor cell states, and immunological signatures. Notably, NF2-altered tumors were enriched for an epithelial-to-mesenchymal transition (EMT) cell state and immune cells, whereas NF2-intact tumors were enriched for a sterol metabolism cell state. Spatial transcriptomic analysis confirmed co-localization of immune cells and EMT tumor cells. Comparisons with immune cells from other brain tumors and peripheral tissues highlighted immunological cell states specific to meningioma. Collectively, these findings refine our genetic and molecular understanding of meningioma heterogeneity and underscore the link between genotype and molecular phenotype.

cancer biology↗

bioRxiv2025

Enhanced anti-nociception by novel dual antagonists for 5HT2aR and mGluR5 in preclinical models of pain

Significant research has focused on developing anti-nociceptive pain treatments by targeting specific molecular candidates. The serotonin 2A receptor (5-HT2AR) and metabotropic glutamate receptor 5 (mGluR5) are recognized as key mediators in neuropathic pain. However, the combined effects of simultaneous inhibition of these targets remain unexplored. This current study investigated the therapeutic potential of concurrently antagonizing 5-HT2AR and mGluR5. Using spinal nerve ligation (SNL) and formalin-induced pain models in male Sprague-Dawley rats, we demonstrated that the simultaneous administration of both antagonists significantly enhanced anti-allodynic and anti-nociceptive effects, resulting in increased allodynia thresholds and reduced pain-related behaviors. This dual antagonism provided pain relief comparable to that of gabapentin and morphine. Furthermore, novel small molecules designed to simultaneously antagonize 5-HT2AR and mGluR5 exerted anti-nociceptive effects by suppressing excitatory postsynaptic responses and inhibiting the phosphorylation of ERK and AKT signaling molecules. Notably, the dual antagonist maintained anti-allodynic efficacy with repeated administration, unlike morphine, which exhibited clear tolerance development with daily use. Moreover, when administered intravenously, the dual antagonist demonstrated a low potential for abuse. These findings indicate that the simultaneous antagonism of 5-HT2AR and mGluR5 represents a promising pharmacological target for the management of chronic pain. This approach may offer enhanced analgesic outcomes while reducing the risk of undesirable side effects, such as tolerance and the potential for abuse.

neuroscience↗

bioRxiv2025

NEMO recruitment at single cytokine-receptor complexes shows quantized dynamics independent of ligand affinity

Cells use a limited number of receptors to sense and process molecular information from their environment. In the classical view of signaling, receptor-ligand affinities determine binding kinetics, in timescales of diffusion, where their time-averaged contact duration regulates rapid cytoplasmic signaling events to coordinate cellular responses. For some cytokines, single receptor-ligand binding events can initiate large multiprotein complexes in the cytoplasm that assemble over tens of minutes, bringing to question how cytokine affinity influences the sensitivity and strength of signaling. Here, we leverage naturally occurring variation of IL-1{beta} from multiple species to determine the impact of affinity on human IL-1 receptor signaling. Using experiments and models we investigate single receptor complexes activated by ligands that vary across multiple orders of magnitude in affinity. Our results show that while the receptor-ligand affinity establishes cytokine response sensitivity, activated IL-1 receptor complexes signal as discrete, quantized packets of signaling flux independent of affinity.

systems biology↗

bioRxiv2025

Mapping the spatial architecture of glioblastoma from core to edge delineates niche-specific tumor cell states and intercellular interactions

Treatment resistance in glioblastoma (GBM) is largely driven by the extensive multi-level heterogeneity that typifies this disease. Despite significant progress toward elucidating GBMs genomic and transcriptional heterogeneity, a critical knowledge gap remains in defining this heterogeneity at the spatial level. To address this, we employed spatial transcriptomics to map the architecture of the GBM ecosystem. This revealed tumor cell states that are jointly defined by gene expression and spatial localization, and multicellular niches whose composition varies along the tumor core-edge axis. Ligand-receptor interaction analysis uncovered a complex network of intercellular communication, including niche- and region-specific interactions. Finally, we found that CD8 positive GZMK positive T cells colocalize with LYVE1 positive CD163 positive myeloid cells in vascular regions, suggesting a potential mechanism for immune evasion. These findings provide novel insights into the GBM tumor microenvironment, highlighting previously unrecognized patterns of spatial organization and intercellular interactions, and novel therapeutic avenues to disrupt tumor-promoting interactions and overcome immune resistance.

