Biology subjects

Sutter, K.

Publications and source records attributed to Sutter, K..

12 recordsLinked to original sources

bioRxiv2025

Differential Control of HIV-1 Replication by IFN-α14 Compared to IFN-α2 Relates to Differences in the Modulation of Host Antiretroviral Restriction Factors

Type I IFN, including IFN-, induces the expression of antiviral restriction factors that can interfere with multiple steps of the HIV-1 replication cycle. Humans have 13 IFN- genes which encode 12 different IFN- subtypes. Our previous work in HIV-1 infected humanized mice showed that IFN-14 treatment more potently controlled HIV-1 than treatment with the clinically approved IFN-2 subtype. However, the mechanisms behind the more potent control of HIV-1 by IFN-14 are unknown. The IFN-14 subtype is known to more potently induce the expression of the restriction factors MX2 and ISG15 and increased APOBEC3G signature mutations in vivo compared to IFN-2. To study the importance of each of these restriction factors in mediating the potent control of HIV-1, we used a CRISPR-Cas9 lentivirus system to create stable knockouts in the MT4C5 cell line that is susceptible to HIV-1 but does not produce measurable amounts of endogenous IFN-. Knock out of ISG15, but not MX2, eliminated differences in viral suppression after IFN-14 and IFN-2 treatment. Similarly, APOBEC3G deletion eliminated differences in viral suppression and the number of infectious particles produced after IFN-14 and IFN-2 treatment. Furthermore, APOBEC3G deletion resulted in significantly fewer GG[->]AG mutations in viral DNA isolated from target cells incubated with supernatant from IFN-14 treated groups. However, APOBEC3G knock out did not result in significant increases in vDNA compared to the wild type in any experimental group. Overall, elimination of APOBEC3G and ISG15 impaired IFN-14-mediated suppression of HIV-1, highlighting them as downstream effectors of IFN-14s more potent anti-HIV-1 activity. IMPORTANCEThis study uncovers the molecular basis for the more potent antiviral activity of IFN-14 compared to the clinically used IFN-2 subtype against HIV-1. Although interferons are known to induce numerous restriction factors, the mechanisms underlying subtype-specific antiviral potency remained unclear. By using CRISPR-Cas9 knockout MT4C5 cell lines, the study identifies ISG15 and APOBEC3G as key effectors mediating IFN-14s enhanced suppression of HIV-1 replication. Loss of either ISG15 or APOBEC3G abolished the differential antiviral effect between IFN-14 and IFN-2, demonstrating their essential roles in IFN-14 driven viral restriction. These findings highlight that individual IFN- subtypes engage distinct downstream pathways and that subtype diversity encodes functional specialization rather than redundancy. Overall, this work advances our understanding of innate immune control of HIV-1 and provides a foundation for developing targeted interferon-based therapies that exploit the unique mechanisms of potent subtypes like IFN- 14.

immunology↗

bioRxiv2025

Time in the city: Exploration and problem-solving behaviours reveal long-term urban adaptation in wild red foxes (Vulpes vulpes)

Urbanisation is one of the most important forms of human-driven landscape change, altering wildlife populations in unprecedented ways. In terms of behaviour, for example, urbanisation is hypothesised to increase the likelihood of observing urban populations touching, exploring, and solving novel food-related tasks compared to rural areas. However, little is known about the impact of spatiotemporal patterns of urbanisation, particularly historical patterns of change, on these behaviours. We tested this in the worlds most urbanised carnivore, the red fox (Vulpes vulpes), by introducing novel food-related tasks (puzzle feeders) to 284 sites throughout Great Britain. We compared tactile and problem-solving behaviours in rural populations, recently colonised urban populations, and long-established urban populations (>40 years). Foxes from 27.4% of locations touched the tasks, foxes from 12.4% of locations solved them. Urban foxes were more likely to touch tasks compared to rural populations. Exploration time, exploratory diversity, and latency to touch tasks did not significantly differ across urban and rural locations. Urbanisation rate from 1994 to 2020 (26 years) did not significantly predict the likelihood of foxes touching or solving tasks across locations. Older urban populations - particularly from London - spent more time exploring tasks and displayed greater exploratory diversity and higher problem-solving success, despite more recent urban populations being equally likely to touch them. Collectively, our findings suggest that certain population characteristics, such as the likelihood of touching/engaging with novelty, potentially emerge early in urbanisation while other characteristics, such as greater exploratory and innovative behaviours, may emerge after long-term urban exposure across many decades. HighlightsO_LIHistorical impacts of urbanisation on wild animal behaviour are unclear. C_LIO_LIWe tested this with wild red foxes responses to novel food objects. C_LIO_LIUrban foxes were more likely to touch and exploit objects, especially from London. C_LIO_LIOlder urban foxes displayed more exploratory and innovative behaviours. C_LIO_LILength of urban exposure may help predict behavioural responses to novelty. C_LI

