Pediatric Respiratory Viral Infection.

Reflecting on this Special Issue dedicated to pediatric respiratory viruses, it is evident that the shadow cast by the global SARS-CoV-2 pandemic has profoundly impacted individuals of all ages and backgrounds, neonates and school-aged children being vulnerable cohorts resulting from the evolving immunological profiles and limited exposures to immunity-building experienced during this unprecedented era [...].

Predictive evolutionary modelling for influenza virus by site-based dynamics of mutations.

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.

Quantitative and qualitative subgenomic RNA profiles of SARS-CoV-2 in respiratory samples: A comparison between Omicron BA.2 and non-VOC-D614G.

The SARS-CoV-2 Omicron variants are notorious for their transmissibility, but little is known about their subgenomic RNA (sgRNA) expression. This study applied RNA-seq to delineate the quantitative and qualitative profiles of canonical sgRNA of 118 respiratory samples collected from patients infected with Omicron BA.2 and compared with 338 patients infected with non-variant of concern (non-VOC)-D614G. A unique characteristic profile depicted by the relative abundance of 9 canonical sgRNAs was reproduced by both BA.2 and non-VOC-D614G regardless of host gender, age and presence of pneumonia. Remarkably, such profile was lost in samples with low viral load, suggesting a potential application of sgRNA pattern to indicate viral activity of individual patient at a specific time point. A characteristic qualitative profile of canonical sgRNAs was also reproduced by both BA.2 and non-VOC-D614G. The presence of a full set of canonical sgRNAs carried a coherent correlation with crude viral load (AUC â€‹= â€‹0.91, 95% CI 0.88-0.94), and sgRNA ORF7b was identified to be the best surrogate marker allowing feasible routine application in characterizing the infection status of individual patient. Further potentials in using sgRNA as a target for vaccine and antiviral development are worth pursuing.

Design and Synthesis of Bicyclo[4.3.0]nonene Nucleoside Analogues.

Nucleoside analogues are effective antiviral agents, and the continuous emergence of pathogenic viruses demands the development of novel and structurally diverse analogues. Here, we present the design and synthesis of novel nucleoside analogues with a carbobicyclic core, which mimics the conformation of natural ribonucleosides. Employing a divergent synthetic route featuring an intermolecular Diels-Alder reaction, we successfully synthesized carbobicyclic nucleoside analogues with high antiviral efficacy against respiratory syncytial virus.

Interactive effects between CDHR3 genotype and rhinovirus species for diagnosis and severity of respiratory tract infections in hospitalized children.

