Biology subjects

Zimmermann, J.

Publications and source records attributed to Zimmermann, J..

At least 55 records · Page 3Linked to original sources

bioRxiv2023

Global neuronal activity drives cerebrospinal fluid motion mediated by brain blood volume changes in humans

In the mammalian brain, the directed motion of cerebrospinal fluid (CSF-flux) is instrumental in the distribution and removal of solutes. Changes in total cerebral blood volume (CBV) have been hypothesized to drive CSF-flux. We tested this hypothesis in two multi-modal brain imaging experiments in healthy humans, in which we drove large changes in total CBV by neuronal burst-suppression under anesthesia, or by transient global vasodilation in a hypercapnic challenge. We developed a technique to monitor CBV changes based on associated changes in total brain volume by functional MRI (fMRI) and measured cerebral blood flow by arterial spin-labeling. Relating CBV-sensitive signals to fMRI-derived measures of macroscopic CSF flow across the basal cisternae, we demonstrate that increasing total CBV extrudes CSF from the skull and decreasing CBV allows its influx. Moreover, CSF largely stagnates when CBV is stable. Together, our results establish the direct coupling between total CBV changes and CSF-flux.

neuroscience↗

bioRxiv2023

Induced neural phase precession through exogeneous electric fields

The gradual shifting of preferred neural spiking relative to local field potentials (LFPs), known as phase precession, plays a prominent role in neural coding. Correlations between the phase precession and behavior have been observed throughout various brain regions. As such, phase precession is suggested to be a global neural mechanism that promotes local neuroplasticity. However, causal evidence and neuroplastic mechanisms of phase precession are lacking so far. Here we show a causal link between LFP dynamics and phase precession. In three experiments, we modulated LFPs in humans, a non-human primate, and computational models using alternating current stimulation. We show that continuous stimulation of motor cortex oscillations in humans lead to a gradual phase shift of maximal corticospinal excitability by [~]90{degrees}. Further, exogenous alternating current stimulation induced phase precession in a subset of entrained neurons ([~]30%) in the non-human primate. Multiscale modeling of realistic neural circuits suggests that alternating current stimulation-induced phase precession is driven by NMDA-mediated synaptic plasticity. Altogether, the three experiments provide mechanistic and causal evidence for phase precession as a global neocortical process. Alternating current-induced phase precession and consequently synaptic plasticity is crucial for the development of novel therapeutic neuromodulation methods.

neuroscience↗

bioRxiv2023

Neural timescales reflect behavioral demands in freely moving rhesus macaques

Previous work has demonstrated remarkably reproducible and consistent hierarchies of neural timescales across cortical areas at rest. The question arises how such stable hierarchies give rise to adaptive behavior that requires flexible adjustment of temporal coding and integration demands. Potentially, this previously found lack of variability in the hierarchical organization of neural timescales could be a reflection of the structure of the laboratory contexts in which they were measured. Indeed, computational work demonstrates the existence of multiple temporal hierarchies within the same anatomical network when the input structure is altered. We posit that unconstrained behavioral environments where relatively little temporal demands are imposed from the experimenter are an ideal test bed to address the question of whether the hierarchical organization and the magnitude of neural timescales reflect ongoing behavioral demands. To tackle this question, we measured timescales of local field potential activity while rhesus macaques were foraging freely in a large open space. We find a hierarchy of neural timescales that is unique to this foraging environment. Importantly, although the magnitude of neural timescales generally expanded with task engagement, the brain areas relative position in the hierarchy was stable across the recording sessions. Notably, the magnitude of neural timescales monotonically expanded with task engagement across a relatively long temporal scale spanning the duration of the recording session. Over shorter temporal scales, the magnitude of neural timescales changed dynamically around foraging events. Moreover, the change in the magnitude of neural timescales contained functionally relevant information, differentiating between seemingly similar events in terms of motor demands and associated reward. That is, the patterns of change were associated with the cognitive and behavioral meaning of these events. Finally, we demonstrated that brain areas were differentially affected by these behavioral demands - i.e., the expansion of neural timescales was not the same across all areas. Together, these results demonstrate that the observed hierarchy of neural timescales is context-dependent and that changes in the magnitude of neural timescales are closely related to overall task engagement and behavioral demands.

