Biology subjects

Schuetz, D.

Publications and source records attributed to Schuetz, D..

9 recordsLinked to original sources

bioRxiv2026

Spontaneous network activity links misrouted interneuron migration to cortical maturation abnormalities

Cortical inhibitory neurons (CIN) populate the neocortex and hippocampus by extensive tangential migration. This process is highly vulnerable to genetic and environmental disturbances and is linked to neuropsychiatric disorders. However, the mechanisms by which transient migratory abnormalities translate into persistent functional deficits remain poorly understood. Here, we utilized a conditional Cxcr4 knockout to investigate the consequences of disrupted migratory guidance - a feature of genetic schizophrenia models. This demonstrated that despite migrating in ectopic cortical layers, CIN quantitatively colonized the neocortex until birth, whereas limbic regions developed a permanent deficit in CIN numbers. Furthermore, CIN failed to populate the neocortical marginal zone, a transient reservoir for late-born CIN destined for superficial cortical layers. Consequently, the layering and molecular identities of CIN, as well as the synaptic connectivity and spontaneous activity of the neuronal network, were significantly altered in the early postnatal neocortex. Although abnormal CIN layering was gradually compensated before maturity, functional differences persisted, as evidenced by facilitated propagation of sensory stimuli between cortical areas. These results demonstrate that CIN migration is an instructive process critical for activity-driven early postnatal network maturation and CIN identity, thus providing a mechanistic link between migratory guidance and the integrity of mature circuits.

neuroscience↗

bioRxiv2025

Robust antibiotic sensitization of pathogenic Pseudomonas aeruginosa via negative hysteresis in the cell envelope

Antibiotic combination in time and space is a key strategy to combat antimicrobial resistance. The success of such treatment designs requires their robust efficacy across treatment conditions and a pathogens genomic diversity. This study found that an initial treatment with a {beta}-lactam antibiotic causes robust cellular sensitization towards an aminoglycoside antibiotic across the high-risk human pathogen Pseudomonas aeruginosa, including resistant strains. This phenomenon of cellular sensitization, termed negative hysteresis, is modulated by the Cpx envelope stress response system and linked to membrane stress during growth. The increase in efficacy is achieved through a {beta}-lactam induced elevated cellular uptake of the subsequently administered aminoglycoside. Negative hysteresis and the Cpx system are linked in several cases to the expression of synergistic drug interactions, thus enhancing efficacy of antibiotic combinations. Overall, our study identifies the phenomenon of negative hysteresis as a robustly inducible phenotype and thus a unique focus for optimizing antimicrobial therapy.

evolutionary biology↗

bioRxiv2025

Resistance variation and bacterial interactions shape the adaptation of a genetically diverse bacterial population to antimicrobial treatment

Bacterial infections are often polymicrobial and subject to the evolution of antimicrobial resistance (AMR). Existing knowledge on AMR in such polymicrobial infections usually relies on observational patient data, for which cause-effect relationships are difficult to infer, or on studying interactions between different bacterial species, ignoring the commonly encountered variation within species. Here, we therefore asked how mixed populations with strains from the same species evolve under antibiotic treatment. We used a genetically diverse population of the high-risk human pathogen Pseudomonas aeruginosa, and first identified strain variation in both AMR and pairwise bacteria-bacteria interactions, the latter ranging from beneficial, neutral, to competitive. Using experimental evolution, we subsequently demonstrate that the response to selection by different antibiotic treatments is significantly influenced by AMR strain variation, bacterial interactions, and also spatial population structure. Moreover, de novo AMR evolution was additionally impacted by variation in resistance rates towards the two considered antibiotics. A second evolution experiment emphasized the central role of strain variation and bacterial interactions in determining the evolutionary outcome. We conclude that ecological dynamics in genetically diverse pathogen populations are key for our general understanding of infection characteristics and AMR evolution, and, therefore, deserve particular attention during treatment of polymicrobial infections.

evolutionary biology↗

bioRxiv2023

Bacterial c-di-GMP plays a key role in the evolution of host-association

Most microbes evolve faster than their hosts and should therefore drive evolution of host-microbe interactions1-3. However, relatively little is known about the characteristics that define the adaptive path of microbes to host-association. In this study we have identified microbial traits that mediate adaptation to hosts by experimentally evolving the bacterium Pseudomonas lurida with the nematode Caenorhabditis elegans. We repeatedly observed the evolution of beneficial host-specialist bacteria with improved persistence in the nematode, achieved by mutations that uniformly upregulate the universal second messenger c-di-GMP. We subsequently upregulated c-di-GMP in different Pseudomonas species, consistently causing increased host-association. Comparison of Pseudomonad genomes from various environments revealed that c-di-GMP underlies adaptation to a variety of hosts, from plants to humans, suggesting that it is fundamental for establishing host-association.

evolutionary biology↗

bioRxiv2020

Negatively charged peptide nanofibrils from immunoglobulin light chain sequester viral particles but lack cell-binding and viral transduction-enhancing properties