Rhinovirus (RV) is the leading pathogen causing childhood wheezing, with rhinovirus C (RV-C) species reported to cause asthma exacerbation. Allele A of single-nucleotide polymorphism (SNP) CDHR3_rs6967330 upregulates epithelial expression of RV-C receptors which results in more severe asthma exacerbations in children. Nevertheless, there are limited data on interactions between CDHR3 variants and their impact on severity of RV-related pediatric respiratory tract infections (RTIs). Medical records of RV-related RTIs in children aged below 18 years who were hospitalized in two public hospitals in 2015-2016 were independently reviewed by two paediatricians. Archived nasopharyngeal aspirates were retrieved for RV detection and sequencing as well as CDHR3 genotyping. HaploView v.5.0 and generalized multifactor dimensionality reduction (GMDR) analysis were employed for haplotypic assignment and gene-environment interaction analyses. Among 1019 studied cases, our results confirmed the relationship between RV-C species and more severe RTIs. Besides the top risk variant rs6967330-A, we identified rs140154310-T to be associated with RV-C susceptibility under the additive model [odds ratio (OR) 2.53, 95% CI 1.15-5.56; P = 0.021]. Rs140154310 was associated with wheezing illness (OR 2.38, 95% CI 1.12-5.04; P = 0.024), with such association being stronger in subjects who wheezed due to RV-C infections (OR 2.71, 95% CI 1.32-5.58; P = 0.007). Haplotype GAG constructed from rs4730125, rs6967330, and rs73195665 was associated with increased risk of RV-C infection (OR 1.71, 95% CI 1.11-2.65; P = 0.016) and oxygen supplementation (OR 1.93, 95% CI 1.13-3.30; P = 0.016). GMDR analyses revealed epistatic interaction between rs140154310 and rs6967330 of CDHR3 for RV-C infection (P = 0.001), RV-C-associated lower RTI (P = 0.004), and RV-C-associated wheeze (P = 0.007). There was synergistic gene-environmental interaction between rs3887998 and RV-C for more severe clinical outcomes (P < 0.001). To conclude, rs140154310-T is another risk variant for RV-C susceptibility and more severe RTIs. Synergistic epistatic interaction is found between CDHR3 SNPs and RV-C for RTI severity, which is likely mediated by susceptibility to RV-C. Haplotypic analysis and GMDR should be included in identifying prediction models of CDHR3 for childhood asthma and RTIs. IMPORTANCE This case-control study investigated the interaction between CDHR3 genotypes and rhinovirus (RV) species on disease severity in Hong Kong children hospitalized for respiratory tract infection (RTI). There were synergistic effects between RV-C and CDHR3 SNPs for RTI severity, which was mainly driven by RV-C. Specifically, rs6967330 and rs140154310 alone and their epistatic interaction were associated with RV-C-related and severe RTIs in our subjects. Therefore, genotyping of CDHR3 SNPs may help physicians formulate prediction models for severity of RV-associated RTIs.

Comparison of the mucosal and systemic antibody responses in Covid-19 recovered patients with one dose of mRNA vaccine and unexposed subjects with three doses of mRNA vaccines.

Background: Immunity acquired from natural SARS-CoV-2 infection and vaccine wanes overtime. This longitudinal prospective study compared the effect of a booster vaccine (BNT162b2) in inducing the mucosal (nasal) and serological antibody between Covid-19 recovered patients and healthy unexposed subjects with two dose of mRNA vaccine (vaccine-only group). Method: Eleven recovered patients and eleven gender-and-age matched unexposed subjects who had mRNA vaccines were recruited. The SARS-CoV-2 spike 1 (S1) protein specific IgA, IgG and the ACE2 binding inhibition to the ancestral SARS-CoV-2 and omicron (BA.1) variant receptor binding domain were measured in their nasal epithelial lining fluid and plasma. Result: In the recovered group, the booster expanded the nasal IgA dominancy inherited from natural infection to IgA and IgG. They also had a higher S1-specific nasal and plasma IgA and IgG levels with a better inhibition against the omicron BA.1 variant and ancestral SARS-CoV-2 when compared with vaccine-only subjects. The nasal S1-specific IgA induced by natural infection lasted longer than those induced by vaccines while the plasma antibodies of both groups maintained at a high level for at least 21 weeks after booster. Conclusion: The booster benefited all subjects to obtain neutralizing antibody (NAb) against omicron BA.1 variant in plasma while only the Covid-19 recovered subjects had an extra enrichment in nasal NAb against omicron BA.1 variant.

Long COVID-19 and the Heart: Is Cardiac Mitochondria the Missing Link?