neuroscience↗

bioRxiv2023

Gut-associated functions are favored during microbiome assembly across C. elegans life

The microbiome expresses a variety of functions that influence host biology. The range of functions depends on composition of the microbiome, which itself can change during the lifetime of the host as a consequence of neutral assembly processes, host-mediated selection, and/or environmental conditions. To date, the exact dynamics of microbiome assembly, the underlying determinants as well as the resulting effects on host-associated functions are not always well understood. Here, we used the nematode Caenorhabditis elegans and a defined community of fully sequenced, naturally associated bacteria to study microbiome dynamics and functions across the lifetime of individual hosts under controlled experimental conditions. By applying the neutral and null models, we demonstrate that bacterial community composition initially shows strongly declining levels of stochasticity, which, however, increase during late worm life, suggesting the action of random assembly processes in aged hosts following first colonization of C. elegans. The adult microbiome is enriched in strains of the genera Ochrobactrum and Enterobacter in comparison to the direct substrate and a host-free control environment. Using pathway analysis, metabolic, and ecological modelling, we further found that the lifetime assembly dynamics lead to an increase in gut-associated functions in the host-associated microbiome, possibly indicating that the initially colonizing bacteria are beneficial for the worm. Overall, our study introduces a framework for studying microbiome assembly dynamics based on the stochastic models and inference of functions, yielding new insights into the processes determining host-associated microbiome composition and function. ImportanceThe microbiome plays a crucial role in host biology, with its functions depending on microbiome composition that can change during a hosts lifetime. To date, the dynamics of microbiome assembly and the resulting functions are not well understood. This study introduces a new approach to characterize the functional consequences of microbiome assembly by modelling both, the relevance of stochastic processes and metabolic characteristics of microbial community changes. The approach was applied to experimental time series data, obtained for the microbiome of the nematode Caenorhabditis elegans. The results revealed significant differences in host-associated and environmental microbiomes. Stochastic processes only played a minor role, and the host showed an increase in beneficial bacteria and an enrichment of gut-associated functions, possibly indicating that the host actively shapes composition of its microbiome. Overall, this study provides a framework for studying microbiome assembly dynamics and yields new insights into C. elegans microbiome functions.

evolutionary biology↗

bioRxiv2023

Amino acid auxotrophies in human gut bacteria are linked to higher microbiome diversity and long-term stability

Amino acid auxotrophies are prevalent among bacteria. They can govern ecological dynamics in microbial communities and indicate metabolic cross-feeding interactions among coexisting genotypes. Despite the ecological importance of auxotrophies, their distribution and impact on the diversity and function of the human gut microbiome remain poorly understood. This study performed the first systematic analysis of the distribution of amino acid auxotrophies in the human gut microbiome using a combined metabolomic, metagenomic, and metabolic modeling approach. Results showed that amino acid auxotrophies are ubiquitous in the colon microbiome, with tryptophan auxotrophy being the most common. Auxotrophy frequencies were higher for those amino acids that are also essential to the human host. Moreover, a higher overall abundance of auxotrophies was associated with greater microbiome diversity and stability, and the distribution of auxotrophs was found to be related to the human hosts metabolome, including trimethylamine oxide, small aromatic acids, and secondary bile acids. Thus, our results suggest that amino acid auxotrophies are important factors contributing to microbiome ecology and host-microbiome metabolic interactions.

microbiology↗

bioRxiv2023

The role of glutathione in periplasmic redox homeostasis and oxidative protein folding in Escherichia coli

