Biology subjects

Simon, V.

Publications and source records attributed to Simon, V..

At least 19 recordsLinked to original sources

bioRxiv2026

N1 neuraminidase monoclonal antibodies 2H08 and 3H03 have decreased binding and inhibition properties against H1N1 influenza viruses circulating after 2018

Influenza viruses are global public health problem. Vaccines are available but have to be updated annually due to antigenic drift of the main vaccine component, the surface glycoprotein hemagglutinin (HA). The second surface glycoprotein of the virus, neuraminidase (NA), has recently moved into the spotlight of vaccine development. However, its antigenic evolution is understudied. We found that two broadly protective N1 NA antibodies, which had previously been shown to bind and inhibit most N1 NA, lost activity to recent N1s from seasonal H1N1 viruses. Here, we show that this drop in activity can mostly be attributed to a change in electrostatic surface potential from neutral to positively charged. This effect was not observed when historic human plasma samples were tested, suggesting that the drop of activity is specific to the two tested mAbs but does not broadly impact the polyclonal human response. Finally, we confirmed that the tested mAbs were fully active against recently emerged pan-zootic clade 2.3.4.4b H5N1 NA.

microbiology↗

bioRxiv2026

Cross-source proteogenomic profiling of human microglia reveals a conserved core membrane protein and HERV signature

Microglia are essential immune cells of the brain parenchyma which are responsible for maintaining homeostasis and responding to brain injury. When activated, they induce immune signaling and become phagocytic. In the context of neurodegenerative diseases, they exhibit both pro- and anti-inflammatory properties. Human endogenous retroviruses (HERVs) are the remnants of ancient retroviral germline infections that integrated into the human genome, and their expression has been directly linked to microglial-mediated neurodegenerative diseases. Despite this, HERV expression is not consistently included in analyses characterizing microglia. Investigating the function of microglia across different diseases is critical for elucidating mechanisms of disease progression and for the development of effective therapeutic interventions. Approaches to studying microglia include isolation from post-mortem brain tissues, differentiation from peripheral blood monocytes or differentiation of induced pluripotent stem cells (iPSC). Ex vivo brain derived microglia (BdMG) are considered most physiologically relevant, but constraints including the unpredictable timing of availability, labor-intensive protocols, and low yields reduce their practicality. Existing alternatives are iPSC-derived microglia (iMG) and monocyte-derived microglia (MDMi) models that circumvent sample accessibility and scalability issues. Here, we explored the transcriptome and proteome of these three microglia sources and identified a common microglia surface marker expression profile, establishing that MDMi and iMG exhibit similar phenotypes relative to BdMG. We also identified a common HERV expression profile across BdMG, iMG and MDMi, indicating deeper similarities across different sources. Altogether, our findings indicate that given the phenotypic similarities of the 2 models, MDMi represent a practical and reliable model for investigating microglial function with iMG models serving for more molecular based approaches, such as CRISPRa/i.

neuroscience↗

bioRxiv2026

A Female-Specific Microglial Redox Program Gates Susceptibility to Obesity

Chronic consumption of energy-dense, high-fat foods persistently exposes hypothalamic circuits that govern body weight to nutrient excess, progressively altering their activity and thereby promoting obesity. Microglia, the brain resident immune cells, sense circulating lipids, but how their intracellular metabolic programs adapt to chronic dietary excess, and how this contributes to obesity risk, is unclear. Here, we reveal a sex-dependent control of calorie overload by hypothalamic microglial cells. In females, but not males, microglia engage a protective metabolic program with increased antioxidant capacity and mitochondrial network remodeling, conferring resistance to early weight gain. Over time, activation of mTORC1 signaling in microglia disrupts mitochondrial functions and dismantles this transient resilience, culminating in weight gain. These findings identify microglial mTORC1 as a sex-specific switch between resilience and vulnerability to obesity and position microglial metabolism as a tractable target for sex-informed weight control.

neuroscience↗

bioRxiv2026

A designed overlapping variant immunogen pool elicits broad sarbecovirus neutralization

