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The Journal of Biological Chemistry Jun 2024The development of safe and effective broad-spectrum antivirals that target the replication machinery of respiratory viruses is of high priority in pandemic preparedness...
The development of safe and effective broad-spectrum antivirals that target the replication machinery of respiratory viruses is of high priority in pandemic preparedness programs. Here, we studied the mechanism of action of a newly discovered nucleotide analog against diverse RNA-dependent RNA polymerases (RdRp) of prototypic respiratory viruses. GS-646939 is the active 5'-triphosphate (TP) metabolite of a 4'-cyano modified C-adenosine analog phosphoramidate prodrug GS-7682. Enzyme kinetics show that the RdRps of human rhinovirus type 16 (HRV-16) and enterovirus 71 (EV-71) incorporate GS-646939 with unprecedented selectivity; GS-646939 is incorporated 20-50-fold more efficiently than its natural ATP counterpart. The RdRp complex of respiratory syncytial virus (RSV) and human metapneumovirus (HMPV) incorporate GS-646939 and ATP with similar efficiency. In contrast, influenza B RdRp shows a clear preference for ATP and human mitochondrial RNA polymerase (h-mtRNAP) does not show significant incorporation of GS-646939. Once incorporated into the nascent RNA strand, GS-646939 acts as a chain-terminator although higher NTP concentrations can partially overcome inhibition for some polymerases. Modeling and biochemical data suggest that the 4'-modification inhibits RdRp translocation. Comparative studies with GS-443902, the active triphosphate form of the 1'-cyano modified prodrugs remdesivir and obeldesivir, reveal not only different mechanisms of inhibition, but also differences in the spectrum of inhibition of viral polymerases. In conclusion, 1'-cyano and 4'-cyano modifications of nucleotide analogs provide complementary strategies to target the polymerase of several families of respiratory RNA viruses.
PubMed: 38945449
DOI: 10.1016/j.jbc.2024.107514 -
Journal of Gastrointestinal and Liver... Jun 2024During the coronavirus disease 2019 (COVID-19) pandemic a significant proportion of patients with severe acute respiratory distress syndrome (ARDS) due to COVID-19...
BACKGROUND AND AIMS
During the coronavirus disease 2019 (COVID-19) pandemic a significant proportion of patients with severe acute respiratory distress syndrome (ARDS) due to COVID-19 infection developed secondary sclerosing cholangitis (SSC) as a hepatobiliary complication.
METHODS
17 patients were endoscopically diagnosed and treated with COVID-19 SSC from February 2020 until October 2022 at our center. We retrospectively reviewed and analyzed the data to define risk factors, establish endoscopic treatment options, and to estimate incidence and outcomes.
RESULTS
258 patients with COVID-19 infection were admitted to our tertiary center and mechanically ventilated. 10 patients developed COVID-19 SSC in-house, and 7 patients were transferred for further endoscopic treatment. All 17 patients were mechanically ventilated, received vasoactive substances and 12 of them were treated with extracorporeal membrane oxygenation therapy. Endoscopic retrograde cholangiography (ERC) was performed in all patients to establish the diagnosis of COVID-19 SSC and evaluate endoscopic treatment options. All ERCs revealed biliary casts. 9 patients had developed severe rarefication of the intrahepatic bile ducts and 4 showed biliary strictures. As endoscopic treatment approaches, casts were removed repeatedly, and strictures were dilated. During the study period, 14 patients died (82%). 3 patients are in follow-up to reassess the need for liver transplantation.
CONCLUSIONS
COVID-19 SSC was observed in 2.6 % of the patients with severe COVID-19 in our center. We show that endoscopic approaches offer the opportunity to extract casts and to treat biliary strictures. As the mortality rate of COVID-19 SSC is high, endoscopic treatment can be of great clinical relevance as a bridge to liver transplantation.