The thiol redox balance in the periplasm of E. coli depends on the DsbA/B pair for oxidative power and the DsbC/D system as its complement for isomerization of non-native disulfides. While the standard redox potentials of those systems are known, the in vivo redox potential imposed onto protein thiol disulfide pairs in the periplasm remains unknown. Here, we used genetically encoded redox probes (roGFP2 and roGFP-iL), targeted to the periplasm, to directly probe the thiol redox homeostasis in this compartment. These probes contain two cysteine residues, that are virtually completely reduced in the cytoplasm, but once exported into the periplasm, can form a disulfide bond, a process that can be monitored by fluorescence spectroscopy. Even in the absence of DsbA, roGFP2, exported to the periplasm, was fully oxidized, suggesting the presence of an alternative system for the introduction of disulfide bonds into exported proteins. However, the absence of DsbA shifted the periplasmic thiol-redox potential from -228 mV to a more reducing -243 mV and the capacity to re-oxidize periplasmic roGFP2 after a reductive pulse was significantly decreased. Re-oxidation in a DsbA strain could be fully restored by exogenous oxidized glutathione (GSSG), while reduced GSH accelerated re-oxidation of roGFP2 in the WT. In line, a strain devoid of endogenous glutathione showed a more reducing periplasm, and was significantly worse in oxidatively folding PhoA, a native periplasmic protein and substrate of the oxidative folding machinery. PhoA oxidative folding could be enhanced by the addition of exogenous GSSG in the WT and fully restored in a {Delta}dsbA mutant. Taken together this suggests the presence of an auxiliary, glutathione-dependent thiol-oxidation system in the bacterial periplasm.

biochemistry↗

bioRxiv2023

Metabolic model predictions enable targeted microbiome manipulation through precision prebiotics

1.The microbiome is increasingly receiving attention as an important modulator of host health and disease. However, while numerous mechanisms through which the microbiome influences its host have been identified, there is still a lack of approaches that allow to specifically modulate the abundance of individual microbes or microbial functions of interest. Moreover, current approaches for microbiome manipulation such as fecal transfers often entail a non-specific transfer of entire microbial communities with potentially unwanted side effects. To overcome this limitation, we here propose the concept of precision prebiotics that specifically modulate the abundance of a microbiome member species of interest. In a first step, we show that defining precision prebiotics by compounds that are only taken up by the target species but no other species in a community is usually not possible due to overlapping metabolic niches. Subsequently, we present a metabolic modeling network framework that allows us to define precision prebiotics for a two-member C. elegans microbiome model community comprising the immune-protective Pseudomonas lurida MYb11 and the persistent colonizer Ochrobactrum vermis MYb71. Thus, we predicted compounds that specifically boost the abundance of the host-beneficial MYb11, four of which were experimentally validated in vitro (L-serine, L-threonine, D-mannitol, and {gamma}-aminobutyric acid). L-serine was further assessed in vivo, leading to an increase in MYb11 abundance also in the worm host. Overall, our findings demonstrate that constraint-based metabolic modeling is an effective tool for the design of precision prebiotics as an important cornerstone for future microbiome-targeted therapies.

systems biology↗

bioRxiv2023

A Structured Evaluation of Genome-Scale Constraint-Based Modeling Tools for Microbial Consortia

