Antifungal Activity and Potential Action Mechanism of Allicin against Trichosporon asahii.

Trichosporon asahii is an emerging opportunistic pathogen that causes potentially fatal disseminated trichosporonosis. The global prevalence of coronavirus disease 2019 (COVID-19) poses an increasing fungal infection burden caused by T. asahii. Allicin is the main biologically active component with broad-spectrum antimicrobial activity in garlic. In this study, we performed an in-depth analysis of the antifungal characteristics of allicin against T. asahii based on physiological, cytological, and transcriptomic assessments. In vitro, allicin inhibited the growth of T. asahii planktonic cells and biofilm cells significantly. In vivo, allicin improved the mean survival time of mice with systemic trichosporonosis and reduced tissue fungal burden. Electron microscopy observations clearly demonstrated damage to T. asahii cell morphology and ultrastructure caused by allicin. Furthermore, allicin increased intracellular reactive oxygen species (ROS) accumulation, leading to oxidative stress damage in T. asahii cells. Transcriptome analysis showed that allicin treatment disturbed the biosynthesis of cell membrane and cell wall, glucose catabolism, and oxidative stress. The overexpression of multiple antioxidant enzymes and transporters may also place an additional burden on cells, causing them to collapse. Our findings shed new light on the potential of allicin as an alternative treatment strategy for trichosporonosis. IMPORTANCE Systemic infection caused by T. asahii has recently been recognized as an important cause of mortality in hospitalized COVID-19 patients. Invasive trichosporonosis remains a significant challenge for clinicians, due to the limited therapeutic options. The present work suggests that allicin holds great potential as a therapeutic candidate for T. asahii infection. Allicin demonstrated potent in vitro antifungal activity and potential in vivo protective effects. In addition, transcriptome sequencing provided valuable insights into the antifungal effects of allicin.

Evaluation of the Mucosal Immunity Effect of Bovine Viral Diarrhea Virus Subunit Vaccine E2Fc and E2Ft.

Classified as a class B infectious disease by the World Organization for Animal Health (OIE), bovine viral diarrhea/mucosal disease is an acute, highly contagious disease caused by the bovine viral diarrhea virus (BVDV). Sporadic endemics of BVDV often lead to huge economic losses to the dairy and beef industries. To shed light on the prevention and control of BVDV, we developed two novel subunit vaccines by expressing bovine viral diarrhea virus E2 fusion recombinant proteins (E2Fc and E2Ft) through suspended HEK293 cells. We also evaluated the immune effects of the vaccines. The results showed that both subunit vaccines induced an intense mucosal immune response in calves. Mechanistically, E2Fc bonded to the Fc γ receptor (FcγRI) on antigen-presenting cells (APCs) and promoted IgA secretion, leading to a stronger T-cell immune response (Th1 type). The neutralizing antibody titer stimulated by the mucosal-immunized E2Fc subunit vaccine reached 1:64, which was higher than that of the E2Ft subunit vaccine and that of the intramuscular inactivated vaccine. The two novel subunit vaccines for mucosal immunity developed in this study, E2Fc and E2Ft, can be further used as new strategies to control BVDV by enhancing cellular and humoral immunity.

High-throughput screening of SARS-CoV-2 main and papain-like protease inhibitors.

The global COVID-19 coronavirus pandemic has infected over 109 million people, leading to over 2 million deaths up to date and still lacking of effective drugs for patient treatment. Here, we screened about 1.8 million small molecules against the main protease (Mpro) and papain like protease (PLpro), two major proteases in severe acute respiratory syndrome-coronavirus 2 genome, and identified 1851Mpro inhibitors and 205 PLpro inhibitors with low nmol/l activity of the best hits. Among these inhibitors, eight small molecules showed dual inhibition effects on both Mpro and PLpro, exhibiting potential as better candidates for COVID-19 treatment. The best inhibitors of each protease were tested in antiviral assay, with over 40% of Mpro inhibitors and over 20% of PLpro inhibitors showing high potency in viral inhibition with low cytotoxicity. The X-ray crystal structure of SARS-CoV-2 Mpro in complex with its potent inhibitor 4a was determined at 1.8 Å resolution. Together with docking assays, our results provide a comprehensive resource for future research on anti-SARS-CoV-2 drug development.

SARS-CoV-2 infection-induced immunity reduces rates of reinfection and hospitalization caused by the Delta or Omicron variants.