cancer biology↗

bioRxiv2024

Time-varying stimuli that prolong IKK activation promote nuclear remodeling and mechanistic switching of NF-κB dynamics

Temporal properties of molecules within signaling networks, such as sub-cellular changes in protein abundance, encode information that mediate cellular responses to stimuli. How dynamic signals relay and process information is a critical gap in understanding cellular behaviors. In this work, we investigate transmission of information about changing extracellular cytokine concentrations from receptor-level supramolecular assemblies of I{kappa}B kinases (IKK) downstream to the nuclear factor {kappa}B (NF-{kappa}B) transcription factor (TF). In a custom robot-controlled microfluidic cell culture, we simultaneously measure input-output (I/O) encoding of IKK-NF-{kappa}B in dual fluorescent-reporter cells. When compared with single cytokine pulses, dose-conserving pulse trains prolong IKK assemblies and lead to disproportionately enhanced retention of nuclear NF-{kappa}B. Using particle swarm optimization, we demonstrate that a mechanistic model does not recapitulate this emergent property. By contrast, invoking mechanisms for NF-{kappa}B-dependent chromatin remodeling to the model recapitulates experiments, showing how temporal dosing that prolongs IKK assemblies facilitates switching to permissive chromatin that sequesters nuclear NF-{kappa}B. Remarkably, using simulations to resolve single-cell receptor data accurately predicts same-cell NF-{kappa}B time courses for more than 80% of our single cell trajectories. Our data and simulations therefore suggest that cell-to-cell heterogeneity in cytokine responses are predominantly due to mechanisms at the level receptor-associated protein complexes.

systems biology↗

bioRxiv2024

Extrachromosomal DNA Associates with Nuclear Condensates and Reorganizes Chromatin Structures to Enhance Oncogenic Transcription

Extrachromosomal, circular DNA (ecDNA) is a prevalent oncogenic alteration in cancer genomes, often associated with aggressive tumor behavior and poor patient outcome. While previous studies proposed a chromatin-based mobile enhancer model for ecDNA-driven oncogenesis, its precise mechanism and impact remains unclear across diverse cancer types. Our study, utilizing advanced multi-omics profiling, epigenetic editing, and imaging approaches in three cancer models, reveals that ecDNA hubs are an integrated part of nuclear condensates and exhibit cancer-type specific chromatin connectivity. Epigenetic silencing of the ecDNA-specific regulatory modules or chemically disrupting liquid-liquid phase separation breaks down ecDNA hubs, displaces MED1 co-activator binding, inhibits oncogenic transcription, and promotes cell death. These findings substantiate the trans-activator function of ecDNA and underscore a structural mechanism driving oncogenesis. This refined understanding expands our views of oncogene regulation and opens potential avenues for novel therapeutic strategies in cancer treatment.

genomics↗

bioRxiv2024

Modeling glioblastoma tumor progression via CRISPR-engineered brain organoids

Glioblastoma (GBM) is an aggressive form of brain cancer that is highly resistant to therapy due to significant intra-tumoral heterogeneity. The lack of robust in vitro models to study early tumor progression has hindered the development of effective therapies. Here, we develop engineered GBM organoids (eGBOs) harboring GBM subtype-specific oncogenic mutations to investigate the underlying transcriptional regulation of tumor progression. Single-cell and spatial transcriptomic analyses revealed that these mutations disrupt normal neurodevelopment gene regulatory networks resulting in changes in cellular composition and spatial organization. Upon xenotransplantation into immunodeficient mice, eGBOs form tumors that recapitulate the transcriptional and spatial landscape of human GBM samples. Integrative single-cell trajectory analysis of both eGBO-derived tumor cells and patient GBM samples revealed the dynamic gene expression changes in developmental cell states underlying tumor progression. This analysis of eGBOs provides an important validation of engineered cancer organoid models and demonstrates their utility as a model of GBM tumorigenesis for future preclinical development of therapeutics.