Harnessing the power of microbial consortia is integral to a diverse range of sectors, from healthcare to biotechnology to environmental remediation. To fully realize this potential, it is critical to understand the mechanisms behind the interactions that structure microbial consortia and determine their functions. Constraint-based reconstruction and analysis (COBRA) approaches, employing genome-scale metabolic models (GEMs), have emerged as the state-of-the-art tool to simulate the behavior of microbial communities from their constituent genomes. In the last decade, many tools have been developed that use COBRA approaches to simulate multi-species consortia, under either steady-state, dynamic, or spatiotemporally varying scenarios. Yet, these tools have not been systematically evaluated regarding their software quality, most suitable application, and predictive power. Hence, it is uncertain which tools users should apply to their system and what are the most urgent directions that developers should take in the future to improve existing capacities. This study conducted a systematic evaluation of COBRA-based tools for microbial communities using datasets from two-member communities as test cases. First, we performed a qualitative assessment in which we evaluated 24 published tools based on a list of FAIR (Findability, Accessibility, Interoperability, and Reusability) features essential for software quality. Next, we quantitatively tested the predictions in a subset of 14 of these tools against experimental data from three different case studies: a) syngas fermentation by C. autoethanogenum and C. kluyveri for the static tools, b) glucose/xylose fermentation with engineered E. coli and S. cerevisiae for the dynamic tools, and c) a Petri dish of E. coli and S. enterica for tools incorporating spatiotemporal variation. Our results show varying performance levels of the best qualitatively assessed tools when examining the different categories of tools. The differences in the mathematical formulation of the approaches and their relation to the results were also discussed. Ultimately, we provide recommendations for refining future GEM microbial modeling tools. Author summaryConstraint-based modeling employing genome-scale reconstructions of microbial species has become one of the most successful approaches for studying, analyzing, and engineering microbial consortia. Over the past decade, many constraint-based modeling tools have been published to examine an immense variety of microbial consortia spanning from the application areas of bioremediation to food and health biotechnology. However, new potential users lack an overview of the quality and performance of existing metabolic modeling tools that would guide their choice. To tackle this issue, we examined 24 tools for genome-scale metabolic modeling of microbial consortia. After an initial qualitative screening, we quantitatively evaluated 14 adequate tools against published experimental data that included different organisms and conditions. We conducted simulations and evaluated model features such as predictive accuracy, computational time, and tractability in capturing critical physiological properties. We found that, generally, more up-to-date, accessible, and documented tools were superior in many important aspects of model quality and performance. Although, in some cases, we observed tradeoffs in older, less elaborate tools that can be more accurate or flexible. This work has broad implications to help researchers navigate the most suitable tools, and suggests to developers opportunities for improvement of the currently existing capabilities for metabolic modeling of multi-species microbial consortia.

systems biology↗

bioRxiv2023

The gene expression classifier ALLCatchR identifies B-precursor ALL subtypes and underlying developmental trajectories across age

Current classifications (WHO-HAEM5 / ICC) define up to 26 molecular B-cell precursor acute lymphoblastic leukemia (BCP-ALL) disease subtypes, which are defined by genomic driver aberrations and corresponding gene expression signatures. Identification of driver aberrations by RNA-Seq is well established, while systematic approaches for gene expression analysis are less advanced. Therefore, we developed ALLCatchR, a machine learning based classifier using RNA-Seq expression data to allocate BCP-ALL samples to 21 defined molecular subtypes. Trained on n=1,869 transcriptome profiles with established subtype definitions (4 cohorts; 55% pediatric / 45% adult), ALLCatchR allowed subtype allocation in 3 independent hold-out cohorts (n=1,018; 75% pediatric / 25% adult) with 95.7% accuracy (averaged sensitivity across subtypes: 91.1% / specificity: 99.8%). High confidence predictions were achieved in 84.6% of samples with 99.7% accuracy. Only 1.2% of samples remained unclassified. ALLCatchR outperformed existing tools and identified novel candidates in previously unassigned samples. We established a novel RNA-Seq reference of human B-lymphopoiesis. Implementation in ALLCatchR enabled projection of BCP-ALL samples to this trajectory, which identified shared patterns of proximity of BCP-ALL subtypes to normal lymphopoiesis stages. ALLCatchR sustains RNA-Seq routine application in BCP-ALL diagnostics with systematic gene expression analysis for accurate subtype allocations and novel insights into underlying developmental trajectories.

cancer biology↗

bioRxiv2022

Bacterial colonizers of Nematostella vectensis are initially selected by the host before interactions between bacteria determine further succession