Significance: Although corona virus disease 2019 (COVID-19) has now gradually been categorized as an endemic, the long-term effect of COVID-19 in causing multiorgan disorders, including a perturbed cardiovascular system, is beginning to gain attention. Nonetheless, the underlying mechanism triggering post-COVID-19 cardiovascular dysfunction remains enigmatic. Are cardiac mitochondria the key to mediating cardiac dysfunction post-severe acute respiratory syndrome coronavirus 2 (post-SARS-CoV-2) infection? Recent Advances: Cardiovascular complications post-SARS-CoV-2 infection include myocarditis, myocardial injury, microvascular injury, pericarditis, acute coronary syndrome, and arrhythmias (fast or slow). Different types of myocardial damage or reduced heart function can occur after a lung infection or lung injury. Myocardial/coronary injury or decreased cardiac function is directly associated with increased mortality after hospital discharge in patients with COVID-19. The incidence of adverse cardiovascular events increases even in recovered COVID-19 patients. Disrupted cardiac mitochondria postinfection have been postulated to lead to cardiovascular dysfunction in the COVID-19 patients. Further studies are crucial to unravel the association between SARS-CoV-2 infection, mitochondrial dysfunction, and ensuing cardiovascular disorders (CVD). Critical Issues: The relationship between COVID-19 and myocardial injury or cardiovascular dysfunction has not been elucidated. In particular, the role of the cardiac mitochondria in this association remains to be determined. Future Directions: Elucidating the cause of cardiac mitochondrial dysfunction post-SARS-CoV-2 infection may allow a deeper understanding of long COVID-19 and resulting CVD, thus providing a potential therapeutic target. Antioxid. Redox Signal. 38, 599-618.

The Sequential Use of Extracorporeal Cytokine Removal Devices in an Adolescent With COVID-19 Receiving Continuous Renal Replacement Therapy.

A 14-year-old male developed multisystem inflammatory syndrome in children (MIS-C) after acquiring the SARS-CoV-2 infection. He deteriorated rapidly requiring inotropic and ventilatory support as well as continuous renal replacement therapy (CRRT) due to rhabdomyolysis-associated acute kidney injury. A hemoadsoprtion column Cytosorb® was first incorporated into the CRRT circuit for myoglobin and cytokines removal, which was followed by sequential use of another type of cytokine-removing hemofilter (Oxiris®) (altogether 100 hours of extracorporeal blood purification [EBP] therapy). There was no major complication related to the EBP therapy. Cytokine profile revealed a marked reduction of levels of several cytokines including tumor necrosis factor-α, interleukin (IL)-6, IL-8, and IL-10 after the EBP therapy. It was noted that both pro-inflammatory and anti-inflammatory cytokines were removed, and the removal efficacy varied between different devices. His condition improved and the serum ferritin, C-reactive protein, and procalcitonin levels also dropped gradually, which correlated well with his clinical progress and the trend of cytokine levels. Our case demonstrated that extracorporeal cytokine removal can be safely applied in children with MIS-C and can be considered as adjunctive therapy in selected patients with critically ill conditions.

Role of Carbon Monoxide in Oxidative Stress-Induced Senescence in Human Bronchial Epithelium.

Prolonged or excessive stimulation from inhaled toxins may cause oxidative stress and DNA damage that can lead to stress-induced senescence in epithelial cells, which can contribute to several airway diseases. Mounting evidence has shown carbon monoxide (CO) confers cytoprotective effects. We investigated the effects of CO on oxidative stress-induced senescence in human airway epithelium and elucidated the underlying molecular mechanisms. Here, CO pretreatment reduced H2O2-mediated increases in total reactive oxygen species (ROS) production and mitochondrial superoxide in a human bronchial epithelial cell line (BEAS-2B). H2O2 treatment triggered a premature senescence-like phenotype with enlarged and flattened cell morphology accompanied by increased SA-ß-gal activity, cell cycle arrest in G0/G1, reduced cell viability, and increased transcription of senescence-associated secretory phenotype (SASP) genes. Additionally, exposure to H2O2 increased protein levels of cellular senescence markers (p53 and p21), reduced Sirtuin 3 (SIRT3) and manganese superoxide dismutase (MnSOD) levels, and increased p53 K382 acetylation. These H2O2-mediated effects were attenuated by pretreatment with a CO-containing solution. SIRT3 silencing induced mitochondrial superoxide production and triggered a senescence-like phenotype, whereas overexpression decreased mitochondrial superoxide production and alleviated the senescence-like phenotype. Air-liquid interface (ALI) culture of primary human bronchial cells, which becomes a fully differentiated pseudostratified mucociliary epithelium, was used as a model. We found that apical and basolateral exposure to H2O2 induced a vacuolated structure that impaired the integrity of ALI cultures, increased goblet cell numbers, decreased SCGB1A1+ club cell numbers, increased p21 protein levels, and increased SASP gene transcription, consistent with our observations in BEAS-2B cells. These effects were attenuated in the apical presence of a CO-containing solution. In summary, we revealed that CO has a pivotal role in epithelial senescence by regulating ROS production via the SIRT3/MnSOD/p53/p21 pathway. This may have important implications in the prevention and treatment of age-associated respiratory pathologies.