bioengineering↗

bioRxiv2023

The Hao-Fountain syndrome protein USP7 regulates neuronal connectivity in the brain via a novel p53-independent ubiquitin signaling pathway

Precise control of protein ubiquitination is essential for brain development, and hence, disruption of ubiquitin signaling networks can lead to neurological disorders. Mutations of the deubiquitinase USP7 cause the Hao-Fountain syndrome (HAFOUS), characterized by developmental delay, intellectual disability, autism, and aggressive behavior. Here, we report that conditional deletion of USP7 in excitatory neurons in the mouse forebrain triggers diverse phenotypes including sensorimotor deficits, learning and memory impairment, and aggressive behavior, resembling clinical features of HAFOUS. USP7 deletion induces neuronal apoptosis in a manner dependent of the tumor suppressor p53. However, most behavioral abnormalities in USP7 conditional mice persist despite p53 loss. Strikingly, USP7 deletion in the brain perturbs the synaptic proteome and dendritic spine morphogenesis independently of p53. Integrated proteomics analysis reveals that the neuronal USP7 interactome is enriched for proteins implicated in neurodevelopmental disorders and specifically identifies the RNA splicing factor Ppil4 as a novel neuronal substrate of USP7. Knockdown of Ppil4 in cortical neurons impairs dendritic spine morphogenesis, phenocopying the effect of USP7 loss on dendritic spines. These findings reveal a novel USP7-Ppil4 ubiquitin signaling link that regulates neuronal connectivity in the developing brain, with implications for our understanding of the pathogenesis of HAFOUS and other neurodevelopmental disorders.

neuroscience↗

bioRxiv2023

NF2 Loss-of-Function and Hypoxia Drive Radiation Resistance in Grade 2 Meningiomas

BackgroundWorld Health Organization Grade 2 meningiomas (G2Ms) exhibit an aggressive natural history characterized by recurrence and therapy resistance. G2Ms with histopathological necrosis have been associated with worse local control (LC) following radiation therapy, but drivers and biomarkers of radiation resistance in these G2Ms remain unknown. MethodsWe performed genetic sequencing and histopathological analysis of 113 G2Ms and investigated the role of intratumoral hypoxia as well as genes of interest through knockdown and clonogenic survival following ionizing radiation. Lastly, we performed transcriptional profiling of our in vitro model and 18 G2M tumors using RNA sequencing. ResultsNF2 loss-of-function (LOF) mutations were associated with necrosis in G2Ms (p=0.0127). Tumors with NF2 mutation and necrosis had worse post-radiation LC compared to NF2 wildtype tumors without necrosis (p=0.035). Under hypoxic conditions, NF2 knockdown increased radiation resistance in vitro (p<0.001). Bulk RNA sequencing of our in vitro model revealed NF2- and hypoxia-specific changes and a 50-gene set signature specific to radiation resistant, NF2 knockdown and hypoxic cells, which could distinguish NF2 mutant and necrotic patient G2Ms by unsupervised clustering. Gene set enrichment analysis of patient tumor and in vitro data revealed downregulation of apoptosis and upregulation of proliferation in NF2-deficient and hypoxic cells, which we validated with functional assays. ConclusionsNF2 LOF in the setting of hypoxia confers radiation resistance through transcriptional programs that reduce apoptosis and promote proliferation. These pathways may identify tumors resistant to radiation and represent therapeutic targets that in the future could improve LC in patients with radiation resistant G2Ms. KEY POINTS1. Spontaneous necrosis with NF2 mutations is associated with radio-resistance in WHO G2Ms. 2. NF2 knockdown in the setting of hypoxia confers radio-resistance to meningioma cells in vitro and is driven by increased cell proliferation and decreased apoptosis. IMPORTANCE OF THE STUDYWorld Health Organization Grade 2 meningiomas (G2M) are often treated with surgical resection followed by radiation, especially in the case of recurrence. However, the mechanisms underlying radiation resistance in G2Ms remain to be identified, and moreover, we lack biomarkers to distinguish G2Ms that will respond to radiotherapy from those that are refractory. In this study we perform histological and molecular analysis of a large cohort of G2Ms to identify predictors of radiation resistance. Using these data and an in vitro model of radiation therapy, we demonstrate that radiation resistance in G2Ms is likely driven by the combination of NF2 gene mutations and the hypoxia that accompanies tumor necrosis. Patients whose tumors bear these two features may therefore benefit from alternative treatments that target specific pathways implicated in radiation resistance.

