A series of block copolymers based on 2-methacryloyloxyethyl phosphorylcholine (MPC) were synthesized by reversible addition fragmentation chain transfer (RAFT) polymerization. Incorporation of dihydrolipoic acid (DHLA) into the hydrophobic block led to formation of block copolymer micelles in water. The micelles were between 15 and 30 nm in diameter, as characterized by dynamic light scattering (DLS), with some size control achieved by adjusting the hydrophobic/hydrophilic balance. Cross-linked micelles were prepared by disulfide formation, and observed to be stable in solution for weeks. The micelles proved amenable to disassembly when treated with a reducing agent, such as dithiothreitol (DTT), and represent a potential delivery platform for chemotherapeutic agents. As a proof-of-concept, camptothecin (CPT) was conjugated to the polymer scaffold through a disulfide linkage, and release of the drug from the micelle was monitored by fluorescence spectroscopy. These CPT-loaded prodrug micelles showed a reduction in release rate compared to physically encapsulated CPT. The use of disulfide conjugation facilitated drug release under reducing conditions, with a half-life (t1/2) of 5.5 hours in the presence of 3 mM DTT, compared to 28 hours in PBS. The toxicity of the micellar prodrugs was evaluated in cell culture against human breast (MCF7) and colorectal (COLO205) cancer cell lines.
Particular host and environmental factors influence susceptibility to severe COVID-19. We analyzed RNA-sequencing data from bronchial epithelial brushings - a relevant tissue for SARS-CoV-2 infection - obtained from three cohorts of uninfected individuals, and investigated how non-genetic and genetic factors affect the regulation of host genes implicated in COVID-19. We found that ACE2 expression was higher in relation to active smoking, obesity, and hypertension that are known risk factors of COVID-19 severity, while an association with interferon-related inflammation was driven by the truncated, non-binding ACE2 isoform. We discovered that expression patterns of a suppressed airway immune response to early SARS-CoV-2 infection, compared to other viruses, are similar to patterns associated with obesity, hypertension, and cardiovascular disease, which may thus contribute to a COVID-19-susceptible airway environment. eQTL mapping identified regulatory variants for genes implicated in COVID-19, some of which had pheWAS evidence for their potential role in respiratory infections. These data provide evidence that clinically relevant variation in the expression of COVID-19-related genes is associated with host factors, environmental exposures, and likely host genetic variation.
Background The large airway epithelial barrier provides one of the first lines of defense against respiratory viruses, including SARS-CoV-2 that causes COVID-19. Substantial inter-individual variability in individual disease courses is hypothesized to be partially mediated by the differential regulation of the genes that interact with the SARS-CoV-2 virus or are involved in the subsequent host response. Here, we comprehensively investigated non-genetic and genetic factors influencing COVID-19-relevant bronchial epithelial gene expression. Methods We analyzed RNA-sequencing data from bronchial epithelial brushings obtained from uninfected individuals. We related ACE2 gene expression to host and environmental factors in the SPIROMICS cohort of smokers with and without chronic obstructive pulmonary disease (COPD) and replicated these associations in two asthma cohorts, SARP and MAST. To identify airway biology beyond ACE2 binding that may contribute to increased susceptibility, we used gene set enrichment analyses to determine if gene expression changes indicative of a suppressed airway immune response observed early in SARS-CoV-2 infection are also observed in association with host factors. To identify host genetic variants affecting COVID-19 susceptibility in SPIROMICS, we performed expression quantitative trait (eQTL) mapping and investigated the phenotypic associations of the eQTL variants. Results We found that ACE2 expression was higher in relation to active smoking, obesity, and hypertension that are known risk factors of COVID-19 severity, while an association with interferon-related inflammation was driven by the truncated, non-binding ACE2 isoform. We discovered that expression patterns of a suppressed airway immune response to early SARS-CoV-2 infection, compared to other viruses, are similar to patterns associated with obesity, hypertension, and cardiovascular disease, which may thus contribute to a COVID-19-susceptible airway environment. eQTL mapping identified regulatory variants for genes implicated in COVID-19, some of which had pheWAS evidence for their potential role in respiratory infections. Conclusions These data provide evidence that clinically relevant variation in the expression of COVID-19-related genes is associated with host factors, environmental exposures, and likely host genetic variation.
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