The microbiota of multicellular organisms undergoes considerable changes during development but the general mechanisms that control community assembly and succession are poorly understood. Here, we use bacterial recolonization experiments in Nematostella vectensis as a model to understand general mechanisms determining bacterial establishment and succession. We compared the dynamic establishment of the microbiome on the germfree host and on inert silica. Following the dynamic reconstruction of microbial communities on both substrates, we show that the initial colonization events are strongly influenced by the host but not by the tube, while the subsequent bacteria-bacteria interactions are the main cause of bacterial succession. Interestingly, the recolonization pattern on adult hosts resembles the ontogenetic colonization succession. This process occurs independently of the bacterial composition of the inoculum and can be followed at the level of individual bacteria, suggesting that priority effects are neglectable for early colonization events in Nematostella. To identify potential metabolic traits associated with initial colonization success and potential metabolic interactions among bacteria associated with bacterial succession, we reconstructed the metabolic networks of bacterial colonizers based on their genomes. These analyses revealed that bacterial metabolic capabilities reflect the recolonization pattern, and the degradation of chitin might be a selection factor during early colonization of the animal. Concurrently, transcriptomic analyses revealed that Nematostella possesses two chitin synthase genes, one of which is upregulated during early recolonization. Our results show that early colonization events are strongly controlled by the host while subsequent colonization depends on metabolic bacteria-bacteria interactions largely independent of host development.

microbiology↗

bioRxiv2022

Systematic evaluation of anatomical details on transcranial electric stimulation and transcranial magnetic stimulation induced electric fields in a non-human primate model

Non-human primates (NHPs) have become key for translational research in noninvasive brain stimulation (NIBS). However, in order to create comparable stimulation conditions to humans it is vital to evaluate and match electric fields across species. Numerical models to simulate electric fields are an important tool for experimental planning in NHPs and translation to human studies. It is thus essential to evaluate how anatomical details in NHP models affect NIBS electric fields. Here, we create a highly accurate head model of a non-human primate (NHP) from 10.5 T MR data. We systematically evaluate how muscle tissue and head size (due to different MRI fields of view) affect simulation results in transcranial electric and magnetic stimulation (TES and TMS). Our findings indicate that the inclusion of muscle can affect TES electric field strength up to 29.5% while TMS is largely unaffected. Additionally, comparing a full head model to a cropped head model illustrates the impact of head size on electric fields for both TES and TMS. We find opposing effects between TES and TMS with an increase up to 13.5% for TES and a decrease up to 21.5% for TMS for the cropped head model compared to the full head model. Our results provide important insights into the level of anatomical detail needed for NHP head models and can inform future translational efforts for NIBS studies. HighlightsO_LIWe created a high resolution non-human primate FEM head model from 10.5 T MR data. C_LIO_LIWe ran transcranial electric and magnetic stimulation (TES and TMS) simulations to evaluate the effects of muscle and head size on the induced electric field in the brain. C_LIO_LIWe simulated both isotropic and anisotropic muscle conductivities. C_LIO_LIMuscle tissue can greatly affect simulation results for TES (increase electric field strength by up to 29.5%), but not for TMS. C_LIO_LIThere are opposing, but large effects of using a full head model versus a cropped head model for both TES (increase up to 13.5%) and TMS (decrease of up to 21.5%) C_LI

neuroscience↗

bioRxiv2022

Prefrontal control of actions in freely moving macaques

Our natural behavioral repertoires include complex coordinated actions of characteristic types. To better understand the organization of action and its neural underpinnings, we examined behavior and neural activity in rhesus macaques performing a freely moving foraging task in an open environment. We developed a novel analysis pipeline that can identify meaningful units of behavior, corresponding to recognizable actions such as sitting, walking, jumping, and climbing. On the basis of action transition probabilities, we found that behavior was organized in a modular and hierarchical fashion. We found that, after regressing out many potential confounders, actions are associated with specific patterns of firing in each of six prefrontal brain regions and that, overall, representation of actions is progressively stronger in more dorsal and more caudal prefrontal regions. Conversely, we found that switching between actions resulted in changed firing rates, with more rostral and more ventral regions showing stronger effects. Together, these results establish a link between control of action state and neuronal activity in prefrontal regions in the primate brain.