molecular biology↗

bioRxiv2023

Sequential early-life viral infections modulate the microbiota and adaptive immune responses to systemic and mucosal vaccination

Increasing evidence points to the microbial exposome as a critical factor in maturing and shaping the host immune system, thereby influencing responses to immune challenges such as infections or vaccines. To investigate the effect of early-life viral exposures on immune development and vaccine responses, we inoculated mice with six distinct viral pathogens in sequence beginning in the neonatal period, and then evaluated their immune signatures before and after intramuscular or intranasal vaccination against SARS-CoV-2. Sequential viral infection drove profound changes in all aspects of the immune system, including increasing circulating leukocytes, altering innate and adaptive immune cell lineages in tissues, and markedly influencing serum cytokine and total antibody levels. Beyond these immune responses changes, these exposures also modulated the composition of the endogenous intestinal microbiota. Although sequentially-infected mice exhibited increased systemic immune activation and T cell responses after intramuscular and intranasal SARS-CoV-2 immunization, we observed decreased vaccine-induced antibody responses in these animals. These results suggest that early-life viral exposures are sufficient to diminish antibody responses to vaccination in mice, and highlight their potential importance of considering prior microbial exposures when investigating vaccine responses.

microbiology↗

bioRxiv2023

Glioblastoma-infiltrating CD8+ T cells are predominantly a clonally expanded GZMK+ effector population

Recent clinical trials have highlighted the limited efficacy of T cell-based immunotherapy in patients with glioblastoma (GBM). To better understand the characteristics of tumor-infiltrating lymphocytes (TIL) in GBM, we performed cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq) and single-cell RNA sequencing (scRNA-seq) with paired V(D)J sequencing, respectively, on TIL from two cohorts of patients totaling 15 patients with high grade glioma, including GBM or astrocytoma, IDH mutant, grade 4 (G4A). Analysis of the CD8+ TIL landscape reveals an enrichment of clonally expanded GZMK+ effector T cells in the tumor compared to matched blood, which was validated at the protein level. Furthermore, integration with other cancer types highlights the lack of a canonically exhausted CD8+ T cell population in GBM TIL. These data suggest that GZMK+ effector T cells represent an important T cell subset within the GBM microenvironment and which may harbor potential therapeutic implications. SignificanceIn order to understand the limited efficacy of immune checkpoint blockade in GBM, we endeavor to understand the TIL landscape through a multi-omics approach. In this study, by highlighting the enrichment of GZMK+ effector T cells and lack of exhausted T cells, we provide a new potential mechanism of resistance to immunotherapy in GBM.

immunology↗

bioRxiv2022

Single-cell multi-omic analysis of the vestibular schwannoma ecosystem uncovers a nerve injury-like state

Vestibular schwannomas (VS) are benign tumors that lead to significant neurologic and otologic morbidity. How VS heterogeneity and the tumor microenvironment (TME) contribute to the pathogenesis of these tumors remains poorly understood. We performed scRNA-seq on 15 VS samples, with paired scATAC-seq in six samples. We identified diverse Schwann cell (SC), stromal, and immune populations in the VS TME and found that repair-like and MHC-II antigen presenting subtype SCs are associated with increased myeloid cell infiltrate, implicating a nerve injury-like process. Deconvolution analysis of RNA-expression data from 175 tumors revealed Injury-like tumors are associated with larger tumor size, and scATAC-seq identified transcription factors associated with nerve repair among SCs from Injury-like tumors. Ligand-receptor analysis and functional in vitro experiments suggested that SCs recruit monocytes. Our study indicates that Injury-like SCs may cause tumor growth via myeloid cell recruitment and identifies molecular pathways that may be targeted to prevent tumor progression.