A central problem in achieving vaccine-based protection against viral infections is eliciting antibodies that are resilient to viral variation. Successive waves of SARS-CoV-2 infection during the COVID19 pandemic were driven by variants that acquired resistance to neutralizing antibodies elicited by prior SARS-CoV-2 variants. To the extent that serum neutralization breadth occurs in individuals with multiple exposures to SARS-CoV-2 antigens, we and others find that it is largely comprised of antibodies that target the variable receptor binding domain (RBD), rather than more conserved spike protein domains. By designing synthetic dimeric RBD immunogens we show that limiting divergence in heterodimeric components favors the generation of cross-reactive B cells and antibodies. We thus devised a vaccine approach based on a two-dose immunization with a pool of five overlapping heterodimeric synthetic RBD variants. Collectively, the RBD heterodimer pool was designed to cover 10% sequence variation and elicited greater antibody cross-reactivity and neutralization breadth than homodimers or heterodimers with highly divergent components. Using an unconventional prospective challenge model in mice, we demonstrate the effectiveness of the RBD heterodimer pool in inducing antibody responses that attenuate infection by future SARS-CoV-2 variants, as well as protection in a challenge model based on a chimeric vesicular stomatitis virus bearing a spike protein from SARS-CoV-1. Significance statementViral antigenic escape undermines both vaccination efforts and the development of herd immunity, resulting in an enormous viral disease burden. A central problem in eliciting vaccine-based protection against some viral infections is achieving antibody neutralization breadth. To elicit collections of antibodies that overcome the problem of limited antibody tolerance of viral variation, we designed a novel strategy based on an overlapping series of immunogens. This immunogen pool conferred at least partial protection against subsequently prevalent SARS-CoV-2 variants as well as a chimeric SARS-CoV-1 based model virus.

microbiology↗

bioRxiv2026

Three immunoregulatory signatures define non-productive HIV infection in CD4+ T memory stem cells

The persistent HIV reservoir constitutes the main obstacle to curing HIV/AIDS disease. Our understanding of how non-productive HIV infections are established in primary human CD4+ T cells during the first round of infection remains, however, incomplete. In this study, we leveraged the HIV reporter virus pMorpheus-V5 to delineate cellular expression patterns that are upregulated in non-productively infected primary CD4+ T memory stem cells (TSCM). We found that CD4+ TSCM harboring non-productive proviruses displayed a distinct transcriptomic signature comprising 118 upregulated genes. This non-productive expression profile was distinct from that of productively infected cells as well as from negative-exposed and mock-infected cells. Among the cellular genes most upregulated in CD4+ T cells harboring non-productive proviruses were CCR4-binding migratory chemokines (CCL22, CCL17), tryptophan catabolic enzymes (IDO1, KYNU), and genes encoding cytoskeletal rearrangement proteins (BASP1, TNFAIP2). Intracellular flow cytometry-based analyses confirmed that non-productively infected CD4+ TSCM cells were enriched for CCL22 and IDO1 co-expression compared to the other CD4+ memory subsets, underscoring a clear CD4+ T cell subset specificity for the upregulation of these two immune gene sets associated with non-productive infections. These findings suggest that primary human CD4+ TSCM harboring non-productive proviruses display a distinct immunoregulatory phenotype which may facilitate immune evasion and contribute to the persistence of the HIV reservoir.

microbiology↗

bioRxiv2026

Defining the Antigenic Topology and Prospective Binding Breadth of Vaccination-induced SARS-CoV-2 Neutralizing Antibodies

Antibodies that neutralize SARS-CoV-2 primarily target the viral spike glycoprotein, yet the breadth of these responses is continually challenged by viral evolution. While extensive structural studies have defined epitopes across the spike protein, how antibodies elicited by the initial mRNA vaccination campaigns perform against subsequently emerging variants remains an important question. Here, we structurally and functionally characterize a panel of early plasmablast-derived human monoclonal antibodies isolated following primary mRNA vaccination, targeting both the receptor-binding domain (RBD) and the N-terminal domain (NTD) of spike. Using cryo-electron microscopy, variant-binding analyses, and viral-fusion inhibition assays, we observe that antibodies directed against immunodominant regions of the RBD and NTD are highly potent but more frequently impacted by variant-associated mutations. In contrast, antibodies engaging a conserved hydrophobic pocket within the NTD exhibit broader reactivity and neutralize through distinct molecular mechanisms. Together, these findings extend prior structural studies of spike-directed antibodies by prospectively assessing the breadth of vaccine-elicited antibodies against later variants and identifying structural features associated with differential escape sensitivity. These results contribute to a growing understanding of how early vaccine-induced antibody repertoires relate to subsequent viral evolution. One sentence summaryAntibody epitopes on SARS-CoV-2 spike determine prospective breadth and vulnerability to viral evolution.

immunology↗

bioRxiv2026

The buried S2 apex of SARS-CoV-2 spike elicits an immunodominant germline-restricted public antibody response