Suppression of influenza virus infection by rhinovirus interference - at the population, individual and cellular levels.

Background: Influenza virus (IV) and the rhinovirus (RV) are the two most common circulating respiratory viruses circulating. Natural viral interference has been suggested between them. The effect of such at the population level has been described in temperate region, while its effect at the individual and cellular levels warrants further validation. In this study, we described the respiratory virus epidemiology and the co-infection landscape in the hospitalized population and investigated the distinct molecular pathways involved in the inhibition of virus replication. Methods: Nasopharyngeal aspirates (NPAs) collected from patients during 2015 to 2019 were examined for the presence of respiratory viruses. The correlation of the monthly prevalence between all the tested respiratory viruses, the co-infection rate and the temporal interference of RV and IV were tested. The viral interference was validated in vitro by conducting sequential RV and IV infections in the well-differentiated primary human airway epithelial cells. The contributing molecular pathways were determined by transcriptome analysis. Findings: A total of 112,926 NPAs were evaluated, and the Enterovirus/RV was the most prevalent respiratory virus detected. The negative correlation between EV/RV and IVs prevalence was independent of age and meteorological factors. Compare with other viruses, EV/RV had a significantly lower incidence of co-infection with IVs. Prior exposure to RV inhibited the replication of IV species A, B and oseltamivir-resistance stain in vitro. RV uniquely downregulated genes related to processing of viral mRNA, ribosomal proteins, translation and influenza infection. Interpretation: Epidemiological surveillance and the sequential infection in vitro suggested viral interference between EV/RV and IV operates at the population, individual and cellular levels. Funding: This study was supported by the General Research Fund (Ref: 24107017 and 14103119 to RWYC) and the Chinese University Direct Grant for Research (Ref: 2019·073 to RWYC).

Rapid evaluation of COVID-19 vaccine effectiveness against symptomatic infection with SARS-CoV-2 variants by analysis of genetic distance.

Timely evaluation of the protective effects of Coronavirus Disease 2019 (COVID-19) vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern is urgently needed to inform pandemic control planning. Based on 78 vaccine efficacy or effectiveness (VE) data from 49 studies and 1,984,241 SARS-CoV-2 sequences collected from 31 regions, we analyzed the relationship between genetic distance (GD) of circulating viruses against the vaccine strain and VE against symptomatic infection. We found that the GD of the receptor-binding domain of the SARS-CoV-2 spike protein is highly predictive of vaccine protection and accounted for 86.3% (P = 0.038) of the VE change in a vaccine platform-based mixed-effects model and 87.9% (P = 0.006) in a manufacturer-based model. We applied the VE-GD model to predict protection mediated by existing vaccines against new genetic variants and validated the results by published real-world and clinical trial data, finding high concordance of predicted VE with observed VE. We estimated the VE against the Delta variant to be 82.8% (95% prediction interval: 68.7-96.0) using the mRNA vaccine platform, closely matching the reported VE of 83.0% from an observational study. Among the four sublineages of Omicron, the predicted VE varied between 11.9% and 33.3%, with the highest VE predicted against BA.1 and the lowest against BA.2, using the mRNA vaccine platform. The VE-GD framework enables predictions of vaccine protection in real time and offers a rapid evaluation method against novel variants that may inform vaccine deployment and public health responses.

Temporal Dynamics of the Nasopharyngeal Microbiome and its Relationship with Childhood Asthma Exacerbation.

