•Host cell proteases activate the spike protein of the SARS-coronavirus.•Activation is essential for viral infectivity and a potential target for intervention.•Cathepsin L activates the spike protein ...in host cell endosomes.•TMPRSS2 activates the spike protein at the plasma membrane.•SARS- and MERS-coronavirus exploit the same proteases for activation.
The severe acute respiratory syndrome (SARS) pandemic revealed that zoonotic transmission of animal coronaviruses (CoV) to humans poses a significant threat to public health and warrants surveillance and the development of countermeasures. The activity of host cell proteases, which cleave and activate the SARS-CoV spike (S) protein, is essential for viral infectivity and constitutes a target for intervention. However, the identities of the proteases involved have been unclear. Pioneer studies identified cathepsins and type II transmembrane serine proteases as cellular activators of SARS-CoV and demonstrated that several emerging viruses might exploit these enzymes to promote their spread. Here, we will review the proteolytic systems hijacked by SARS-CoV for S protein activation, we will discuss their contribution to viral spread in the host and we will outline antiviral strategies targeting these enzymes. This paper forms part of a series of invited articles in Antiviral Research on “From SARS to MERS: 10years of research on highly pathogenic human coronaviruses.’’
•This study combines the mpox virus detection in wastewater and the number of hospitalizations.•The mpox virus DNA was detected in the wastewater when no mpox cases were reported.•Wastewater-based ...epidemiology can determine the scale of an epidemic.
Wastewater-based epidemiology can determine the scale of a mpox epidemic and thus is a promising additional tool that can complete data gathered by the clinical monitoring approach and predict more accurately the development and progress of the current mpox outbreak.
We collected daily average samples from two wastewater treatment plants (WTPs): Central and Left-Bank, in Poznan, Poland from July to December 2022. The mpox DNA was detected using real-time polymerase chain reaction and compared with the number of hospitalizations.
We detected the mpox DNA in the Central WTP in weeks 29, 43, and 47 and the Left-Bank WTP mostly from mid-September till the end of October. A total of 22 patients with mpox were reported by the public health authority from July to December 2022, with the highest number of hospitalized individuals from mid-July to mid-August. The mpox virus detection does not correlate with the number of hospitalizations in Poznan, Poland.
Our results suggest that the scale of the mpox epidemic is underestimated, and many mpox virus-infected individuals are not identified by the public health authority.
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•Novel ferrocenyl nucleotides were obtained with a CuAAC reaction.•Compounds were investigated by cyclic voltammetry.•Fully deprotected dinucleotide shows better activity against A549 cancer cells ...than cisPt.
The copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) reaction was used as a major tool for the synthesis of the artificial 5ʹ-T-click(Fc)-T-clickʹ(Fc)-A-3ʹtrinucleotide and its dinucleotide congeners. The synthesized nucleotides are redox-active. Their CVs in DMSO show irreversible redox processes, attributed to the Fe2+/Fe3+ oxidation–reduction of the ferrocenyl unit and the oxidation–reduction processes associated with the follow-up reaction products with the solvent. One of obtained dinucleotides was more active than cisplatin against lung cancer A549 cells. It also showed less toxic effect in non-tumoral human HEK293T cells than cisplatin drug.
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Influenza A viruses (IAV) are commonly used to infect animal cell cultures for research purposes and vaccine production. Their replication is influenced strongly by the multiplicity of infection ...(MOI), which ranges over several orders of magnitude depending on the respective application. So far, mathematical models of IAV replication have paid little attention to the impact of the MOI on infection dynamics and virus yields. To address this issue, we extended an existing model of IAV replication in adherent MDCK cells with kinetics that explicitly consider the time point of cell infection. This modification does not only enable the fitting of high MOI measurements, but also the successful prediction of viral release dynamics of low MOI experiments using the same set of parameters. Furthermore, this model allows the investigation of defective interfering particle (DIP) propagation in different MOI regimes. The key difference between high and low MOI conditions is the percentage of infectious virions among the total virus particle release. Simulation studies show that DIP interference at a high MOI is determined exclusively by the DIP content of the seed virus while, in low MOI conditions, it is predominantly controlled by the de novo generation of DIPs. Overall, the extended model provides an ideal framework for the prediction and optimization of cell culture-derived IAV manufacturing and the production of DIPs for therapeutic use.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The influenza virus hemagglutinin (HA) facilitates viral entry into target cells. Cleavage of HA by host cell proteases is essential for viral infectivity, and the responsible enzymes are potential ...targets for antiviral intervention. The type II transmembrane serine protease (TTSP) TMPRSS2 has been identified as an HA activator in cell culture and in the infected host. However, it is less clear whether TMPRSS2-related enzymes can also activate HA for spread in target cells. Moreover, the activity of cellular serine protease inhibitors against HA-activating TTSPs is poorly understood. Here, we show that TMPRSS11A, another member of the TTSP family, cleaves and activates the influenza A virus (FLUAV) HA and the Middle East respiratory syndrome coronavirus spike protein (MERS-S). Moreover, we demonstrate that TMPRSS11A is expressed in murine tracheal epithelium, which is a target of FLUAV infection, and in human trachea, suggesting that the protease could support FLUAV spread in patients. Finally, we show that HA activation by the TMPRSS11A-related enzymes human airway tryptase and DESC1, but not TMPRSS11A itself, is blocked by the cellular serine protease inhibitor hepatocyte growth factor activator inhibitor type-1 (HAI-1). Our results suggest that TMPRSS11A could promote FLUAV spread in target cells and that HA-activating TTSPs exhibit differential sensitivity to blockade by cellular serine protease inhibitors.