The continued mutational pressure on the SARS-CoV-2 S1 subunit underscores the need to target the conserved S2 region for pan-coronavirus vaccine development. A detailed molecular understanding of S2-directed immune responses is therefore essential. In this study, we identified the S2 apex as the most immunodominant epitope within the S2 subunit, eliciting robust antibody responses despite occlusion by S1, using electron-microscopy-based polyclonal epitope mapping (EMPEM) of plasma from infected and vaccinated individuals. Structure-guided sequence analysis with antibody databases revealed that antibodies targeting a poorly characterized S2 Apex-B site form a convergent public clonotype, which is predominantly derived from the IGHV3-30 germline with a 14-residue CDRH3 containing a G/S-G-S/N-Y motif. This clonotype is extensively expanded, accounting for up to 40% of total spike-reactive antibody sequence counts in individual vaccinated donors. This study elucidates the molecular basis the high-frequency elicitation of this non-neutralizing clonotype emphasizing that its immunodominance acts as a primary hurdle for universal coronavirus vaccines and underscore the need for precision antigen design to redirect immunity toward more potent neutralizing targets.

immunology↗

bioRxiv2025

Characterization of the glycoproteins of novel fish influenza B-like viruses

Novel influenza-like virus sequences previously identified in fish and amphibians were found to cluster as a sister clade of influenza B viruses, but have thus far remained uncharacterized. We demonstrate that salamander influenza-like virus (SILV) HA is functionally divergent from influenza B virus HA and does not bind to 2,3- and 2,6-linked sialic acids. However, the HAs of Siamese algae-eater influenza-like virus (SAEILV) and chum salmon influenza-like virus (CSILV) bind to 2,3 linked sialic acid. Furthermore, SAEILV HA binds to sialyated Lewis X, is activated by human airway enzymes and is fusogenic at a wide range of pH conditions. SAEILV NA has a highly conserved active site and a similar structure to other known NAs. We also determined the cryo-electron microscopy structure of the HA of a previously described virus from the same sister clade, the Wuhan spiny eel influenza virus (WSEIV). Importantly, no cross-reactive antibodies against these HAs or NAs were found in the human serum, suggesting that humans are immunologically naive to these viruses. One sentence summaryNovel influenza like-viruses, displayed different target receptor specificity and limited antigenic conservation of the HA and NA relative to influenza B Viruses.

microbiology↗

bioRxiv2025

SLAP controls mTORC2 integrity via UBE3C-mediated mLST8 ubiquitination to mediate its tumour suppressive function in colorectal cancer

The mechanistic target of rapamycin complex 2 (mTORC2) signaling pathway, which regulates cell growth and migration, exhibits oncogenic function in colorectal cancer (CRC). mTORC2 signaling is primarily activated by a complex assembly of mTOR, RICTOR, SIN1, and mLST8, but how dysregulation of this mechanism contributes to its oncogenic function remains elusive. Here, we show that the Src-Like Adaptor Protein (SLAP), a negative regulator of tyrosine kinase signaling receptors, controls mTORC2 integrity to mediate its tumor-suppressive function in CRC. Mechanistically, SLAP interacts with mLST8 and promotes non-degradative ubiquitination, thereby reducing mTORC2 integrity and mTORC2-AKT signaling. The E3 ubiquitin ligase UBE3C was identified as a novel SLAP interactor involved in this ubiquitination process. Functionally, SLAP inhibition of CRC cell growth and invasion was dependent upon mTORC2 signaling inhibition. In immunodeficient mice CRC xenografts, SLAP depletion enhanced mTORC2 activity and sensitized CRC cells to mTOR catalytic inhibitors. Thus, our study uncovers a novel SLAP-mediated ubiquitination mechanism of mTORC2 dysregulation with potential therapeutic utility in CRC.

cancer biology↗

bioRxiv2025

Convergent and clonotype-enriched mutations in the light chain drive affinity maturation of a public antibody