Topics: Humans; COVID-19; Male; Female; Cholangitis, Sclerosing; Middle Aged; Retrospective Studies; Cholangiopancreatography, Endoscopic Retrograde; Tertiary Care Centers; Aged; SARS-CoV-2; Adult; Treatment Outcome; Risk Factors; Liver Transplantation
PubMed: 38944874
DOI: 10.15403/jgld-5476 -
Journal of Gastrointestinal and Liver... Jun 2024
Topics: Humans; Mucormycosis; COVID-19; Melena; SARS-CoV-2; Male; Antifungal Agents; Middle Aged
PubMed: 38944868
DOI: 10.15403/jgld-5302 -
Journal of Gastrointestinal and Liver... Jun 2024
Topics: Humans; COVID-19; COVID-19 Vaccines; SARS-CoV-2; Vaccination; Liver Diseases; Chronic Disease
PubMed: 38944866
DOI: 10.15403/jgld-5619 -
Journal of Gastrointestinal and Liver... Jun 2024
Topics: Humans; Antiviral Agents; Hepatitis D; Hepatitis Delta Virus
PubMed: 38944856
DOI: 10.15403/jgld-5627 -
Nature Communications Jun 2024Evolution of SARS-CoV-2 alters the antigenicity of the immunodominant spike (S) receptor-binding domain and N-terminal domain, undermining the efficacy of vaccines and...
Evolution of SARS-CoV-2 alters the antigenicity of the immunodominant spike (S) receptor-binding domain and N-terminal domain, undermining the efficacy of vaccines and antibody therapies. To overcome this challenge, we set out to develop a vaccine focusing antibody responses on the highly conserved but metastable S subunit, which folds as a spring-loaded fusion machinery. We describe a strategy for prefusion-stabilization and high yield recombinant production of SARS-CoV-2 S trimers with native structure and antigenicity. We demonstrate that our design strategy is broadly generalizable to sarbecoviruses, as exemplified with the SARS-CoV-1 (clade 1a) and PRD-0038 (clade 3) S subunits. Immunization of mice with a prefusion-stabilized SARS-CoV-2 S trimer elicits broadly reactive sarbecovirus antibodies and neutralizing antibody titers of comparable magnitude against Wuhan-Hu-1 and the immune evasive XBB.1.5 variant. Vaccinated mice were protected from weight loss and disease upon challenge with XBB.1.5, providing proof-of-principle for fusion machinery sarbecovirus vaccines.
Topics: Animals; Mice; Antibodies, Neutralizing; Antibodies, Viral; Spike Glycoprotein, Coronavirus; SARS-CoV-2; Humans; COVID-19; Female; COVID-19 Vaccines; Mice, Inbred BALB C
PubMed: 38944664
DOI: 10.1038/s41467-024-49656-5 -
Nature Communications Jun 2024The widespread administration of COVID-19 vaccines has prompted a need to understand their safety profile. This investigation focuses on the safety of inactivated and...
The widespread administration of COVID-19 vaccines has prompted a need to understand their safety profile. This investigation focuses on the safety of inactivated and mRNA-based COVID-19 vaccines, particularly concerning potential cardiovascular and haematological adverse events. A retrospective cohort study was conducted for 1.3 million individuals residing in Abu Dhabi, United Arab Emirates, who received 1.8 million doses of the inactivated BBIBP CorV (by SinoPharm) and mRNA-based BNT162b2 (Pfizer-BioNTech) vaccines between June 1, 2021, and June 30, 2022. The study's primary outcome was to assess the occurrence of selected cardiovascular and haematological events leading to hospitalization or emergency room visits within 21 days post-vaccination. Results showed no significant increase in the incidence rates of these events compared to the subsequent 22 to 42 days following vaccination. Analysis revealed no elevated risk for adverse outcomes following first (IRR 1·03; 95% CI 0·82-1·31), second (IRR 0·92; 95% CI 0·72-1·16) and third (IRR 0·82; 95% CI 0·66-1·00) doses of either vaccine. This study found no substantial link between receiving either mRNA and inactivated COVID-19 vaccines and a higher likelihood of cardiovascular or haematological events within 21 days after vaccination.
Topics: Humans; Retrospective Studies; United Arab Emirates; Male; Female; COVID-19 Vaccines; Middle Aged; Adult; COVID-19; Cardiovascular Diseases; BNT162 Vaccine; Vaccines, Inactivated; SARS-CoV-2; Vaccination; Aged; Young Adult; Hematologic Diseases; Adolescent
PubMed: 38944652
DOI: 10.1038/s41467-024-49744-6 -
International Journal of Infectious... Jun 2024In Japan, influenza activity was low throughout the COVID-19 pandemic until the 2022-23 season, when the first influenza outbreak occurred since the 2020-21 season. In...
