Biology subjects

Szczepanski, A.

Publications and source records attributed to Szczepanski, A..

6 recordsLinked to original sources

bioRxiv2026

A 10-year longitudinal study reveals bat-driven SARSr-CoV evolution

Bats are recognized reservoirs for several zoonoses and have an exceptional tolerance to viruses, likely linked with strong evolutionary selection in immune genes. Notably, in light of the emergence history of severe acute respiratory syndrome coronavirus (SARS-CoV), SARS-CoV-2 is hypothesized to have originated from Rhinolophus bats as well. In-depth studies are still needed, however, to unravel how SARS-related coronaviruses (SARSr-CoVs) persist and thrive in nature through evolution, virus-host interactions, and cross-species transmission. Here we present a pioneering 10-year longitudinal study of BBCoV-EPI1, a SARSr-CoV in Rhinolophus bats that revealed the complexity of virus-host interactions and the tempo at which new viral lineages emerge. Our results demonstrated the impacts of host life cycles (hibernation, female gathering, weaning juveniles, and mating periods) on strong seasonal oscillations in viral prevalence. These pronounced fluctuations drove viral diversification through bottlenecks, founder effects and Darwinian selection, counterbalanced by high mutation rates, fast gradualism, and recombination. We also found that host-cell enzymes are major contributors to BBCoV-EPI1 evolution in bats. The antiviral effect of APOBEC3 detected here in bats is weaker than it is in humans. Conversely, the ADAR enzyme had an unexpectedly strong and beneficial influence on viral evolution, even though the high mutation rate of RNA viruses is usually attributed to viral polymerases' low replication fidelity. We discovered that key BBCoV-EPI1 innovations in Rhinolophus bats were mostly located in proteins involved in cell-cycle hijack and in blocking bat cells' antiviral response, rather than in the Spike (S). We also showed that the BBCoV-EPI1 S protein efficiently uses angiotensin-converting enzyme 2 (ACE2) receptor to enter Rhinolophus bat cells, but not to enter human or sympatric species cells, due to amino-acid differences at the S-ACE2 interface. Last, this work identifies 101 critical amino-acid changes frequently associated with viral fitness shift, and paves the way for future experimental studies focusing on the capacity of SARSr-CoVs to adapt to hosts and cross the species barrier.

microbiology↗

bioRxiv2022

POU2AF2/C11orf53 functions as a co-activator of POU2F3 by maintaining chromatin accessibility and enhancer activity

Small cell lung cancer (SCLC), accounting for around 13% of all lung cancers, often results in rapid tumor growth, early metastasis, and acquired therapeutic resistance. The POU class 2 homeobox 3 (POU2F3) is a master regulator of tuft cell identity and defines a subtype of SCLC tumors (SCLC-P subtype) that lack the expression of neuroendocrine (NE) markers. Here, we have identified a previously uncharacterized protein, C11orf53, which is co-expressed with POU2F3 in both SCLC cell lines and patient samples, defining the same SCLC-P subtype. C11orf53 is an essential gene for the cell survivability of SCLC-P subtype, based on genome-wide CRISPR screening and genetic depletion of C11orf53 or POU2F3, inducing apoptosis in different SCLC-P subtype cell lines. Furthermore, our biochemical and genome-wide studies have demonstrated that C11orf53 is a novel chromatin-bound protein that occupies broad active enhancer domains and regulates gene expression at active enhancers. Mechanistically, C11orf53 directly interacts with POU2F3 at the POU domain, and is recruited to chromatin by POU2F3. Consequently, depletion of C11orf53 dramatically reduced enhancer H3K27ac levels and chromatin accessibility, resulting in a reduction of the expression of POU2F3-dependent tuft cell markers. Based on the expression pattern and molecular function of C11orf53, we have renamed it as "POU Class 2 Homeobox Associating Factor 2" (POU2AF2). In summary, our study has identified a new co-activator of POU2 family transcription factors, and sheds light on the therapeutic potential of targeting POU2AF2/POU2F3 heterodimer in human SCLC.

cancer biology↗

bioRxiv2021

Efficacy of antiviral drugs against the omicron variant of SARS-CoV-2.

The Omicron variant of the SARS-CoV-2 virus was first detected in South Africa in November 2021. The analysis of the sequence data in the context of earlier variants suggested that it may show very different characteristics, including immune evasion and increased transmission. These assumptions were partially confirmed, and the reduction in protection in convalescent patients and vaccinated individuals have been confirmed. Here, we have evaluated the efficacy of antivirals against SARS-CoV-2 variants, Omicron, Delta, and the early 2020 isolate.

microbiology↗

bioRxiv2021

Acriflavine, a clinically aproved drug, inhibits SARS-CoV-2 and other betacoronaviruses

SO_SCPLOWUMMARYC_SCPLOWThe COVID-19 pandemic caused by SARS-CoV-2 has been socially and economically devastating. Despite an unprecedented research effort, effective therapeutics are still missing to limit severe disease and mortality. Using high-throughput screening, we identified acriflavine as a potent papain-like protease (PLpro) inhibitor. NMR titrations and a co-crystal structure confirm that acriflavine blocks the PLpro catalytic pocket in an unexpected binding mode. We show that the drug inhibits viral replication at nanomolar concentration in cellular models, in vivo in mice and ex vivo in human airway epithelia, with broad range activity against SARS-CoV-2 and other betacoronaviruses. Considering that acriflavine is an inexpensive drug approved in some countries, it may be immediately tested in clinical trials and play an important role during the current pandemic and future outbreaks.

microbiology↗

bioRxiv2020

HTCC as a highly effective polymeric inhibitor of SARS-CoV-2 and MERS-CoV

The beginning of 2020 brought us information about the novel coronavirus emerging in China. Rapid research resulted in the characterization of the pathogen, which appeared to be a member of the SARS-like cluster, commonly seen in bats. Despite the global and local efforts, the virus escaped the healthcare measures and rapidly spread in China and later globally, officially causing a pandemic and global crisis in March 2020. At present, different scenarios are being written to contain the virus, but the development of novel anticoronavirals for all highly pathogenic coronaviruses remains the major challenge. Here, we describe the antiviral activity of previously developed by us HTCC compound (N-(2-hydroxypropyl)-3-trimethylammonium chitosan chloride), which may be used as potential inhibitor of currently circulating highly pathogenic coronaviruses - SARS-CoV-2 and MERS-CoV.

microbiology↗

bioRxiv2020

Replication of SARS-CoV-2 in human respiratory epithelium

SARS-CoV-2 emerged by the end of 2019 to rapidly spread in 2020. At present, it is of utmost importance to understand the virus biology and to rapidly assess the potential of existing drugs and develop new active compounds. While some animal models for such studies are under development, most of the research is carried out in the Vero E6 cells. Here, we propose fully differentiated human airway epithelium cultures as a model for studies on the SARS-CoV-2. Further, we also provide basic characteristics of the system.

microbiology↗