animal behavior and cognition↗

bioRxiv2025

PD-1 signaling is essential for the early accumulation of HBV-specific CD8+ T cells during HBV infection

Background & AimsProgrammed cell death Protein 1(PD-1) is one of the key inhibitory receptors that regulates CD8 T cell exhaustion during chronic viral infection. However, the role of PD-1 in modulating effector T cell differentiation and function during early phase of hepatitis B virus (HBV) infection remains poorly defined. MethodsUsing adoptive transfer of wild-type or PD-1 KO HBV-specific TCR transgenic (C93-TCRtg) CD8 T cells, flow cytometry, and transcriptome sequencing, we systematically profiled early PD-1 dynamics in splenic and intrahepatic T cells and evaluated how PD-1 deficiency shapes anti-HBV T cell responses in acute self-resolving (AR) and chronic (CH) HBV mouse models. ResultsAcute HBV infection induced sustained PD-1 upregulation on intrahepatic/splenic CD8 T cells, which predominantly exhibited an effector phenotype. PD-1 cells displayed enhanced proliferation, cytotoxicity, and effector cytokine production compared to PD-1- counterparts. Adoptive transfer of PD-1 KO C93-TCRtg CD8 T cells resulted in significantly impaired early expansion in both spleen and liver during acute infection, accompanied by reduced granzyme B expression while maintaining IFN-{gamma}, TNF-, or IL-2 production. Transcriptomic analysis revealed that PD-1 deficiency was associated with the upregulation of apoptosis gene signatures. In chronic HBV infection, PD-1 KO cells failed to expand long-term and exhibited exacerbated exhaustion evidenced by a loss of IFN-{gamma} production. ConclusionsPD-1 is essential for the early expansion and survival of HBV-specific CD8 T cells during acute infection and does not suppress their effector cytokine function. Its absence impairs proliferation and promotes exhaustion of HBV-specific CD8 T cell in chronic infections. Impact and implicationsOur study redefines PD-1s role in acute HBV infection. Rather than merely constraining effector function, PD-1 is essential for the early expansion and survival of HBV-specific CD8+ T cells, acting as a safeguard against activation-induced apoptosis. The context-dependent functions position PD-1 as a critical rheostat calibrating the magnitude and quality of the antiviral CD8+ T cell response, with significant implications for immunotherapeutic strategies targeting this pathway in hepatitis B.

immunology↗

bioRxiv2024

Does early-stage Alzheimer's disease affect the dynamics of motor adaptation?

Alzheimers disease (AD) is characterized by an initial decline in declarative memory, while non-declarative memory processing remains relatively intact. Error-based motor adaptation is traditionally seen as a form of non-declarative memory, but recent findings suggest that it involves both fast, declarative and slow, non-declarative adaptive processes. If the declarative memory system shares resources with the fast process in motor adaptation, it can be hypothesized that the fast, but not the slow, process is disturbed in AD patients. To test this, we studied 20 early-stage AD patients and 21 age-matched controls of both sexes using a reach adaptation paradigm that relies on spontaneous recovery after sequential exposure to opposing force fields. Adaptation was measured using error clamps and expressed as an adaptation index (AI). Although patients with AD showed slightly lower adaptation to the force field than the controls, both groups demonstrated effects of spontaneous recovery. The time course of the AI was fitted by a hierarchical Bayesian two-state model in which each dynamic state is characterized by a retention and learning rate. Compared to controls, the retention rate of the fast process was the only parameter that was significantly different (lower) in the AD patients, confirming that the memory of the declarative, fast process is disturbed by AD. The slow adaptive process was virtually unaffected. Since the slow process learns only weakly from error, our results provide neurocomputational evidence for the clinical practice of errorless learning of everyday tasks in people with dementia.