Public antibodies that recognize conserved epitopes are critical for vaccine development, and identifying somatic hypermutations (SHMs) that enhance antigen affinity in these public responses is key to guiding vaccine design for better protection. We propose that affinity-enhancing SHMs are selectively enriched in public antibody clonotypes, surpassing the background frequency seen in antibodies carrying the same V genes, but with different epitope specificities. Employing a human IGHV4-59/IGKV3-20 public antibody as a model, we compare SHM signatures in antibodies also using these V genes, but recognizing other epitopes. Critically, this comparison identified clonotype-enriched mutations in the light chain. Our analyses also show that these SHMs, in combination, enhance binding to a previously uncharacterized viral epitope, with antibody responses to it increasing after multiple vaccinations. Our findings offer a framework for identifying affinity-enhancing SHMs in public antibodies based on convergence and clonotype-enrichment and can help guide vaccine design aimed to elicit public antibodies. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=138 SRC="FIGDIR/small/642041v1_ufig1.gif" ALT="Figure 1"> View larger version (39K): org.highwire.dtl.DTLVardef@1c4559eorg.highwire.dtl.DTLVardef@d12202org.highwire.dtl.DTLVardef@fca57org.highwire.dtl.DTLVardef@ad5041_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIClonotype-enriched SHMs are identified in the light chain of a public antibody, M15 C_LIO_LIThese light chain SHMs enhance affinity of M15 C_LIO_LIM15 targets a previously undescribed, conserved viral epitope C_LIO_LISerum antibody levels targeting this epitope increase after repeated vaccinations C_LI

immunology↗

bioRxiv2025

Identification of a multi-omics factor predictive of long COVID in the IMPACC study

Following SARS-CoV-2 infection, [~]10-35% of COVID-19 patients experience long COVID (LC), in which often debilitating symptoms persist for at least three months. Elucidating the biologic underpinnings of LC could identify therapeutic opportunities. We utilized machine learning methods on biologic analytes and patient reported outcome surveys provided over 12 months after hospital discharge from >500 hospitalized COVID-19 patients in the IMPACC cohort to identify a multi-omics "recovery factor". IMPACC participants who experienced LC had lower recovery factor scores compared to participants without LC. Biologic characterization revealed increased levels of plasma proteins associated with inflammation, elevated transcriptional signatures of heme metabolism, and decreased androgenic steroids in LC patients. The recovery factor was also associated with altered circulating immune cell frequencies. Notably, recovery factor scores were predictive of LC occurrence in patients as early as hospital admission, irrespective of acute disease severity. Thus, the recovery factor identifies patients at risk of LC early after SARS-CoV-2 infection and reveals LC biomarkers and potential treatment targets.

systems biology↗

bioRxiv2025

Functional regulation of the mitotic kinesin HSET by Intraflagellar Transport proteins.

HSET is a mitotic kinesin essential for centrosome clustering in cells harboring supernumerary centrosomes. Work in cellulo revealed that IntraFlagellar Transport proteins (IFT) interact with the kinesin HSET to promote efficient extra centrosome clustering and subsequent cancer cell proliferation. However, whether and how IFT proteins regulate HSET activity is unknown. Using a reconstituted in vitro system combining purified HSET and IFT proteins with TIRF microscopy approaches, we identified a minimal subcomplex made of IFT52/IFT70 directly binding to HSET. We show that this binding induces HSET oligomerization promoting the formation of processive HSET complexes. We also show that HSETs increased processivity upon IFT52/70 binding accounts for an increased ability to slide microtubules and to organize dynamic microtubule networks in vitro. Overall, this work shows that IFT proteins can directly promote the processive motility of a mitotic kinesin and provides a mechanistic explanation for the contribution of IFT proteins to efficient centrosome clustering.

cell biology↗

bioRxiv2025

MDL-001: An Oral, Safe, and Well-Tolerated Broad-Spectrum Inhibitor of Viral Polymerases

Endemic viral respiratory illnesses caused by influenza, RSV, and coronaviruses impose a global disease burden of hundreds of millions of infections and hundreds of thousands of deaths annually. Chronic hepatitis B and C infections persist in 254 million and 58 million people worldwide, respectively. No approved therapy addresses these viruses simultaneously. MDL-001 is an oral, direct-acting, broad-spectrum antiviral targeting the Thumb-1 allosteric site of viral polymerases. Here, we report MDL-001 inhibits influenza A/B, RSV, SARS-CoV-2, endemic human coronaviruses, and hepatitis B/C/D viruses with nanomolar EC90 potency in vitro. MDL-001 demonstrated equivalent in vivo efficacy to oseltamivir against mouse-lethal influenza A virus infection, reducing lung viral load by 2.6 log10 and preventing weight loss and mortality. MDL-001 demonstrated equivalent symptom reduction to subcutaneous remdesivir after SARS-CoV-2 infection. MDL-001 treatment reduced SARS-CoV-2 lung viral titers by 2.9 log10, superior to literature reported 1.4 log10 and 1.0 log10 reductions for nirmatrelvir and molnupiravir, respectively. MDL-001 reduced HCV viremia by 3.3 log10, equivalent to sofosbuvir. Oral MDL-001 reduced plasma HBV surface antigen by 2.5 log10, exceeding tenofovir alafenamide from Day 8 through Day 21. MDL-001 demonstrated an in vitro EC50 of 79.4 nM against infection with RSV strain A2, a 416-fold improvement over literature-reported ribavirin. Oral pharmacokinetics studies demonstrate MDL-001 is rapidly absorbed and partitioned into Lung (Kp=39-52) and Liver (Kp=71-104) tissues. MDL-001 produced no treatment-related adverse events across 376 animals and showed no hERG, Ames genotoxicity, or micronucleus safety issues. These findings support MDL-001 as a broad-spectrum, direct-acting non-nucleoside antiviral clinical candidate.