During the COVID-19 pandemic, several vaccines were developed to limit the spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, due to SARS-CoV-2 mutations and uneven ...vaccination coverage among populations, a series of COVID-19 waves have been caused by different variants of concern (VOCs). Despite the updated vaccine formulations for the new VOC, the benefits of additional COVID-19 vaccine doses have raised many doubts, even among high-risk groups such as healthcare workers (HCWs). We examined the factors underlying hesitancy to receive COVID-19 booster vaccine doses and analysed the anti-SARS-CoV-2 IgG antibody response after booster vaccination among HCWs. Our study found that 42% of the HCWs were hesitant about the second booster dose, while 7% reported no intent to get vaccinated with any additional doses. As reasons for not vaccinating, participants most frequently highlighted lack of time, negative experiences with previous vaccinations, and immunity conferred by past infections. In addition, we found the lowest post-vaccination antibody titres among HCWs who did not receive any vaccine booster dose and the highest among HCWs vaccinated with two booster doses.
The cellular protease TMPRSS2 cleaves and activates the influenza virus hemagglutinin (HA) and TMPRSS2 expression is essential for viral spread and pathogenesis in mice. Moreover, severe acute ...respiratory syndrome coronavirus (SARS-CoV) and other respiratory viruses are activated by TMPRSS2. However, previous studies on viral activation by TMPRSS2 focused on a 492 amino acids comprising form of the protein (isoform 2) while other TMPRSS2 isoforms, generated upon alternative splicing of the tmprss2 mRNA, have not been characterized. Here, we show that the mRNA encoding a TMPRSS2 isoform with an extended N-terminal cytoplasmic domain (isoform 1) is expressed in lung-derived cell lines and tissues. Moreover, we demonstrate that TMPRSS2 isoform 1 colocalizes with HA and cleaves and activates HA. Finally, we show that isoform 1 activates the SARS-CoV spike protein for cathepsin L-independent entry into target cells. Our results indicate that TMPRSS2 isoform 1 is expressed in viral target cells and might contribute to viral activation in the host.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Alveolar echinococcosis (AE) is a chronic zoonotic disease caused by the larval form of
. In humans, it may become a serious chronic infection of the liver which resembles a slow malignant process ...leading to death when untreated. The aim of the study was an assessment of the risk factors of the
infections and the description of AE clinical course in the group of 36 patients with confirmed AE, hospitalized at the Department and Clinic of Tropical and Parasitic Diseases, Poznan University of Medical Sciences between 2013 and 2022. Among the study participants, most patients cultivated land, bred livestock, worked in the forest, or were employed in animal shelters. The
infection was diagnosed based on imaging and immunoassay techniques within 6 months in the majority of patients hospitalized in the Department. All patients hospitalized in the Department initiated anti-parasitic therapy at the moment of the diagnosis. Pharmacological treatment combined with surgery was applied in most of the study participants, who were presented with more advanced stages of infection. We conclude the following: 1. For humans in the risk group, regular abdominal imaging examinations and the detection of specific antibodies against
are recommended. 2. Regular screening tests in the hyperendemic areas of AE would increase the early detection of the disease and to improve the clinical prognosis in this extremely life-threatening parasitic disease.
The type II transmembrane serine protease (TTSP) TMPRSS2 cleaves and activates the influenza virus and coronavirus surface proteins. Expression of TMPRSS2 is essential for the spread and pathogenesis ...of H1N1 influenza viruses in mice. In contrast, H3N2 viruses are less dependent on TMPRSS2 for viral amplification, suggesting that these viruses might employ other TTSPs for their activation. Here, we analyzed TTSPs, reported to be expressed in the respiratory system, for the ability to activate influenza viruses and coronaviruses. We found that MSPL and, to a lesser degree, DESC1 are expressed in human lung tissue and cleave and activate the spike proteins of the Middle East respiratory syndrome and severe acute respiratory syndrome coronaviruses for cell-cell and virus-cell fusion. In addition, we show that these proteases support the spread of all influenza virus subtypes previously pandemic in humans. In sum, we identified two host cell proteases that could promote the amplification of influenza viruses and emerging coronaviruses in humans and might constitute targets for antiviral intervention. Importance: Activation of influenza viruses by host cell proteases is essential for viral infectivity and the enzymes responsible are potential targets for antiviral intervention. The present study demonstrates that two cellular serine proteases, DESC1 and MSPL, activate influenza viruses and emerging coronaviruses in cell culture and, because of their expression in human lung tissue, might promote viral spread in the infected host. Antiviral strategies aiming to prevent viral activation might thus need to encompass inhibitors targeting MSPL and DESC1.
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