neuroscience↗

bioRxiv2023

Targeted mutations in IFNα2 improve its antiviral activity against various viruses

During viral infections, type I interferons (IFN) are induced and play a key role in counteracting initial viral spread. Twelve different human IFN subtypes exist that bind the same receptor; however, they elicit unique host responses and display distinct potencies of antiviral activities. Our previous studies on HIV and HBV demonstrated that the clinically used IFN2 is not the most effective one among the IFN subtypes. By sequence modeling, we identified a region in helix B with mainly conserved residues at the outside facing IFNAR1, but variable residues at the inside facing the core of IFN, potentially representing a putative tunable anchor to tune pleiotropic IFN responses. Using site-directed mutagenesis various mutations were introduced into the IFN2b backbone targeting sites which are important for binding to IFNAR1 and IFNAR2, the putative tunable anchor, or outside these three regions. Selected mutations were based on sequence differences to high antiviral subtypes IFN6 and IFN14. Treatment assays against HBV and HIV identified several critical residues for the antiviral activity of IFN mainly in the IFNAR1 binding region. Combined mutations of the IFN2 IFNAR1/2 binding sites or the IFNAR1 binding region plus the putative tunable anchor by those of IFN14 further augmented activation of different downstream signaling cascades providing a molecular correlate for the enhanced antiviral activity. We describe here important functional residues within IFN subtype molecules, which enabled us to design novel and innovative drugs that may have the potential to be used in clinical trials against a variety of different viral infections. ImportanceThe potency of IFN to restrict viruses was already discovered in 1957. However, until today only IFN2 out of the 12 distinct human IFN subtypes has been therapeutically used against chronic viral infections. There is convincing evidence that other IFN subtypes are far more efficient than IFN2 against many viruses. In order to identify critical antiviral residues within the IFN subtype sequence, we designed hybrid molecules based on the IFN2 backbone with individual sequence motifs from the more potent subtypes IFN6 and IFN14. In different antiviral assays with HIV or HBV, residues binding to IFNAR1 as well as combinations of residues in the IFNAR1 binding region, the putative tunable anchor, and residues outside these regions were identified to be crucial for the antiviral activity of IFN. Thus, we designed artificial IFN molecules, based on the clinically approved IFN2 backbone, but with highly improved antiviral activity against several viruses.

immunology↗

bioRxiv2023

Cellular hnRNPA0 limits HIV-1 production by interference with LTR-activity and programmed ribosomal frame-shifting

