Biology subjects

Stenger, S.

Publications and source records attributed to Stenger, S..

9 recordsLinked to original sources

bioRxiv2026

Interleukin-6 responses to acute stress are not altered in alcohol use disorder despite elevated baseline inflammation

Acute stress activates the immune system, leading to the release of pro-inflammatory cytokines, such as interleukin-6 (IL-6). Chronic alcohol consumption alters the physiological stress systems and is associated with increased chronic inflammation. However, it remains unclear how IL-6 responds to acute stress in individuals with alcohol use disorder (AUD). Forty patients with AUD during early abstinence and 37 healthy controls (HC) completed two study visits. On one day, an acute stress induction task was performed, and on the other, a non-stressful control task, with the order of tasks being balanced. Plasma IL-6 and C-reactive protein (CRP) were measured as inflammatory markers at baseline and changes in IL-6 were assessed 90 minutes after the experimental manipulation. Patients with AUD showed significantly elevated baseline IL-6 and CRP compared to HC and the levels correlated positively with the amount of consumed alcohol in patients. IL-6 responses to the stress intervention did not differ between groups. Increases in IL-6 were observed on stress and control days and were larger when samples were collected via an indwelling catheter than with a butterfly needle. These findings suggest that IL-6 responses to acute stress do not differ between AUD and HC, despite increased baseline inflammation. Furthermore, the results indicate that blood collection methods can influence IL-6 measurements and highlight the importance of methodological considerations.

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↗

bioRxiv2020

Systematic analysis of innate immune antagonism reveals vulnerabilities of SARS-CoV-2

The innate immune system constitutes a powerful barrier against viral infections. However, it may fail because successful emerging pathogens, like SARS-CoV-2, evolved strategies to counteract it. Here, we systematically assessed the impact of 29 SARS-CoV-2 proteins on viral sensing, type I, II and III interferon (IFN) signaling, autophagy and inflammasome formation. Mechanistic analyses show that autophagy and type I IFN responses are effectively counteracted at different levels. For example, Nsp14 induces loss of the IFN receptor, whereas ORF3a disturbs autophagy at the Golgi/endosome interface. Comparative analyses revealed that antagonism of type I IFN and autophagy is largely conserved, except that SARS-CoV-1 Nsp15 is more potent in counteracting type I IFN than its SARS-CoV-2 ortholog. Altogether, however, SARS-CoV-2 counteracts type I IFN responses and autophagy much more efficiently than type II and III IFN signaling. Consequently, the virus is relatively resistant against exogenous IFN-/{beta} and autophagy modulation but remains highly vulnerable towards IFN-{gamma} and -{lambda} treatment. In combination, IFN-{gamma} and -{lambda} act synergistically, and drastically reduce SARS-CoV-2 replication at exceedingly low doses. Our results identify ineffective type I and II antagonism as weakness of SARS-CoV-2 that may allow to devise safe and effective anti-viral therapies based on targeted innate immune activation.

microbiology↗

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

Alpha-1 antitrypsin inhibits SARS-CoV-2 infection

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19). To identify factors of the respiratory tract that suppress SARS-CoV-2, we screened a peptide/protein library derived from bronchoalveolar lavage, and identified 1-antitrypsin (1-AT) as specific inhibitor of SARS-CoV-2. 1-AT targets the viral spike protein and blocks SARS-CoV-2 infection of human airway epithelium at physiological concentrations. Our findings show that endogenous 1-AT restricts SARS-CoV-2 and repurposes 1-AT-based drugs for COVID-19 therapy.

microbiology↗

bioRxiv2020

Holder Pasteurization Inactivates SARS-CoV-2 in Human Breast Milk

SARS-CoV-2 RNA has been detected in the human breast milk of infected mothers, raising concerns regarding the safety of breastfeeding upon infection. We here show that holder pasteurization inactivates SARS-CoV-2 and provides an alternative and safe option for infected mothers to continue feeding breast milk to their infants.

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↗

bioRxiv2020

The Zinc Finger Antiviral Protein restricts SARS-CoV-2

Recent evidence shows that the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is highly sensitive to interferons (IFNs). However, the underlying antiviral effectors remain to be defined. Here, we show that Zinc finger antiviral protein (ZAP) that specifically targets CpG dinucleotides in viral RNA sequences restricts SARS-CoV-2. We demonstrate that ZAP and its cofactors KHNYN and TRIM25 are expressed in human lung cells. Type I, II and III IFNs all strongly inhibited SARS-CoV-2 and further induced ZAP expression. Strikingly, SARS-CoV-2 and its closest relatives from bats show the strongest CpG suppression among all known human and bat coronaviruses, respectively. Nevertheless, knock-down of ZAP significantly increased SARS-CoV-2 production in lung cells, particularly upon treatment with IFN- or IFN-{gamma}. Thus, our results identify ZAP as an effector of the IFN response against SARS-CoV-2, although this pandemic pathogen may be preadapted to the low CpG environment in humans. HighlightsO_LISARS-CoV-2 and its closest bat relatives show strong CpG suppression C_LIO_LIIFN-{beta}, -{gamma} and -{lambda} inhibit SARS-CoV-2 with high efficiency C_LIO_LIZAP restricts SARS-CoV-2 and contributes to the antiviral effect of IFNs C_LI

microbiology↗