pharmacology and toxicology↗

bioRxiv2024

Unraveling SARS-CoV-2 Host-Response Heterogeneity through Longitudinal Molecular Subtyping

Hospitalized COVID-19 patients exhibit diverse immune responses during acute infection, which are associated with a wide range of clinical outcomes. However, understanding these immune heterogeneities and their links to various clinical complications, especially long COVID, remains a challenge. In this study, we performed unsupervised subtyping of longitudinal multi-omics immunophenotyping in over 1,000 hospitalized patients, identifying two critical subtypes linked to mortality or mechanical ventilation with prolonged hospital stay and three severe subtypes associated with timely acute recovery. We confirmed that unresolved systemic inflammation and T-cell dysfunctions were hallmarks of increased severity and further distinguished patients with similar acute respiratory severity by their distinct immune profiles, which correlated with differences in demographic and clinical complications. Notably, one critical subtype (SubF) was uniquely characterized by early excessive inflammation, insufficient anticoagulation, and fatty acid dysregulation, alongside higher incidences of hematologic, cardiac, and renal complications, and an elevated risk of long COVID. Among the severe subtypes, significant differences in viral clearance and early antiviral responses were observed, with one subtype (SubC) showing strong early T-cell cytotoxicity but a poor humoral response, slower viral clearance, and greater risks of chronic organ dysfunction and long COVID. These findings provide crucial insights into the complex and context-dependent nature of COVID-19 immune responses, highlighting the importance of personalized therapeutic strategies to improve both acute and long-term outcomes.

immunology↗

bioRxiv2024

Chronic Viral Reactivation and Associated Host Immune Response and Clinical Outcomes in Acute COVID-19 and Post-Acute Sequelae of COVID-19

Chronic viral infections are ubiquitous in humans, with individuals harboring multiple latent viruses that can reactivate during acute illnesses. Recent studies have suggested that SARS- CoV-2 infection can lead to reactivation of latent viruses such as Epstein-Barr Virus (EBV) and cytomegalovirus (CMV), yet, the extent and impact of viral reactivation in COVID-19 and its effect on the host immune system remain incompletely understood. Here we present a comprehensive multi-omic analysis of viral reactivation of all known chronically infecting viruses in 1,154 hospitalized COVID-19 patients, from the Immunophenotyping Assessment in a COVID-19 Cohort (IMPACC) study, who were followed prospectively for twelve months. We reveal significant reactivation of Herpesviridae, Enteroviridae, and Anelloviridae families during acute stage of COVID-19 (0-40 days post- hospitalization), each exhibiting distinct temporal dynamics. We also show that viral reactivation correlated with COVID-19 severity, demographic characteristics, and clinical outcomes, including mortality. Integration of cytokine profiling, cellular immunophenotyping, metabolomics, transcriptomics, and proteomics demonstrated virus-specific host responses, including elevated pro-inflammatory cytokines (e.g. IL-6, CXCL10, and TNF), increased activated CD4+ and CD8+ T-cells, and upregulation of cellular replication genes, independent of COVID-19 severity and SARS-CoV-2 viral load. Notably, persistent Anelloviridae reactivation during convalescence ([≥]3 months post-hospitalization) was associated with Post-Acute Sequelae of COVID-19 (PASC) symptoms, particularly physical function and fatigue. Our findings highlight a remarkable prevalence and potential impact of chronic viral reactivation on host responses and clinical outcomes during acute COVID-19 and long term PASC sequelae. Our data provide novel immune, transcriptomic, and metabolomic biomarkers of viral reactivation that may inform novel approaches to prognosticate, prevent, or treat acute COVID- 19 and PASC.

immunology↗

bioRxiv2024

T cell epitope mapping reveals immunodominance of evolutionarily conserved regions within SARS-CoV-2 proteome.