The interplay between host factors and viral components has a profound impact on the viral replication efficiency and fitness. Heterogeneous nuclear ribonucleoproteins (hnRNPs), in particular members of the subfamily A/B, have been broadly studied as HIV-1 host dependency factors, however, the least related member hnRNPA0 has so far not been functionally studied in its potential role affecting viral replication. In this study, we revealed that hnRNPA0 overexpression in HEK293T cells significantly reduced HIV-1 long terminal repeat (LTR) activity up to 3.5-fold, leading to a significant decrease in total viral mRNA (5.5-fold) and protein levels (3-fold). Conversely, knockdown of hnRNPA0 enhanced LTR activity, suggesting its negative regulatory role in viral gene expression. Moreover, the splicing pattern of HIV-1 remained largely unaffected by altered hnRNPA0 levels indicating changes in viral mRNA expression predominantly occurred at the transcriptional level. Moreover, hnRNPA0 overexpression was found to significantly reduce the programmed ribosomal frameshift efficiency of HIV-1, resulting in a shift in the HIV-1 p55/p15 ratio, compromising viral fitness. Synergistic inhibition of LTR activity and thus reduced viral mRNA transcription and impaired ribosomal frameshifting efficiency, which is important for viral infectivity, were detrimental to HIV-1 replication. Additionally, our study revealed that hnRNPA0 levels were lower in therapy naive HIV-1-infected individuals compared to healthy controls and temporarily repressed after IFN-I treatment in HIV-1 target cells. Our findings highlight the significant role of hnRNPA0 in HIV-1 replication and suggests that its IFN-I regulated expression levels are decisive for viral fitness. ImportanceRNA binding proteins, in particular heterogeneous nuclear ribonucleoproteins (hnRNPs) have been extensively studied as host dependency factors for HIV-1 since they are involved in multiple cellular gene expression processes. However, the functional role of hnRNPA0, the least related member of the hnRNPA/B family, and its potential impact on viral replication remains unclear. For the first time, our findings demonstrate the significance of hnRNPA0 in restricting viral replication efficiency. We demonstrate that hnRNPA0 plays a pleiotropic role in limiting viral replication being a negative regulator of viral transcription and significantly impairing ribosomal frameshifting. Our study also revealed hnRNPA0 as an IFN-regulated host factor that is temporarily repressed after IFN-I treatment in HIV-1 target cells and lower expressed in therapy-naive HIV-1-infected individuals compared to healthy controls. Understanding the mode of action between hnRNPA0 and HIV-1 might help to identify novel therapeutically strategies against HIV-1 and other viruses.

microbiology↗

bioRxiv2021

Even well-practiced movements benefit from repetition

Professional golf players spend years practicing, but will still perform one or two practice swings without a ball before executing the actual swing. Why do they do this? In this study we tested the hypothesis that repeating a well-practiced movement leads to a reduction of movement variability. To operationalize this hypothesis, participants were tested in a center- out reaching task with four different targets, on four different days. To probe the effect of repetition they performed random sequences from one to six movements to the same target. Our findings show that, with repetition, movements are not only initiated earlier but their variability is reduced across the entire movement trajectory. Furthermore, this effect is present within and across the four sessions. Together, our results suggest that movement repetition changes the tradeoff between movement initiation and movement precision. New & NoteworthyProfessional athletes practice movements that they have performed thousands of times in training just before it is their turn in a game. Why do they do this? Our results indicate that both initial and endpoint variability reduce with repetition in a short sequence of reaching movements. This means that even well-practiced movements benefit from practice.

neuroscience↗

bioRxiv2021

Interferon-α subtype treatment induces the repression of SRSF1 in HIV-1 target cells and affects HIV-1 post integration steps

Efficient replication of HIV-1 depends on balanced levels of host cell components, including cellular splicing factors. Type I interferons (IFN-I), playing a crucial role in the innate immune defense against viral infections, are well known to induce the transcription of IFN-stimulated genes (ISGs) including potent host restriction factors. Not so well known is, that IFN-repressed genes (IRepGs) also affect viral infections by downregulating host dependency factors that are essential for viral replication. So far, knowledge about IRepGs involved in HIV-1 infection is very limited. Here, we demonstrate that expression levels of the serine/arginine-rich splicing factor 1 (SRSF1) were repressed upon treatment with IFN subtypes in HIV-1 susceptible cell lines as well as primary cells. Furthermore, we could demonstrate in two independent patient cohorts that HIV-1 infection and the concomitant inflammation during the acute and chronic phase, resulted in the strong induction of ISGs, but at the same time significantly repressed SRSF1. 4sU-labeling of newly transcribed mRNAs revealed that IFN-mediated repression of SRSF1 originated from a transcriptional shutdown. Experimental downregulation as well as overexpression of SRSF1 expression levels resulted in crucial changes in HIV-1 LTR-transcription, alternative splice site usage and virus production. While lower SRSF1 levels resulted in low vif mRNA levels and thus severely reduced viral infectivity, higher levels of SRSF1 impaired LTR-Tat-activity and HIV-1 particle production. Our data highlight the so far undescribed role of SRSF1 acting as an IFN-repressed cellular dependency factor decisively regulating HIV-1 post integration steps. Author SummaryIFN-I play a central role in the innate immune defense against viral infections by regulating the expression of interferon stimulated genes (ISGs) and interferon repressed genes (IRepGs). The stimulation of host restriction factors and the reduction of host dependency factors decisively affects the efficiency of HIV-1 replication. After the stable integration of the provirus into the host chromosome, HIV-1 exploits the host cell transcription and splicing machinery for its replication. A network of conserved splice sites and splicing regulatory elements maintain balanced levels of viral transcripts essential for virus production and immune evasion. We demonstrate the so far undescribed role of the splicing factor SRSF1 as an IRepG crucially involved in HIV-1 RNA processing. In HIV-1 infected individuals, we observed inversely proportional expression of high ISG15 and low SRSF1 levels, which were restored in ART treated patients. We could demonstrate, that IFN-I stimulation of HIV-1 target cells resulted in a significant repression of SRSF1 RNA and protein levels. Since low SRSF1 expression decisively reduced HIV-1 vif mRNA levels, a severe impairment of viral replication was observed in APOBEC3G expressing cells. As overexpression negatively affected HIV-1 LTR transcription and virus production, balanced levels of SRSF1 are indispensable for efficient replication.

