The discovery of novel potent neuraminidase (NA) inhibitors remains an attractive approach for treating infectious diseases caused by influenza. In this study, we describe the design and synthesis of ...novel N-substituted oseltamivir derivatives for probing the 150-cavity which is nascent to the activity site of NA. NA inhibitory studies showed that new derivatives demonstrated the inhibitory activity with IC50 values at nM level against NA of a clinical influenza virus strain. Moreover, the in silico ADME predictions showed that the selected compounds had comparable properties with oseltamivir carboxylate, which demonstrated the druggablity of these derivatives. Furthermore, molecular docking studies showed that the most potent compound 6f and 10i could adopt different modes of binding interaction with NA, which may provide novel solutions for treating oseltamivir-resistant influenza. Based on the research results, we consider that compounds 6f and 10i have the potential for further studies as novel antiviral agents.
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•Hybridization of oseltamivir with heteroaryl groups generated novel anti-influenza agents.•Compound 6f and 10i displayed IC50 values at nM level against neuraminidase of a clinical isolate.•In silico ADME predictions showed that 6f and 10i had comparable properties with oseltamivir.•Molecular docking studies showed 6f and 10i adopted different binding modes with neuraminidase.
Interleukin-38 has recently been shown to have anti-inflammatory properties in lung inflammatory diseases. However, the effects of IL-38 in viral pneumonia remains unknown. In the present study, we ...demonstrate that circulating IL-38 concentrations together with IL-36α increased significantly in influenza and COVID-19 patients, and the level of IL-38 and IL-36α correlated negatively and positively with disease severity and inflammation, respectively. In the co-cultured human respiratory epithelial cells with macrophages to mimic lung microenvironment in vitro, IL-38 was able to alleviate inflammatory responses by inhibiting poly(I:C)-induced overproduction of pro-inflammatory cytokines and chemokines through intracellular STAT1, STAT3, p38 MAPK, ERK1/2, MEK, and NF-κB signaling pathways. Intriguingly, transcriptomic profiling revealed that IL-38 targeted genes were associated with the host innate immune response to virus. We also found that IL-38 counteracts the biological processes induced by IL-36α in the co-culture. Furthermore, the administration of recombinant IL-38 could mitigate poly I:C-induced lung injury, with reduced early accumulation of neutrophils and macrophages in bronchoalveolar lavage fluid, activation of lymphocytes, production of pro-inflammatory cytokines and chemokines and permeability of the alveolar-epithelial barrier. Taken together, our study indicates that IL-38 plays a crucial role in protection from exaggerated pulmonary inflammation during poly(I:C)-induced pneumonia, thereby providing the basis of a novel therapeutic target for respiratory viral infections.
We elucidated the anti-inflammatory mechanisms of IL-38 in allergic asthma. Human bronchial epithelial cells and eosinophils were cocultured upon stimulation with the viral RLR ligand poly ...(I:C)/LyoVec or infection-related cytokine TNF-α to induce expression of cytokines/chemokines/adhesion molecules. House dust mite (HDM)-induced allergic asthma and humanized allergic asthma NOD/SCID murine models were established to assess anti-inflammatory mechanisms in vivo. IL-38 significantly inhibited induced proinflammatory IL-6, IL-1β, CCL5, and CXCL10 production, and antiviral interferon-β and intercellular adhesion molecule-1 expression in the coculture system. Mass cytometry and RNA-sequencing analysis revealed that IL-38 could antagonize the activation of the intracellular STAT1, STAT3, p38 MAPK, ERK1/2, and NF-κB pathways, and upregulate the expression of the host defense-related gene POU2AF1 and anti-allergic response gene RGS13. Intraperitoneal injection of IL-38 into HDM-induced allergic asthma mice could ameliorate airway hyperreactivity by decreasing the accumulation of eosinophils in the lungs and inhibiting the expression of the Th2-related cytokines IL-4, IL-5, and IL-13 in the bronchoalveolar lavage fluid (BALF) and lung homogenates. Histological examination indicated lung inflammation was alleviated by reductions in cell infiltration and goblet cell hyperplasia, together with reduced Th2, Th17, and innate lymphoid type 2 cell numbers but increased proportions of regulatory T cells in the lungs, spleen, and lymph nodes. IL-38 administration suppressed airway hyperreactivity and asthma-related IL-4 and IL-5 expression in humanized mice, together with significantly decreased CCR3
eosinophil numbers in the BALF and lungs, and a reduced percentage of human CD4
CRTH2
Th2 cells in the lungs and mediastinal lymph nodes. Together, our results demonstrated the anti-inflammatory mechanisms of IL-38 and provided a basis for the development of a regulatory cytokine-based treatment for allergic asthma.