Despite distinct nasopharyngeal microbiome (NPM) profiles between asthmatics and healthy subjects, little is known about the NPM dynamics and its relation to childhood asthma exacerbation (AE). We investigated NPM changes by longitudinally collecting 135 flocked nasopharyngeal swabs (FNPSs) from 33 school-age asthmatic children at six time points (2 to 4-week intervals) from September to December 2017 in Hong Kong. Subjects were categorized into AE and stable asthma (AS) groups according to whether they experienced any exacerbation during follow-up. One-off FNPSs from nine nonasthmatic children were included as controls. Microbiota profiles were analyzed using 16S rRNA gene sequencing. All 144 NPMs were classified into six microbiome profile groups (MPGs), each dominated by Moraxella, Corynebacterium 1, Dolosigranulum, Staphylococcus, Streptococcus, or Anoxybacillus. The microbial diversity and compositions of NPM in exacerbation samples were different from both baseline samples and those from healthy controls. Moraxella and Dolosigranulum-dominated NPM exhibited high temporal stability revealed by MPG transition analysis. NPM diversity decreased whereas microbial composition remained similar over time. The relative abundances of Moraxella increased while Corynebacterium 1, Anoxybacillus, and Pseudomonas decreased longitudinally. However, these temporal patterns did not differ between AE and AS groups, suggesting that short-term dynamic patterns were not sufficient to predict AE occurrence. Asthmatic NPM underwent Moraxella expansion during AE and presented a high microbiome resilience (recovery potential) after AE resolution. Microbial pathways involved in methane, ketone bodies, and vitamin B3 metabolisms were enhanced during AE and primarily contributed by Moraxella. IMPORTANCE Evidence on the dynamic changes of NPM in asthmatic patients remains limited. Here, we present that asthmatic NPMs deviating from a healthy status still showed resilience after disturbance. Our data imply from a longitudinal perspective that Moraxella increase is closely related to AE occurrence. The finding of functional dysbiosis (imbalance) during AE offers a plausible explanation for the known association between nasopharyngeal Moraxella expansion and increased AE risk. This work serves as a basis for future long-term prospective studies leveraging multiomics approaches to elucidate the temporal association between NPM and pediatric AE.

Independent effect of weather, air pollutants, and seasonal influenza on risk of tuberculosis hospitalization: An analysis of 22-year hospital admission data.

BACKGROUND: While influenza infections and environmental factors have been documented as potential drivers of tuberculosis, no investigations have simultaneously examined their impact on tuberculosis at a population level. This study thereby made use of Hong Kong's surveillance data over 22 years to elucidate the temporal association between environmental influences, influenza infections, and tuberculosis activity. METHODS: Weekly total numbers of hospital admissions due to tuberculosis, meteorological data, and outdoor air pollutant concentrations in Hong Kong during 1998-2019 were obtained. All-type influenza-like illness positive (ILI+) rate and type-specific ILI+ rates were used as proxies for influenza activity. Quasi-Poisson generalized additive models together with distributed lag non-linear models were used to assess the association of interest. RESULTS: A total of 164,116 hospital admissions due to tuberculosis were notified in public settings over a period of 22 years. The cumulative adjusted relative risk (ARR) of hospital admission due to tuberculosis was 1.07 (95% CI, 1.00-1.14) when the mean ambient temperature increased from 15.1 °C (the 5th percentile) to 24.5 °C (median). Short-term exposure to air pollutants was not found to be statistically significantly related to tuberculosis hospitalization. Accounting for the environmental covariates in the analysis, the cumulative ARR of tuberculosis admission was elevated to 1.05 (95% CI, 1.01-1.08) when the rate of ILI+ total increased from zero to 19.9 per 1000 consultations, the 95th percentile. CONCLUSION: Our findings demonstrated that increased influenza activity and higher temperature were related to a higher risk of tuberculosis admissions. Stepping up the promotion of influenza vaccination, especially before the summer season, may lower the risk of tuberculosis infection/reactivation for vulnerable groups (e.g. elderly born before the launch of Bacillus Calmette-Guérin vaccination programme).