During a pandemic, effective vaccines are typically in short supply, particularly at onset intervals when the wave is accelerating. We conducted an observational, retrospective analysis of aggregated data from all patients who tested positive for SARS-CoV-2 during the waves caused by the Delta and Omicron variants, stratified based on their known previous infection and vaccination status, throughout the University of Texas Medical Branch (UTMB) network. Next, the immunity statuses within each medical parameter were compared to naïve individuals for the effective decrease of occurrence. Lastly, we conducted studies using mice and pre-pandemic human samples for IgG responses to viral nucleocapsid compared to spike protein toward showing a functional component supportive of the medical data results in relation to the immunity types. During the Delta and Omicron waves, both infection-induced and hybrid immunities were associated with a trend of equal or greater decrease of occurrence than vaccine-induced immunity in hospitalizations, intensive care unit admissions, and deaths in comparison to those without pre-existing immunity, with hybrid immunity often trending with the greatest decrease. Compared to individuals without pre-existing immunity, those vaccinated against SARS-CoV-2 had a significantly reduced incidence of COVID-19, as well as all subsequent medical parameters. Though vaccination best reduces health risks associated with initial infection toward acquiring immunity, our findings suggest infection-induced immunity is as or more effective than vaccination in reducing the severity of reinfection from the Delta or Omicron variants, which should inform public health response at pandemic onset, particularly when triaging towards the allotment of in-demand vaccinations.

The Pharmacological Mechanism of Xiyanping Injection for the Treatment of Novel Coronavirus Pneumonia (COVID-19): Based on Network Pharmacology Strategy.

Purpose: The possible mechanism of Xiyanping injection treatment COVID-19 is discussed through the network pharmacology. Methods: Obtaining the chemical structure of Xiyanping injection through the patent application and obtaining control compounds I, II, III, IV, V, Yanhuning injection (VI, VII), Chuanhuning injection (VIII, IX), 10 compounds were analyzed by D3Targets-2019-nCoV. The human anti-COVID-19 gene in COVID-19 DisGeNET was intersected with the CTD Andrographolide target gene and then combined with D3Targets-2019-nCoV, resulting in 93 genes, using the Venny 2.1 platform. The PPI network was constructed by the String platform and Cytoscape 3.8.2 platform. The GO, KEGG, and tissue of the target were analyzed using the Metascape platform and DAVID platform. The gene expression in the respiratory system was analyzed using the ePlant platform. The CB-Dock is used for the docking verification and degree values of the first 20 genes. Results: Finally, 1599 GO and 291 KEGG results were obtained. GO is mostly associated with the cell stress response to chemicals, the cell response to oxidative stress, and the cell response to reactive oxygen species. In total, 218 KEGG pathway concentrations were related to infection and other diseases and 73 signaling pathways mostly related to inflammation and immune pathways, such as TNF signaling pathway and MAPK signaling pathway. The molecular docking results show that Xiyanping injection, compound III, has a good docking relationship with 20 target proteins such as HSP90AA1. Tissue has 22 genes that are pooled in the lungs. Conclusion: Xiyanping injection may inhibit the release of various inflammatory factors by inhibiting intracellular pathways such as MAPK and TNF. It acts on protein targets such as HSP90AA1 and plays a potential therapeutic role in COVID-19. Thus, compound III may be treated as a potential new drug for the treatment of COVID-19 and the Xiyanping injection may treat patients with COVID-19 infection.

Application of animal models to compare and contrast the virulence of current and future potential SARS-CoV-2 variants.

Since severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was first identified during late 2019, the sustained spread of this pathogen within the human population has caused worldwide disruption with staggering infection rates and death tolls. Due to the accumulation of mutations in SARS-CoV-2, the virus has evolved into many variants, five of which have been listed as variants of concern VOCs by the World Health Organization (WHO). Multiple animal models of SARS-CoV-2 have been developed to evaluate vaccines and drugs and to assess the pathogenicity, transmissibility and antiviral measures of these VOCs. Here, we review the cutting-edge research based on mouse, hamster, ferret and non-human primate models for evaluating SARS-CoV-2 with a focus on the Omicron variant, and highlight the importance of updating vaccines in a timely manner in order to mitigate the negative effects of SARS-CoV-2 infections in the human population.

Short-term effects of distance training on peritoneal dialysis-related complications during the transmission control of COVID-19 epidemic in China.