microbiology↗

bioRxiv2021

Differential interferon-α subtype immune signatures suppress SARS-CoV-2 infection

Type I interferons (IFN-I) exert pleiotropic biological effects during viral infections, balancing virus control versus immune-mediated pathologies and have been successfully employed for the treatment of viral diseases. Humans express twelve IFN-alpha () subtypes, which activate downstream signalling cascades and result in distinct patterns of immune responses and differential antiviral responses. Inborn errors in type I IFN immunity and the presence of anti-IFN autoantibodies account for very severe courses of COVID-19, therefore, early administration of type I IFNs may be protective against life-threatening disease. Here we comprehensively analysed the antiviral activity of all IFN subtypes against SARS-CoV-2 to identify the underlying immune signatures and explore their therapeutic potential. Prophylaxis of primary human airway epithelial cells (hAEC) with different IFN subtypes during SARS-CoV-2 infection uncovered distinct functional classes with high, intermediate and low antiviral IFNs. In particular IFN5 showed superior antiviral activity against SARS-CoV-2 infection. Dose-dependency studies further displayed additive effects upon co-administered with the broad antiviral drug remdesivir in cell culture. Transcriptomics of IFN-treated hAEC revealed different transcriptional signatures, uncovering distinct, intersecting and prototypical genes of individual IFN subtypes. Global proteomic analyses systematically assessed the abundance of specific antiviral key effector molecules which are involved in type I IFN signalling pathways, negative regulation of viral processes and immune effector processes for the potent antiviral IFN5. Taken together, our data provide a systemic, multi-modular definition of antiviral host responses mediated by defined type I IFNs. This knowledge shall support the development of novel therapeutic approaches against SARS-CoV-2.

cell biology↗

bioRxiv2020

SARS-CoV-2-specific T cell memory is long-lasting in the majority of convalsecent COVID-19 individuals

An unaddressed key question in the current coronavirus disease 2019 (COVID-19) pandemic is the duration of immunity for which specific T cell responses against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are an indispensable element. Being situated in Wuhan where the pandemic initiated enables us to conduct the longest analyses of memory T cell responses against SARS-CoV-2 in COVID-19 convalescent individuals (CIs). Magnitude and breadth of SARS-CoV-2 memory CD4 and CD8 T cell responses were heterogeneous between patients but robust responses could be detected up to 9 months post disease onset in most CIs. Loss of memory CD4 and CD8 T cell responses were observed in only 16.13% and 25.81% of CIs, respectively. Thus, the overall magnitude and breadth of memory CD4 and CD8 T cell responses were quite stable and not inversely correlated with the time from disease onset. Interestingly, the only significant decrease in the response was found for memory CD4 T cells in the first 6-month post COVID-19 disease onset. Longitudinal analyses revealed that the kinetics of SARS-CoV-2 memory CD4 and CD8 T cell responses were quite heterogenous between patients. Loss of memory CD4 T cell responses was observed more frequently in asymptomatic cases than after symptomatic COVID-19. Interestingly, the few CIs in which SARS-CoV-2-specific IgG responses disappeared showed more durable memory CD4 T cell responses than CIs who remained IgG-positive for month. Collectively, we provide the first comprehensive characterization of the long-term memory T cell response in CIs, suggesting that SARS-CoV-2-specific T cell immunity is long-lasting in the majority of individuals.