neuroscience↗

bioRxiv2022

Widespread coding of navigational variables in prefrontal cortex

To navigate, we must represent information about our place in the environment. Traditional research highlights the role of the hippocampal complex in this process. Spurred by recent research highlighting the widespread cortical encoding of cognitive and motor variables previously thought to have localized function, we hypothesized that navigational variables would be likewise encoded widely, especially in the prefrontal cortex, which is often associated with control of volitional behavior. We recorded neural activity from six prefrontal structures while macaques performed a foraging task in an open enclosure. In all six regions, we found strong encoding of allocentric position, head direction, egocentric boundary distance, and linear and angular velocity. These encodings were not accounted for by distance or time to reward. Strength of coding of all variables increase along a ventral-to-dorsal gradient. Together these results argue that encoding of navigational variables is not localized to the hippocampal complex and support the hypothesis that navigation is continuous with other forms of flexible cognition in the service of action.

neuroscience↗

bioRxiv2022

Patterns of convergent somatic hypermutations in the adaptive immune response of Mus musculus

We analyzed a dataset of 964 clonally unrelated murine antibodies for which structures have been deposited in the PDB. 454 of the 964 antibodies have gapless germline assignments and do not have excessive numbers of computationally identified somatic hypermutations (SHMs). About 5,500 SHMs were identified, of which approximately 3,500 are in the framework. We then searched for correlated convergent SHMs, i.e. groups of SHMs that arose independently in different antibodies but at the same sequence position and with the same germline and mature amino acid identity. A surprisingly large number of groups of correlated convergent SHMs were found. 329 antibodies share at least two, 161 antibodies share at least three, 87 antibodies share at least four, and 53 antibodies share at least five identical SHMs with another antibody in the dataset. We then analyzed whether any of the correlated SHMs are forming structural cluster. Approximately 400 clusters where CFWMs are located within 10 [A] of each other were identified. 158 of these clusters are in the framework region. Identification of such structural clusters of correlated convergent SHMs may help identify adaptive mutations that act in an antigen-independent manner.

immunology↗

bioRxiv2022

Rapid generation of precision preclinical cancer models using regulatable in vivo base editing

Single nucleotide variants (SNVs) comprise the majority of cancer-associated genetic changes and can have diverse effects on protein function. Despite a comprehensive catalogue of SNVs across human cancers, little is known about their impact on tumor initiation and progression. To enable the functional interrogation of cancer-associated SNVs, we developed a murine system for temporal and regulatable in vivo cytosine base editing (iBE). The iBE mice show robust, doxycycline-dependent expression across a broad range of tissues with no evidence of DNA or RNA off-target effects. Transient iBE induction drives efficient creation of individual or multiple SNVs in intestinal, lung, and pancreatic organoids, while temporal iBE regulation allows controlled sequential genome editing. Moreover, in situ delivery of plasmid-based or synthetic sgRNAs to target tissues facilitates the simple and rapid generation of pre-clinical cancer models. Overall, iBE is a powerful in vivo platform to define and interrogate the genetic drivers of cancer.

cancer biology↗

bioRxiv2022

Best practice recommendations for sample preservation in metabarcoding studies: a case study on diatom environmental samples

