Biology subjects

Rosenbaum, P.

Publications and source records attributed to Rosenbaum, P..

6 recordsLinked to original sources

bioRxiv2026

TMPRSS2 reduces antibody recognition of SARS-CoV-2 spike

The serine protease TMPRSS2 acts as a cofactor for SARS-CoV-2 entry by cleaving the viral spike (S) to initiate fusion. Whether TMPRSS2 has an impact on humoral immune response against S remains poorly characterized. Here, we show that TMPRSS2 impairs antibody binding to S. In S-expressing and infected cells, TMPRSS2 decreases monoclonal antibody (mAb) and immune serum binding, as well as antibody-dependent cellular cytotoxicity (ADCC) induction. Using a panel of 39 mAbs targeting various S regions, we observe that those binding to the S2 subunit are the most affected by TMPRSS2. TMPRSS2 promotes a partial shedding of S1 and changes S2 conformation. This processing reduces Angiotensin-Converting Enzyme 2 (ACE2) binding while increasing cell-cell fusion. We further observe that the capacity of TMPRSS2 to decrease antibody recognition is conserved across coronaviruses and shared with other TMPRSS proteins. However, TMPRSS2 expression in infected cells does not impact significantly virions infectivity or the antibody recognition, as measured by flow virometry. Collectively, our findings suggest that TMPRSS2 processing of S favors a fusion intermediate conformation which is less sensitive to antibody recognition.

immunology↗

bioRxiv2025

Polyfunctionality of broadly reactive non-neutralizing SARS-CoV-2 RBD antibodies

SARS-CoV-2 antibodies targeting the receptor binding domain (RBD) of the spike protein can potently neutralize infection and exert additional antiviral functions. Here, we characterize the functional profiles of human RBD-specific memory B-cell antibodies elicited by ancestral SARS-CoV-2 infection. While SARS-CoV2 neutralizing antibodies, mainly class 1 and 3 anti-RBD antibodies, often lose binding and neutralizing capacities against Omicron variants, most non-neutralizers remain broadly reactive. Despite their restricted cross-reactivity, neutralizing antibodies mediate Fc-effector functions including antibody-dependent cellular cytotoxicity, phagocytosis, and complement deposition. Most neutralizers also enhance binding of antibodies that target the SARS-CoV-2 spike fusion peptide via receptor-mimetic allostery. In contrast, broadly reactive non-neutralizers fail to trigger phagocytic or allosteric effects. Thus, viral escape compromises antibody neutralizing as well as other antiviral activities, leaving broadly reactive, non-polyfunctional antibodies that exert minimal immune pressure less effective at controlling infection.

immunology↗

bioRxiv2025

Generative model of SARS-CoV-2 variants under functional and immune pressure unveils viral escape potential and antibody resilience

The evolutionary trajectory of SARS-CoV-2 is shaped by competing pressures for ACE2 binding, viability, and escape from neutralizing antibodies targeting its receptor-binding domain (RBD). Here, we present EscapeMap, a modular framework that enables prediction and design of variants escaping antibodies. EscapeMap integrates deep mutational scanning data for ACE2 and 31 monoclonal antibodies with a generative sequence model trained on pre-pandemic Coronaviridae. To experimentally probe escape potential, we designed RBD variants under pressure from four clinically relevant antibodies (SA55, S2E12, S309, VIR-7229). Among these designs, bearing up to 21 mutations from wildtype, 50% expressed as stable proteins. Binding assays confirm that S309 and VIR-7229 retain recognition across diverse mutation combinations. EscapeMap accurately forecasts which antibodies are vulnerable to escape by our designed sequences. Finally, by identifying correlated escape routes, we predict and experimentally verify, antibody combinations less prone to simultaneous escape, offering a quantitative basis for guiding therapeutic strategies.

bioinformatics↗

bioRxiv2023

Distinct evolution of SARS-CoV-2 Omicron XBB and BA.2.86 lineages combining increased fitness and antibody evasion

The unceasing circulation of SARS-CoV-2 leads to the continuous emergence of novel viral sublineages. Here, we isolated and characterized XBB.1, XBB.1.5, XBB.1.9.1, XBB.1.16.1, EG.5.1.1, EG.5.1.3, XBF, BA.2.86.1 and JN.1 variants, representing >80% of circulating variants in January 2024. The XBB subvariants carry few but recurrent mutations in the spike, whereas BA.2.86.1 and JN.1 harbor >30 additional changes. These variants replicated in IGROV-1 but no longer in Vero E6 and were not markedly fusogenic. They potently infected nasal epithelial cells, with EG.5.1.3 exhibiting the highest fitness. Antivirals remained active. Neutralizing antibody (NAb) responses from vaccinees and BA.1/BA.2-infected individuals were markedly lower compared to BA.1, without major differences between variants. An XBB breakthrough infection enhanced NAb responses against both XBB and BA.2.86 variants. JN.1 displayed lower affinity to ACE2 and higher immune evasion properties compared to BA.2.86.1. Thus, while distinct, the evolutionary trajectory of these variants combines increased fitness and antibody evasion.

microbiology↗

bioRxiv2021

Mapping circuit dynamics during function and dysfunction

Neural circuits can generate many spike patterns, but only some are functional. The study of how circuits generate and maintain functional dynamics is hindered by a poverty of description of circuit dynamics across functional and dysfunctional states. For example, although the regular oscillation of a central pattern generator is well characterized by its frequency and the phase relationships between its neurons, these metrics are ineffective descriptors of the irregular and aperiodic dynamics that circuits can generate under perturbation or in disease states. By recording the circuit dynamics of the well-studied pyloric circuit in C. borealis, we used statistical features of spike times from neurons in the circuit to visualize the spike patterns generated by this circuit under a variety of conditions. This unsupervised approach captures both the variability of functional rhythms and the diversity of atypical dynamics in a single map. Clusters in the map identify qualitatively different spike patterns hinting at different dynamical states in the circuit. State probability and the statistics of the transitions between states varied with environmental perturbations, removal of descending neuromodulation, and the addition of exogenous neuromodulators. This analysis reveals strong mechanistically interpretable links between complex changes in the collective behavior of a neural circuit and specific experimental manipulations, and can constrain hypotheses of how circuits generate functional dynamics despite variability in circuit architecture and environmental perturbations.

neuroscience↗

bioRxiv2020

LOX-1+ immature neutrophils predict severe COVID-19 patients at risk of thrombotic complications

RationalLymphopenia and neutrophil/lymphocyte ratio may have prognostic value in coronavirus disease 2019 (COVID-19) severity. ObjectiveWe sought to investigate the representation of neutrophil subsets in severe and critical COVID-19 patients based on Intensive Care Units (ICU) and non-ICU admission. MethodsWe developed a multi-parametric neutrophil profiling strategy based on known neutrophil markers to distinguish COVID-19 phenotypes in critical and severe patients. ResultsOur results showed that 80% of ICU patients develop strong myelemia with CD10-CD64+ immature neutrophils. Cellular profiling revealed two distinct neutrophil subsets expressing either the lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) or the Interleukin-3 receptor alpha (CD123), both significantly overrepresented in ICU patients compared to non-ICU patients. The proportion of LOX-1-expressing immature neutrophils positively correlated with clinical severity, with the cytokine storm (IL-1{beta}, IL-6, IL-8, TNF), and with intravascular coagulation. Importantly, high proportions of LOX-1+-immature neutrophils are associated with high risks of severe thrombosis. ConclusionsTogether these data suggest that point of care enumeration of LOX-1-immature neutrophils might help distinguish patients at risk of thrombosis complication and most likely to benefit from intensified anticoagulant therapy.

immunology↗