Mucosal Antibody Response to SARS-CoV-2 in Paediatric and Adult Patients: A Longitudinal Study.

BACKGROUND: SARS-CoV-2 enters the body through inhalation or self-inoculation to mucosal surfaces. The kinetics of the ocular and nasal mucosal-specific-immunoglobulin A(IgA) responses remain under-studied. METHODS: Conjunctival fluid (CF, n = 140) and nasal epithelial lining fluid (NELF, n = 424) obtained by paper strips and plasma (n = 153) were collected longitudinally from SARS-CoV-2 paediatric (n = 34) and adult (n = 47) patients. The SARS-CoV-2 spike protein 1(S1)-specific mucosal antibody levels in COVID-19 patients, from hospital admission to six months post-diagnosis, were assessed. RESULTS: The mucosal antibody was IgA-predominant. In the NELF of asymptomatic paediatric patients, S1-specific IgA was induced as early as the first four days post-diagnosis. Their plasma S1-specific IgG levels were higher than in symptomatic patients in the second week after diagnosis. The IgA and IgG levels correlated positively with the surrogate neutralization readout. The detectable NELF "receptor-blocking" S1-specific IgA in the first week after diagnosis correlated with a rapid decline in viral load. CONCLUSIONS: Early and intense nasal S1-specific IgA levels link to a rapid decrease in viral load. Our results provide insights into the role of mucosal immunity in SARS-CoV-2 exposure and protection. There may be a role of NELF IgA in the screening and diagnosis of SARS-CoV-2 infection.

Profiling of SARS-CoV-2 Subgenomic RNAs in Clinical Specimens.

SARS-CoV-2 transcribes a set of subgenomic RNAs (sgRNAs) essential for the translation of structural and accessory proteins to sustain its life cycle. We applied RNA-seq on 375 respiratory samples from individual COVID-19 patients and revealed that the majority of the sgRNAs were canonical transcripts with N being the most abundant (36.2%), followed by S (11.6%), open reading frame 7a (ORF7a; 10.3%), M (8.4%), ORF3a (7.9%), ORF8 (6.0%), E (4.6%), ORF6 (2.5%), and ORF7b (0.3%); but ORF10 was not detected. The profile of most sgRNAs, except N, showed an independent association with viral load, time of specimen collection after onset, age of the patient, and S-614D/G variant with ORF7b and then ORF6 being the most sensitive to changes in these characteristics. Monitoring of 124 serial samples from 10 patients using sgRNA-specific real-time RT-PCR revealed a potential of adopting sgRNA as a marker of viral activity. Respiratory samples harboring a full set of canonical sgRNAs were mainly collected early within 1 to 2 weeks from onset, and most of the stool samples (90%) were negative for sgRNAs despite testing positive by diagnostic PCR targeting genomic RNA. ORF7b was the first to become undetectable and again being the most sensitive surrogate marker for a full set of canonical sgRNAs in clinical samples. The potential of using sgRNA to monitor viral activity and progression of SARS-CoV-2 infection, and hence as one of the objective indicators to triage patients for isolation and treatment should be considered. IMPORTANCE Attempts to use subgenomic RNAs (sgRNAs) of SARS-CoV-2 to identify active infection of COVID-19 have produced diverse results. In this work, we applied next-generation sequencing and RT-PCR to profile the full spectrum of SARS-CoV-2 sgRNAs in a large cohort of respiratory and stool samples collected throughout infection. Numerous known and novel discontinuous transcription events potentially encoding full-length, deleted and frameshift proteins were observed. In particular, the expression profile of canonical sgRNAs was associated with genomic RNA level and clinical characteristics. Our study found sgRNAs as potential biomarkers for monitoring infectivity and progression of SARS-CoV-2 infection, which provides an alternative target for the management and treatment of COVID-19 patients.