cancer biology↗

bioRxiv2021

The conventional dendritic cell 1 subset primes CD8+ T cells and traffics tumor antigen to drive anti-tumor immunity in the brain

The central nervous system (CNS) antigen presenting cell (APC) which primes anti-tumor CD8+ T cell responses remains undefined. Elsewhere, the conventional dendritic cell 1 (cDC1) performs this role. However, steady-state brain cDC1 are rare; cDC localize to choroid plexus and dura. Using preclinical glioblastoma models and cDC1-deficient mice, we explored the role of cDC1 in CNS anti-tumor immunity. We determined that cDC1 mediate checkpoint blockade-induced survival benefit and prime neoantigen-specific CD8+ T cells against brain tumors. We observed that cDC, including cDC1, isolated from the tumor, the dura, and the CNS-draining cervical lymph nodes harbored a traceable fluorescent tumor-antigen. In patient samples, we observed several APC subsets (including the CD141+ cDC1-equivalent) infiltrating glioblastomas, meningiomas, and dura. In these same subsets, we identified a tumor-specific fluorescent metabolite of 5- aminolevulinic acid, which labels tumor cells during fluorescence-guided glioblastoma resection. Together, these data elucidate the specialized behavior of cDC1 and suggest cDC1 play a significant role in CNS anti-tumor immunity. One Sentence SummaryCNS cDC1 engage in previously undefined behavior to establish immune responses against brain tumors.

immunology↗

bioRxiv2021

Gonadal sex patterns p21-induced cellular senescence in mouse and human glioblastoma

Males exhibit higher incidence and worse prognosis for the majority of cancers, including glioblastoma (GBM). Disparate survival may be related to sex-biased responses to treatment, including radiation. Using a mouse model of GBM, we show that female cells are more sensitive to radiation, and that senescence represents a major component of the radiation therapeutic response in both sexes. Correlation analyses revealed that the CDK inhibitor p21 and irradiation induced senescence were differentially regulated between male and female cells. Indeed, female cellular senescence was more sensitive to changes in p21 levels, a finding that was observed in both wildtype and transformed murine astrocytes and patient-derived GBM cell lines. Using a novel Four Core Genotypes model of GBM, we further show that sex differences in p21-induced senescence are patterned by gonadal sex. These data suggest that sex differences in p21 induced senescence contribute to the female survival advantage in GBM.

cancer biology↗

bioRxiv2021

Increased complement activation is a distinctive feature of severe SARS-CoV-2 infection.

Complement activation has been implicated in the pathogenesis of severe SARS-CoV-2 infection. However, it remains to be determined whether increased complement activation is a broad indicator of critical illness (and thus, no different in COVID-19). It is also unclear which pathways are contributing to complement activation in COVID-19, and, if complement activation is associated with certain features of severe SARS-CoV-2 infection, such as endothelial injury and hypercoagulability. To address these questions, we investigated complement activation in the plasma from patients with COVID-19 prospectively enrolled at two tertiary care centers. We compared our patients to two non-COVID cohorts: (a) patients hospitalized with influenza, and (b) patients admitted to the intensive care unit (ICU) with acute respiratory failure requiring invasive mechanical ventilation (IMV). We demonstrate that circulating markers of complement activation (i.e., sC5b-9) are elevated in patients with COVID-19 compared to those with influenza and to patients with non-COVID-19 respiratory failure. Further, the results facilitate distinguishing those who are at higher risk of worse outcomes such as requiring ICU admission, or IMV. Moreover, the results indicate enhanced activation of the alternative complement pathway is most prevalent in patients with severe COVID-19 and is associated with markers of endothelial injury (i.e., Ang2) as well as hypercoagulability (i.e., thrombomodulin and von Willebrand factor). Our findings identify complement activation to be a distinctive feature of COVID-19, and provide specific targets that may be utilized for risk prognostication, drug discovery and personalized clinical trials. SUMMMARYComplement has been implicated in COVID-19. However, whether this is distinctive of COVID-19 remains unanswered. Ma et al report increased complement activation in COVID-19 compared to influenza and non-COVID respiratory failure, and demonstrate alternative pathway activation as a key marker of multiorgan failure and death.

immunology↗