Human respiratory syncytial virus (RSV) infection is the most important cause of acute lower respiratory tract infection in infants, neonates, and young children, even leading to hyperinflation and atelectasis. Oxymatrine (OMT), originating from natural herbs, possessed potential antivirus activity against influenza A virus, Coxsackie B3 virus, and RSV, whereas the absence of an in vivo study indicated the difficulties in overcoming the physiological obstacles. Since RSV basically replicated in lung tissue, in this study, we fabricated and characterized a chitosan (CS)-coated liposome with OMT loaded for the treatment of lethal RSV infection via inhalation. The results uncovered that OMT, as a hydrophilic drug, was liable to diffuse in the mucus layer and penetrate through the gas–blood barrier to enter systemic circulation quickly, which might restrict its inhibitory effect on RSV replication. The CS-coated liposome enhanced the distribution and retention of OMT in lung tissue without restriction from mucus, which contributed to the improved alleviative effect of OMT on lethal RSV-infected mice. Overall, this study provides a novel inhalation therapy for RSV infection, and the CS-coated liposome might be a potential inhalable nanocarrier for hydrophilic drugs to prevent pulmonary infections.

We previously explored a panel of adjuvants formulated with pre-fusion RSV-F protein and found that AS02 may be a promising candidate adjuvant for developing RSV-F subunit vaccines with improved immunogenicity and desired immune response type. In this study, we performed a head-to-head comparison of the effect of intramuscular injection to that of subcutaneous injection on the immune response and protective efficacy of recombinant RSV-F subunit vaccine with or without adjuvants (Alhydrogel, squalene-based emulsion adjuvants MF59, AS03, and AS02) in BALB/c mice. After inoculations, antigen-specific antibodies, neutralizing antibodies, antibody subtypes, cytokines, and the persistence of immune response were evaluated. Moreover, challenge tests were also performed to illustrate the possible effect of inoculation routes and adjuvant on virus clearance and histochemistry changes in the lungs of mice. The results indicated that intramuscular inoculation is a more effective and antigen dose-sparing route to enhance the immune response, although subcutaneous inoculation induced faster and stronger IgG antibodies after the initial immunization. Furthermore, adjuvant, but not immunization route, is a more critical factor to affect the humoral/cellular immune response and the immune bias. In addition, adjuvant inoculated via the intramuscular route is safer than that via the subcutaneous route, especially for AS02. This study highlights the importance of the adjuvant and immunization routes in the design and clinical transformation of adjuvanted vaccines. Further investigation is needed to illustrate the mechanism underlying the above difference in both efficiency and safety.

Since the occurrence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in December 2019, SARS-CoV-2 has led to a global coronavirus disease 2019 (COVID-19) pandemic. A better understanding of the SARS-CoV-2 receptor ACE2 at the genetic level would help combat COVID-19, particularly for long COVID. We performed a genetic analysis of ACE2 and searched for its common potential single nucleotide polymorphisms (SNPs) with minor allele frequency >0.05 in both European and Chinese populations that would contribute to ACE2 gene expression variation. We thought that the variation of the ACE2 expression would be an important biological feature that would strongly affect COVID-19 symptoms, such as “brain fog”, which is highlighted by the fact that ACE2 acts as a major cellular receptor for SARS-CoV-2 attachment and is highly expressed in brain tissues. Based on the human GTEx gene expression database, we found rs2106809 exhibited a significant correlation with the ACE2 expression among multiple brain and artery tissues. This expression correlation was replicated in an independent European brain eQTL database, Braineac. rs2106809*G also displays significantly higher frequency in Asian populations than in Europeans and displays a protective effect (p = 0.047) against COVID-19 hospitalization when comparing hospitalized COVID-19 cases with non-hospitalized COVID-19 or SARS-CoV-2 test-negative samples with European ancestry from the UK Biobank. Furthermore, we experimentally demonstrated that rs2106809*G could upregulate the transcriptional activity of ACE2. Therefore, integrative analysis and functional experiment strongly support that ACE2 SNP rs2106809 is a functional brain eQTL and its potential involvement in long COVID, which warrants further investigation.

Absence of Association between a Long COVID and Severe COVID-19 Risk Variant of FOXP4 and Lung Cancer

Sex-biased difference in coronavirus disease 2019 (COVID-19) hospitalization has been observed as that male patients tend to be more likely to be hospitalized than female patients. However, due to the insufficient sample size and existed studies that more prioritized to sex-stratified COVID-19 genome-wide association study (GWAS), the searching for sex-biased genetic variants showing differential association signals between sexes with COVID-19 hospitalization was severely hindered. We hypothesized genetic variants would show potentially sex-biased genetic effects on COVID-19 hospitalization if they display significant differential association effect sizes between male and female COVID-19 patients. By integrating two COVID-19 GWASs, including hospitalized COVID-19 patients vs. general population separated into males (case = 1,917 and control = 221,174) and females (case = 1,343 and control = 262,886), we differentiated the association effect sizes of each common single nucleotide polymorphism (SNP) within the two GWASs. Twelve SNPs were suggested to show differential COVID-19 associations between sexes. Further investigation of genes (n = 58) close to these 12 SNPs resulted in the identification of 34 genes demonstrating sex-biased differential expression in at least one GTEx tissue. Finally, 5 SNPs are mapped to 8 genes, including rs1134004 (GADD45G), rs140657166 (TRIM29 and PVRL1), rs148143613 (KNDC1 and STK32C), rs2443615 (PGAP2 and TRIM21), and rs2924725 (CSMD1). The 8 genes display significantly differential gene expression in blood samples derived from COVID-19 patients compared to healthy controls. These genes are potential genetic factors contributing to sex differences in COVID-19 hospitalization and warranted for further functional studies.