OBJECTIVE: To observe the effects of distance training on patients with continuous ambulatory peritoneal dialysis (CAPD) during the transmission control of the COVID-19 epidemic in China. MATERIALS AND METHODS: CAPD patients from Xijing Hospital received a traditional training before the transmission control of COVID-19 epidemic, while they received a distance training dominated by WeChat and telephone during the transmission control of COVID-19 epidemic in China. Incidence and cure rate of PD-related peritonitis and catheter-related non-infectious complications were compared. All patients were followed up for 30 days from the date of complication. RESULTS: PD-related peritonitis, catheter displacement, and catheter occlusion had no significant difference, and the cure rate of PD-related peritonitis, catheter displacement, and catheter occlusion also had no significant difference in two comparisons despite the cure rate of PD-related peritonitis being slightly higher before (90.9%) than during (80%) the transmission control of COVID-19 epidemic. CONCLUSION: Distance training mode had a similar effect compared to the traditional training mode in the prevention and treatment of PD-related peritonitis and catheter-related non-infectious complications. PRACTICE IMPLICATIONS: Distance training model is an effective training mode that can be implemented in a short time during the epidemic period of serious infectious diseases.

Host AAA+ ATPase TER94 Plays Critical Roles in Building the Baculovirus Viral Replication Factory and Virion Morphogenesis.

TER94 is a multifunctional AAA+ ATPase crucial for diverse cellular processes, especially protein quality control and chromatin dynamics in eukaryotic organisms. Many viruses, including coronavirus, herpesvirus, and retrovirus, coopt host cellular TER94 for optimal viral invasion and replication. Previous proteomics analysis identified the association of TER94 with the budded virions (BVs) of baculovirus, an enveloped insect large DNA virus. Here, the role of TER94 in the prototypic baculovirus Autographa californica multiple nucleopolyhedrovirus (AcMNPV) life cycle was investigated. In virus-infected cells, TER94 accumulated in virogenic stroma (VS) at the early stage of infection and subsequently partially rearranged in the ring zone region. In the virions, TER94 was associated with the nucleocapsids of both BV and occlusion-derived virus (ODV). Inhibition of TER94 ATPase activity significantly reduced viral DNA replication and BV production. Electron/immunoelectron microscopy revealed that inhibition of TER94 resulted in the trapping of nucleocapsids within cytoplasmic vacuoles at the nuclear periphery for BV formation and blockage of ODV envelopment at a premature stage within infected nuclei, which appeared highly consistent with its pivotal function in membrane biogenesis. Further analyses showed that TER94 was recruited to the VS or subnuclear structures through interaction with viral early proteins LEF3 and helicase, whereas inhibition of TER94 activity blocked the proper localization of replication-related viral proteins and morphogenesis of VS, providing an explanation for its role in viral DNA replication. Taken together, these data indicated the crucial functions of TER94 at multiple steps of the baculovirus life cycle, including genome replication, BV formation, and ODV morphogenesis.IMPORTANCE TER94 constitutes an important AAA+ ATPase that associates with diverse cellular processes, including protein quality control, membrane fusion of the Golgi apparatus and endoplasmic reticulum network, nuclear envelope reformation, and DNA replication. To date, little is known regarding the role(s) of TER94 in the baculovirus life cycle. In this study, TER94 was found to play a crucial role in multiple steps of baculovirus infection, including viral DNA replication and BV and ODV formation. Further evidence showed that the membrane fission/fusion function of TER94 is likely to be exploited by baculovirus for virion morphogenesis. Moreover, TER94 could interact with the viral early proteins LEF3 and helicase to transport and further recruit viral replication-related proteins to establish viral replication factories. This study highlights the critical roles of TER94 as an energy-supplying chaperon in the baculovirus life cycle and enriches our knowledge regarding the biological function of this important host factor.

The within-host viral kinetics of SARS-CoV-2.

In this work, we use a within-host viral dynamic model to describe the SARS-CoV-2 kinetics in the host. Chest radiograph score data are used to estimate the parameters of that model. Our result shows that the basic reproductive number of SARS-CoV-2 in host growth is around 3.79. Using the same method we also estimate the basic reproductive number of MERS virus is 8.16 which is higher than SARS-CoV-2. The PRCC method is used to analyze the sensitivities of model parameters. Moreover, the drug effects on virus growth and immunity effect of patients are also implemented to analyze the model.