As SARS-CoV-2 variants continue to emerge capable of evading neutralizing antibodies, it has become increasingly important to fully understand the breadth and functional profile of T cell responses to determine their impact on the immune surveillance of variant strains. Here, sampling healthy individuals, we profiled the kinetics and polyfunctionality of T cell immunity elicited by mRNA vaccination. Modeling of anti-spike T cell responses against ancestral and variant strains of SARS-CoV-2 suggested that epitope immunodominance and cross-reactivity are major predictive determinants of T cell immunity. To identify immunodominant epitopes across the viral proteome, we generated a comprehensive map of CD4+ and CD8+ T cell epitopes within non-spike proteins that induced polyfunctional T cell responses in convalescent patients. We found that immunodominant epitopes mainly resided within regions that were minimally disrupted by mutations in emerging variants. Conservation analysis across historical human coronaviruses combined with in silico alanine scanning mutagenesis of non-spike proteins underscored the functional importance of mutationally-constrained immunodominant regions. Collectively, these findings identify immunodominant T cell epitopes across the mutationally-constrained SARS-CoV-2 proteome, potentially providing immune surveillance against emerging variants, and inform the design of next-generation vaccines targeting antigens throughout SARS-CoV-2 proteome for broader and more durable protection. One Sentence SummaryPolyfunctional CD8+ and CD4+ T cells directed against SARS-CoV-2 target mutationally constrained regions of the viral proteome.

immunology↗

bioRxiv2024

Dissecting human monoclonal antibody responses from mRNA- and protein-based XBB.1.5 COVID-19 monovalent vaccines

The emergence of highly contagious and immune-evasive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants has required reformulation of coronavirus disease 2019 (COVID-19) vaccines to target those new variants specifically. While previous infections and booster vaccinations can enhance variant neutralization, it is unclear whether the monovalent version, administered using either mRNA or protein-based vaccine platforms, can elicit de novo B-cell responses specific for Omicron XBB.1.5 variants. Here, we dissected the genetic antibody repertoire of 603 individual plasmablasts derived from five individuals who received a monovalent XBB.1.5 vaccination either with mRNA (Moderna or Pfizer/BioNtech) or adjuvanted protein (Novavax). From these sequences, we expressed 100 human monoclonal antibodies and determined binding, affinity and protective potential against several SARS-CoV-2 variants, including JN.1. We then select two vaccine-induced XBB.1.5 mAbs, M2 and M39. M2 mAb was a de novo, antibody, i.e., specific for XBB.1.5 but not ancestral SARS-CoV-2. M39 bound and neutralized both XBB.1.5 and JN.1 strains. Our high-resolution cryo-electron microscopy (EM) structures of M2 and M39 in complex with the XBB.1.5 spike glycoprotein defined the epitopes engaged and revealed the molecular determinants for the mAbs specificity. These data show, at the molecular level, that monovalent, variant-specific vaccines can elicit functional antibodies, and shed light on potential functional and genetic differences of mAbs induced by vaccinations with different vaccine platforms. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=43 SRC="FIGDIR/small/602781v1_ufig1.gif" ALT="Figure 1000"> View larger version (16K): org.highwire.dtl.DTLVardef@7c4708org.highwire.dtl.DTLVardef@11b66acorg.highwire.dtl.DTLVardef@1f1cec7org.highwire.dtl.DTLVardef@3e72fe_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2024

SARS-CoV-2 Omicron Envelope T9I adaptation confers resistance to autophagy

To date, five variants of concern (VOCs) of SARS-CoV-2 have emerged that show increased fitness and/or immune evasion. While the continuously evolving escape from humoral immune responses has been analyzed in detail, adaptation of SARS-CoV-2 to human innate immune defenses such as autophagy is less understood. Here, we demonstrate that mutation T9I in the structural envelope (E) protein confers autophagy resistance of Omicron VOCs (BA.1, BA.5 and XBB.1.5) compared to 2020 SARS-CoV-2 or the Delta VOC. Mechanistic analyses revealed that Omicron-associated E T9I shows increased inhibition of autophagic flux and colocalization/interaction with autophagosomes, thus shielding incoming SARS-CoV-2 S pseudotyped virions from autophagy. Rare Omicron isolates carrying ancestral E T9 remain sensitive towards autophagy whereas recombinant early 2020 SARS-CoV-2 expressing E T9I shows increases resistance against autophagy. Our data indicate that the E T9I mutation drives autophagy resistance of the Omicron variants and thus may have contributed to their effective spread.

microbiology↗