microbiology↗

bioRxiv2020

Impaired cytotoxic CD8+ T cell response in elderly COVID-19 patients

SARS-CoV-2 infection induces a T cell response that most likely contributes to virus control in COVID-19 patients, but may also induce immunopathology. Until now, the cytotoxic T cell response has not been very well characterized in COVID-19 patients. Here, we analyzed the differentiation and cytotoxic profile of T cells in 30 cases of mild COVID-19 during acute infection. SARS-CoV-2 infection induced a cytotoxic response of CD8+ T cells, but not CD4+ T cells, characterized by the simultaneous production of granzyme A and B, as well as perforin within different effector CD8+ T cell subsets. PD-1 expressing CD8+ T cells also produced cytotoxic molecules during acute infection indicating that they were not functionally exhausted. However, in COVID-19 patients over the age of 80 years the cytotoxic T cell potential was diminished, especially in effector memory and terminally differentiated effector CD8+ cells, showing that elderly patients have impaired cellular immunity against SARS-CoV-2. Our data provides valuable information about T cell responses in COVID-19 patients that may also have important implications for vaccine development. ImportanceCytotoxic T cells are responsible for the elimination of infected cells and are key players for the control of viruses. CD8+ T cells with an effector phenotype express cytotoxic molecules and are able to perform target cell killing. COVID-19 patients with a mild disease course were analyzed for the differentiation status and cytotoxic profile of CD8+ T cells. SARS-CoV-2 infection induced a vigorous cytotoxic CD8+ T cell response. However, this cytotoxic profile of T cells was not detected in COVID-19 patients over the age of 80 years. Thus, the absence of a cytotoxic response in elderly patients might be a possible reason for the more frequent severity of COVID-19 in this age group in comparison to younger patients.

immunology↗

bioRxiv2019

HIV infection does not alter Interferon α/β receptor expression on mucosal immune cells

The innate immune response induced by type I interferons (IFNs) play a critical role in the establishment of HIV infection. IFNs are induced early in HIV infection and trigger an antiviral defense program by signaling through the IFNa/b receptor (IFNAR), which consists of two subunits, IFNAR1 and IFNAR2. Changes in IFNAR expression in HIV target cells, as well as other immune cells, could therefore have important consequences for initial HIV spread. It was previously reported that IFNAR2 expression is increased in peripheral blood CD4+ CXCR4+ T cells of HIV+ patients compared to HIV uninfected controls, suggesting that HIV infection may alter the IFN responsiveness of target cells. However, the earliest immune cells affected by HIV in vivo reside in the gut-associated lymphoid tissue (GALT). To date, it remains unknown if IFNAR expression is altered in GALT immune cells in the context of HIV infection and exposure to IFNs, including the 12 IFNa subtypes. Here, we analyzed the expression of surface bound and soluble IFNAR2 on Lamina propria mononuclear cells (LPMCs) isolated from the GALT of HIV- individuals and in plasma samples of HIV+ patients. IFNAR2 expression varied between different T cells, B cells and natural killer cells, but was not altered following HIV infection. Furthermore, expression of the soluble IFNAR2a isoform was not changed in HIV+ patients compared to healthy donors, nor in LPMCs after HIV-1 infection ex vivo. Even though the 12 human IFN subtypes trigger different biological responses and vary in their affinity to both receptor subunits, stimulation of LPMCs with different recombinant IFN subtypes did not result in any significant changes in IFNAR2 surface expression. Our data suggests that potential changes in the IFN responsiveness of mucosal immune cells during HIV infection is unlikely dictated by changes in IFNAR2 expression.

immunology↗