Inhibition of Influenza Virus Replication by Oseltamivir Derivatives.

Characterized by the high morbidity and mortality and seasonal surge, the influenza virus (IV) remains a major public health challenge. Oseltamivir is commonly used as a first-line antiviral. As a neuraminidase inhibitor, it attenuates the penetration of viruses through the mucus on the respiratory tract and inhibits the release of virus progeny from infected cells. However, over the years, oseltamivir-resistant strains have been detected in the IV surveillance programs. Therefore, new antivirals that circumvent the resistant strains would be of great importance. In this study, two novel secondary amine derivatives of oseltamivir CUHK326 (6f) and CUHK392 (10i), which bear heteroaryl groups of M2-S31 proton channel inhibitors, were designed, synthesized and subjected to biological evaluation using plaque assay. Influenza A virus (A/Oklahoma/447/2008, H1N1), influenza B viruses (B/HongKong/CUHK33261/2012), an oseltamivir-resistant influenza A virus (A/HongKong/CUHK71923/2009, H1N1) and an oseltamivir-resistant influenza B virus (B/HongKong/CUHK33280/2012) were included in the antiviral effect assessment compared to oseltamivir carboxylate (OC). Both novel compounds significantly reduced the plaque size of seasonal IV A and B, and performed similarly to OC at their corresponding half-maximal inhibitory concentration (IC50). CUHK392 (10i) functioned more effectively than CUHK326 (6f). More importantly, these compounds showed an inhibitory effect on the oseltamivir-resistant strain under 10 nM with selective index (SI) of >200.

Quantifying the effect of government interventions and virus mutations on transmission advantage during COVID-19 pandemic.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic has become a major public health threat. This study aims to evaluate the effect of virus mutation activities and policy interventions on COVID-19 transmissibility in Hong Kong. METHODS: In this study, we integrated the genetic activities of multiple proteins, and quantified the effect of government interventions and mutation activities against the time-varying effective reproduction number Rt. FINDINGS: We found a significantly positive relationship between Rt and mutation activities and a significantly negative relationship between Rt and government interventions. The results showed that the mutations that contributed most to the increase of Rt were from the spike, nucleocapsid and ORF1b genes. Policy of prohibition on group gathering was estimated to have the largest impact on mitigating virus transmissibility. The model explained 63.2% of the Rt variability with the R2. CONCLUSION: Our study provided a convenient framework to estimate the effect of genetic contribution and government interventions on pathogen transmissibility. We showed that the S, N and ORF1b protein had significant contribution to the increase of transmissibility of SARS-CoV-2 in Hong Kong, while restrictions of public gathering and suspension of face-to-face class are the most effective government interventions strategies.

Temporal Patterns in the Evolutionary Genetic Distance of SARS-CoV-2 during the COVID-19 Pandemic.

During coronavirus disease 2019 (COVID-19) pandemic, the genetic mutations of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) occurred frequently. Some mutations in the spike protein are considered to promote transmissibility of the virus, while the mutation patterns in other proteins are less studied and may also be important in understanding the characteristics of SARS-CoV-2. We used the sequencing data of SARS-CoV-2 strains in California to investigate the time-varying patterns of the evolutionary genetic distance. The accumulative genetic distances were quantified across different time periods and in different viral proteins. The increasing trends of genetic distance were observed in spike protein (S protein), the RNA-dependent RNA polymerase (RdRp) region and nonstructural protein 3 (nsp3) of open reading frame 1 (ORF1), and nucleocapsid protein (N protein). The genetic distances in ORF3a, ORF8, and nsp2 of ORF1 started to diverge from their original variants after September 2020. By contrast, mutations in other proteins appeared transiently, and no evident increasing trend was observed in the genetic distance to the original variants. This study presents distinct patterns of the SARS-CoV-2 mutations across multiple proteins from the aspect of genetic distance. Future investigation shall be conducted to study the effects of accumulative mutations on epidemics characteristics.