The development of DNA metabarcoding and High-Throughput Sequencing for diatoms is nowadays offering an interesting approach to assess their communities in freshwater and marine ecosystems. In the context of the implementation of these genomic methods to environmental monitoring, protocol constraints are moving from scientific to operational applications, requiring operational guidelines and standards. In particular, the first steps of the diatom metabarcoding process, which consist of sampling and storage, have been addressed in various ways in scientific and pilot studies. The objective of this study was to compare three currently applied preservation protocols through different storage durations (ranging from one day to one year) for phytobenthos and phytoplankton samples intended for diatom DNA metabarcoding analysis. The experimental design included four freshwater and two marine samples from sites of diverse ecological characteristics. The impact of the preservation and storage was assessed through diatom metabarcoding endpoints: DNA quality and quantity, diversity and richness, community composition and ecological index values (for freshwater samples). The yield and quality of extracted DNA only decreased for freshwater phytobenthos samples preserved with ethanol. Diatom diversity was not affected and their taxonomic composition predominantly reflects the site origin. Only rare taxa (below 100 reads) differed among methods and durations. Thus, importance of preservation method choice is important for low-density species (rare, invasive, threatened or toxic species). However, for biomonitoring purposes, freshwater ecological index values were not affected whatever the preservation method and duration considered (including ethanol preservation), reflecting the site ecological status. This study proved that diatom metabarcoding is robust enough to replace or complement the current approach based on morphotaxonomy, paving the way to new possibilities for biomonitoring. Thus, accompanied by operational standards, the method will be ready to be confidently deployed and prescribed in future regulatory monitoring.

molecular biology↗

bioRxiv2022

The metabolite-controlled ubiquitin conjugase Ubc8 promotes mitochondrial protein import by enhancing assembly of the TOM complex

Mitochondria are essential organelles that play a key role in cellular energy metabolism. Transitions between glycolytic and respiratory conditions induce considerable adaptations of the cellular proteome. These metabolism-dependent changes are particularly pronounced for the protein composition of mitochondria. Here we show that the yeast cytosolic ubiquitin conjugase Ubc8 plays a crucial role in the remodeling process when cells transition from respiratory to fermentative conditions. Ubc8 is a conserved and well-studied component of the catabolite control system that is known to regulate the stability of gluconeogenesis enzymes. Unexpectedly, we found that Ubc8 also promotes the assembly of the translocase of the outer membrane of mitochondria (TOM) and stabilizes its cytosol-exposed receptor subunit Tom22. Ubc8 deficiency results in a compromised protein import into mitochondria and a subsequent accumulation of mitochondrial precursor proteins in the cytosol. Our observations show that Ubc8, which is controlled by the prevailing metabolic conditions, promotes the switch from glucose synthesis to glucose usage in the cytosol and induces the biogenesis of the mitochondrial TOM machinery in order to improve mitochondrial protein import during phases of metabolic transition.

biochemistry↗

bioRxiv2022

Intranasal Immunization with a Proteosome-Adjuvanted SARS-CoV2 Spike Protein-Based Vaccine is Immunogenic and Efficacious in Mice & Hamsters

With the persistence of the SARS-CoV-2 pandemic and the emergence of novel variants, the development of novel vaccine formulations with enhanced immunogenicity profiles could help reduce disease burden in the future. Intranasally delivered vaccines offer a new modality to prevent SARS-CoV-2 infections through the induction of protective immune responses at the mucosal surface where viral entry occurs. Herein, we evaluated a novel protein subunit vaccine formulation containing a resistin-trimerized prefusion Spike antigen (SmT1v3) and a proteosome-based mucosal adjuvant (BDX301) formulated to enable intranasal immunization. In mice, the formulation induced robust antigen-specific IgG and IgA titers, in the blood and lungs, respectively. In addition, the formulations were highly efficacious in a hamster challenge model, reducing viral load and body weight loss. In both models, the serum antibodies had strong neutralizing activity, preventing the cellular binding of the viral Spike protein based on the ancestral reference strain, the Beta (B.1.351) and Delta (B.1.617.2) variants of concern. As such, this intranasal vaccine formulation warrants further development as a novel SARS-CoV-2 vaccine.

immunology↗