The coronavirus disease 2019 (COVID-19) pandemic has posed substantial challenges to the formulation of preventive interventions, particularly since the effects of physical distancing measures and ...upcoming vaccines on reducing susceptible social contacts and eventually halting transmission remain unclear. Here, using anonymized mobile geolocation data in China, we devise a mobility-associated social contact index to quantify the impact of both physical distancing and vaccination measures in a unified way. Building on this index, our epidemiological model reveals that vaccination combined with physical distancing can contain resurgences without relying on stay-at-home restrictions, whereas a gradual vaccination process alone cannot achieve this. Further, for cities with medium population density, vaccination can reduce the duration of physical distancing by 36% to 78%, whereas for cities with high population density, infection numbers can be well-controlled through moderate physical distancing. These findings improve our understanding of the joint effects of vaccination and physical distancing with respect to a city’s population density and social contact patterns.Vaccination combined with physical distancing can suppress resurgences without relying on stay-at-home restrictions. To achieve herd immunity, cities with a higher population density require more stringent physical distancing measures with longer durations.
The threat of a pandemic outbreak of influenza virus A H5N1 has become a major concern worldwide. The nucleoprotein (NP) of the virus binds the RNA genome and acts as a key adaptor between the virus ...and the host cell. It, therefore, plays an important structural and functional role and represents an attractive drug target. Here, we report the 3.3-Å crystal structure of H5N1 NP, which is composed of a head domain, a body domain, and a tail loop. Our structure resolves the important linker segments (residues 397-401, 429-437) that connect the tail loop with the remainder of the molecule and a flexible, basic loop (residues 73-91) located in an arginine-rich groove surrounding Arg150. Using surface plasmon resonance, we found the basic loop and arginine-rich groove, but mostly a protruding element containing Arg174 and Arg175, to be important in RNA binding by NP. We also used our crystal structure to build a ring-shaped assembly of nine NP subunits to model the miniribonucleoprotein particle previously visualized by electron microscopy. Our study of H5N1 NP provides insight into the oligomerization interface and the RNA-binding groove, which are attractive drug targets, and it identifies the epitopes that might be used for universal vaccine development.--Ng, A. K.-L., Zhang, H., Tan, K., Li, Z., Liu, J.-h., Chan, P. K.-S., Li, S.-M., Chan, W.-Y., Au, S. W.-N., Joachimiak, A., Walz, T., Wang, J.-H., Shaw, P.-C. Structure of the influenza virus A H5N1 nucleoprotein: implications for RNA binding, oligomerization, and vaccine design.
Influenza virus continuously evolves to escape human adaptive immunity and generates seasonal epidemics. Therefore, influenza vaccine strains need to be updated annually for the upcoming flu season ...to ensure vaccine effectiveness. We develop a computational approach, beth-1, to forecast virus evolution and select representative virus for influenza vaccine. The method involves modelling site-wise mutation fitness. Informed by virus genome and population sero-positivity, we calibrate transition time of mutations and project the fitness landscape to future time, based on which beth-1 selects the optimal vaccine strain. In season-to-season prediction in historical data for the influenza A pH1N1 and H3N2 viruses, beth-1 demonstrates superior genetic matching compared to existing approaches. In prospective validations, the model shows superior or non-inferior genetic matching and neutralization against circulating virus in mice immunization experiments compared to the current vaccine. The method offers a promising and ready-to-use tool to facilitate vaccine strain selection for the influenza virus through capturing heterogeneous evolutionary dynamics over genome space-time and linking molecular variants to population immune response.
Acute exacerbations of chronic obstructive pulmonary disease (AECOPD) and asthma are associated with a variety of precipitating factors including infection. This study assessed the infective viral ...etiologies by real-time multiplex polymerase chain reaction of patients hospitalized with AECOPD and asthma exacerbations. In addition, infective etiologies were assessed for association with the clinical outcome of the patients.
Adults admitted with AECOPD and asthma exacerbations between August 2016 and July 2017 were recruited. Nasopharyngeal aspirate (NPA) samples were obtained from the patients within 1-2 days of admission and subjected to pathogen detection and human rhinovirus (HRV) typing.