In Japan, influenza activity was low throughout the COVID-19 pandemic until the 2022-23 season, when the first influenza outbreak occurred since the 2020-21 season. In our influenza surveillance during the COVID-19 pandemic, co-infection with SARS-CoV-2 and influenza virus had not been detected; however, in January 2024, we identified three pediatric outpatients co-infected with these viruses: one with SARS-CoV-2 Omicron EG.5 sublineage HK.3 and influenza A(H3N2) and two with SARS-CoV-2 Omicron BA.2.86 sublineage JN.1.5 and influenza A(H1N1)pdm09. We evaluated the susceptibility of SARS-CoV-2 against RNA-dependent RNA polymerase inhibitors (remdesivir and molnupiravir) and 3C-like protease inhibitors (nirmatrelvir and ensitrelvir), and that of influenza viruses against neuraminidase inhibitors (oseltamivir, peramivir, zanamivir, and laninamivir) and the cap-dependent endonuclease inhibitor baloxavir. All viruses tested were susceptible to these antiviral drugs and did not possess amino acid substitutions associated with reduced antiviral susceptibility. The patients were treated with anti-influenza drugs and did not develop severe symptoms despite the co-infection. Since SARS-CoV-2 and influenza viruses continue to evolve, continuous monitoring of their circulation remains essential to assess public health measures and support clinical management.
PubMed: 38944411
DOI: 10.1016/j.ijid.2024.107134 -
The Journal of Biological Chemistry Jun 2024Z-nucleic acid structures play vital roles in cellular processes and have implications in innate immunity due to their recognition by Zα domains containing proteins...
Z-nucleic acid structures play vital roles in cellular processes and have implications in innate immunity due to their recognition by Zα domains containing proteins (Z-DNA/Z-RNA binding proteins, ZBPs). Although Zα domains have been identified in six proteins, including viral E3L, ORF112, and I73R, as well as, cellular ADAR1, ZBP1, and PKZ, their prevalence across living organisms remains largely unexplored. In this study, we introduce a computational approach to predict Zα domains, leading to the revelation of previously unidentified Zα domain-containing proteins in eukaryotic organisms, including non-metazoan species. Our findings encompass the discovery of new ZBPs in previously unexplored giant viruses, members of the Nucleocytoviricota phylum. Through experimental validation, we confirm the Zα functionality of select proteins, establishing their capability to induce the B-to-Z conversion. Additionally, we identify Zα-like domains within bacterial proteins. While these domains share certain features with Zα domains, they lack the ability to bind to Z-nucleic acids or facilitate the B-to-Z DNA conversion. Our findings significantly expand the ZBP family across a wide spectrum of organisms and raise intriguing questions about the evolutionary origins of Zα-containing proteins. Moreover, our study offers fresh perspectives on the functional significance of Zα domains in virus sensing and innate immunity and opens avenues for exploring hitherto undiscovered functions of ZBPs.
PubMed: 38944123
DOI: 10.1016/j.jbc.2024.107504 -
BMC Public Health Jun 2024There are limited population-representative data that describe the potential burden of Post-COVID conditions (PCC) in Mexico. We estimated the prevalence of PCC overall...
BACKGROUND
There are limited population-representative data that describe the potential burden of Post-COVID conditions (PCC) in Mexico. We estimated the prevalence of PCC overall and by sociodemographic characteristics among a representative sample of adults previously diagnosed with COVID-19 in Mexico. We additionally, characterized the PCC symptoms, and estimated the association between diagnosed type-2 diabetes and hypertension with PCC.
METHODS
We used data from the 2021 National Health and Nutrition Survey in Mexico, a nationally and regionally representative survey, from August 1st to October 31st, 2021. Using the WHO definition, we estimated the prevalence of PCC by sociodemographics and prevalence of PCC symptoms. We fit multivariable log-binomial regression models to estimate the associations.
RESULTS
The prevalence of PCC was 37.0%. The most common persistent symptoms were fatigue (56.8%), myalgia or arthralgia (47.5%), respiratory distress and dyspnea (42.7%), headache (34.0%), and cough (25.7%). The prevalence was higher in older people, women, and individuals with low socioeconomic status. There was no significant association between hypertension and PCC or diabetes and PCC prevalence.
CONCLUSIONS
About one-third of the adult Mexican population who had COVID-19 in 2021 had Post-COVID conditions. Our population-based estimates can help assess potential priorities for PCC-related health services, which is critical in light of our weak health system and limited funding.
Topics: Humans; COVID-19; Mexico; Male; Female; Cross-Sectional Studies; Middle Aged; Adult; Prevalence; Aged; Survivors; Young Adult; Hypertension; Adolescent; Diabetes Mellitus, Type 2; Sociodemographic Factors; SARS-CoV-2
PubMed: 38943168
DOI: 10.1186/s12889-024-19274-3