Positively charged naturally occurring or engineered peptide nanofibrils (PNF) are effective enhancers of lentiviral and retroviral transduction, an often rate limiting step in gene transfer and gene therapy approaches. These polycationic PNF are thought to bridge the electrostatic repulsions between negatively charged membranes of virions and cells, thereby enhancing virion attachment to and infection of target cells. Here, we analyzed PNF which are formed by the peptide AL1, which represents a fragment of an immunoglobulin light chain that causes systemic AL amyloidosis. We found that negatively charged AL1 PNF interact with viral particles to a comparable extent as positively charged PNF. However, AL1 PNF lacked cell binding activity and consequently did not enhance retroviral infection. These findings show that virion capture and cell binding of PNF are mediated by different mechanisms, offering avenues for the design of advanced PNF with selective functions.

cell biology↗

bioRxiv2020

Cellular Protrusions Engage Viral Infection Enhancing EF-C Peptide Nanofibrils

Self-assembling peptide nanofibrils (PNF) have gained increasing attention as versatile molecules in material science and biomedicine. One important application of PNF is to enhance retroviral gene transfer, a technology that has been central to the development of gene therapy. The best-investigated and commercially available PNF is derived from a 12-mer peptide termed EF-C. The mechanism of transduction enhancement depends on the polycationic surface of EF-C PNF, which binds to the negatively charged membranes of viruses and cells thereby overcoming electrostatic repulsion and increasing virion attachment and fusion. Assuming an even distribution of charges at the surfaces of virions and cells would result in an evenly distributed interaction of the virions with the cell surface. However, we here report that PNF do not randomly bind at the cell surface but are actively engaged by cellular protrusions. Chemical suppression of protrusion formation in cell lines and primary CD4+ T cells greatly reduced fibril binding and hence virion binding. Thus, the mechanism of PNF-mediated viral transduction enhancement involves active engagement of virus-loaded fibrils by cellular protrusions.

cell biology↗

bioRxiv2020

IFITM proteins promote SARS-CoV-2 infection in human lung cells

Interferon-induced transmembrane proteins (IFITMs 1, 2 and 3) are thought to restrict numerous viral pathogens including severe acute respiratory syndrome coronaviruses (SARS-CoVs). However, most evidence comes from single-round pseudovirus infection studies of cells that overexpress IFITMs. Here, we verified that artificial overexpression of IFITMs blocks SARS-CoV-2 infection. Strikingly, however, endogenous IFITM expression was essential for efficient infection of genuine SARS-CoV-2 in human lung cells. Our results indicate that the SARS-CoV-2 Spike protein interacts with IFITMs and hijacks them for efficient viral entry. IFITM proteins were expressed and further induced by interferons in human lung, gut, heart and brain cells. Intriguingly, IFITM-derived peptides and targeting antibodies inhibited SARS-CoV-2 entry and replication in human lung cells, cardiomyocytes and gut organoids. Our results show that IFITM proteins are important cofactors for SARS-CoV-2 infection of human cell types representing in vivo targets for viral transmission, dissemination and pathogenesis and suitable targets for therapeutic approaches.

microbiology↗

bioRxiv2020

An enzyme-based immunodetection assay to quantify SARS-CoV-2 infection

SARS-CoV-2 is a novel pandemic coronavirus that caused a global health and economic crisis. The development of efficient drugs and vaccines against COVID-19 requires detailed knowledge about SARS-CoV-2 biology. Several techniques to detect SARS-CoV-2 infection have been established, mainly based on counting infected cells by staining plaques or foci, or by quantifying the viral genome by PCR. These methods are laborious, time-consuming and expensive and therefore not suitable for a high sample throughput or rapid diagnostics. We here report a novel enzyme-based immunodetection assay that directly quantifies the amount of de novo synthesized viral spike protein within fixed and permeabilized cells. This in-cell ELISA enables a rapid and quantitative detection of SARS-CoV-2 infection in microtiter format, regardless of the virus isolate or target cell culture. It follows the established method of performing ELISA assays and does not require expensive instrumentation. Utilization of the in-cell ELISA allows to e.g. determine TCID50 of virus stocks, antiviral efficiencies (IC50 values) of drugs or neutralizing activity of sera. Thus, the in-cell spike ELISA represents a promising alternative to study SARS-CoV-2 infection and inhibition and may facilitate future research. HighlightsO_LIDetermination of SARS-CoV-2 infection by enzymatically quantifying the expression of viral spike protein in bulk cell cultures C_LIO_LITargeting a highly conserved region in the S2 subunit of the S protein allows broad detection of several SARS-CoV-2 isolates in different cell lines C_LIO_LIScreening of antivirals in microtiter format and determining the antiviral activity as inhibitory concentrations 50 (IC50) C_LI

microbiology↗

bioRxiv2020

Remdesivir but not famotidine inhibits SARS-CoV-2 replication in human pluripotent stem cell-derived intestinal organoids

Gastrointestinal symptoms in COVID-19 are associated with prolonged symptoms and increased severity. We employed human intestinal organoids derived from pluripotent stem cells (PSC-HIOs) to analyze SARS-CoV-2 pathogenesis and to validate efficacy of specific drugs in the gut. Certain, but not all cell types in PSC-HIOs express SARS-CoV-2 entry factors ACE2 and TMPRSS2, rendering them susceptible to SARS-CoV-2 infection. Remdesivir, a promising drug to treat COVID-19, effectively suppressed SARS-CoV-2 infection of PSC-HIOs. In contrast, the histamine-2-blocker famotidine showed no effect. Thus, PSC-HIOs provide an interesting platform to study SARS-CoV-2 infection and to identify or validate drugs.

microbiology↗