Altogether 402 patients with AECOPD, 80 stable COPD, 100 asthma exacerbation and 21 stable asthma subjects were recruited. Among those admitted for AECOPD and asthma exacerbations, 141(35.1%) and 45(45.0%) respectively had pathogens identified in the NPA specimens. The commonest virus identified was influenza A followed by HRV. HRV typing identified HRV-A and HRV-C as the more common HRV with a wide variety of genotypes. Identification of pathogens in NPA or HRV typing otherwise did not affect clinical outcomes including the hospital length of stay, readmission rates and mortality except that identification of pathogens in asthma exacerbation was associated with a lower rate of readmissions at 30 and 60 days.
Many respiratory viruses were associated with AECOPD and asthma exacerbation. HRV-A and HRV-C were the more common HRV associated with exacerbations. Identification of pathogens in NPA was associated with less readmissions for asthma patients at 30 and 60 days.
ClinicalTrials.gov NCT02866357 .
Background: Cervical cancer is one of the most common cancers in women and about 90% of cervical cancer can be reduced by regular screening. The Pap smear has been well in place as a primary cervical ...screening method since 1950s; however, coverage is still not optimal. This study explored the feasibility of HPV self-sampling in two under-screened population groups in Hong Kong (HK): never screened and not regularly screened females, to estimate the uptake rate and preference rate in the future. Materials and Methods: This was a cross-sectional study to explore the acceptability and feasibility of HPV self-sampling in two age groups: aged 25–35 and aged ≥45, which were reported as the highest proportion of the under-screened population in HK between 2017 and 2018. The study invited eligible women from an HPV study cohort to perform HPV self-sampling at home by themselves. The number of specimens returned from participants was recorded and used to determine the feasibility of HPV self-sampling in the community. The participants were asked to fill in the questionnaires before and after HPV self-sampling to indicate their attitudes, acceptability, and future preference for HPV self-sampling as an acceptable alternative primary cervical cancer screening method. Results: A total of 177 subjects participated in the present study and have achieved a good overall uptake rate of 73% (129/177) who returned the self-collected cervicovaginal sample for HPV testing. Among the under-screened population, there was a higher response rate in aged ≥45 than those aged 25–35. The findings also revealed that women who were under-screened, including those who have never been screened, were more likely to prefer HPV self-sampling than those who had regular screening. This study found that the acceptability of HPV self-sampling was fairly positive among the respondents. The findings also indicated that HPV self-sampling was not only beneficial to enhance their health awareness but also to promote the cervical cancer screening uptake rate, especially among the under-screened or never screened populations. Conclusions: HPV self-sampling would be a solution to overcome the perceived barriers in clinician-based screening. The findings also indicated that it could be feasible to use as an alternative primary cervical cancer screening.
Adjuvanted herpes zoster (HZ) subunit (HZ/su) vaccine is recommended for healthy adults aged ≥50 years, yet vaccine efficacy is expected to wane over time. Age-sex specific cost-effectiveness ...analyses of HZ/su vaccine are warranted to inform decision-making on vaccine policy. We aimed to determine the optimal gender-specific age for cost-effective HZ/su vaccination in Hong Kong.
A Markov model was used to compare outcomes with and without HZ/su in healthy males and females at age 50-80 years. Model outcome measures were total cost, HZ cases, and HZ-associated quality-adjusted life-years (QALYs) loss. Incremental cost per QALY saved (ICER) by HZ/su was estimated for each age-sex group. Sensitivity analyses were performed to examine robustness of model results.
HZ/su reduced incidence of HZ in both males and females aged 50-80 years and the numbers needed to vaccinate to avoid one HZ case were lowest at age 60 years for males (6.05) and females (5.50). The highest QALY-saved occurred in females (0.00396 QALYs) and males (0.00379 QALYs) who were vaccinated at 60 years old. The ICERs were lowest at age 60-70 years for both genders. Using 1× gross domestic product per capita of Hong Kong (USD46,153) as willingness-to-pay threshold, HZ/su vaccine was accepted to be cost-effective for all female and male age groups at vaccine cost = USD160, for female aged 50-79 years and male aged 54-74 years at vaccine cost = USD200, and for female aged 59-71 years at vaccine cost = USD240.
HZ/su vaccine is more likely to be cost-effective for males and females aged between 60-70 years than the extreme age groups (less than 60 years and older than 70 years) in Hong Kong. The age range for cost-effective acceptance of HZ/su vaccine appears to be broader in females than males given the same vaccine cost and willingness-to-pay threshold.
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