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The impact of the microenvironment on innate lymphoid cell (ILC)-mediated immunity in humans remains largely unknown. Here we used full-length Smart-seq2 single-cell RNA-sequencing to unravel tissue-specific transcriptional profiles and heterogeneity of CD127 + ILCs across four human tissues. Correlation analysis identified gene modules characterizing the migratory properties of tonsil and blood ILCs, and signatures of tissue-residency, activation and modified metabolism in colon and lung ILCs. Trajectory analysis revealed potential differentiation pathways from circulating and tissue-resident naïve ILCs to a spectrum of mature ILC subsets. In the lung we identified both CRTH2 + and CRTH2 − ILC2 with lung-specific signatures, which could be recapitulated by alarmin-exposure of circulating ILC2. Finally, we describe unique TCR-V(D)J-rearrangement patterns of blood ILC1-like cells, revealing a subset of potentially immature ILCs with TCR-δ rearrangement. Our study provides a useful resource for in-depth understanding of ILC-mediated immunity in humans, with implications for disease.

Surfaces on transit vehicles are frequently touched and could potentially act as reservoirs for micro-organism transmission. Regular cleaning and disinfection to minimize the spread of micro-organisms is operationally challenging due to the need to keep vehicles in circulation. The application of copper (Cu) alloys to high- touch surfaces could help reduce the risk of cross-contamination, however, little is known about the durability and efficacy of engineered copper surfaces after prolonged use. Three Cu products (decal, thermal fabrication, and alloy covers) were assessed over a 12-month period. These Cu products were randomly installed on 110 stanchions on three buses and four train (SkyTrain) cars in Vancouver and three buses, two subway cars, and two streetcars in Toronto with mirrored control surfaces directly opposite. Bacterial counts (Colony forming units, CFU) and ATP bioluminescence (ATPB) were measured every two months after peak morning routes. Durability of the Cu products were assessed monthly through visual inspection and colorimetry assays or by ex-situ microscopy. Cu products on stanchions reduced the mean colony forming units (CFU) of all vehicles by 42.7% in the mean CFU (0.573 (CI 95% 0.453–0.726), p-value < 0.001) compared to control surfaces. The three Cu products exhibited an overall 87.1% reduction in the mean ATPB readings (0.129 (CI 95% 0.059–0.285, p-value < 0.001) compared to controls. Surface Cu concentration for all three products was consistent throughout the 12-month period. Electron microscopy (SEM) and Energy-dispersive X-ray Spectroscopy (EDS) cross-sectional analysis showed no change in thickness or dealloying of Cu products, however SEM top-down analysis revealed substantial carbon accumulation on all surfaces. Cu products installed on transit vehicles maintained antimicrobial efficacy and durability after 12 months of use.

Copper has well-documented antibacterial effects but few have evaluated it after prolonged use and against bacteria and viruses. Coupons from three copper formulations (solid, thermal coating, and decal applications) and carbon steel controls were subjected to 200 rounds simulated cleaning using a Wiperator™ and either an accelerated hydrogen peroxide, quaternary ammonium, or artificial sweat products. Antibacterial activity against S. aureus and P. aeruginosa was then evaluated using a modified Environmental Protection Agency protocol. Antiviral activity against coronavirus (229E) and norovirus (MNV-1) surrogates was assessed using the TCID50 method. Results were compared to untreated control coupons. One hour after inoculation, S. aureus exhibited a difference in log kill of 1.16 to 4.87 and P. aeruginosa a log kill difference of 3.39–5.23 (dependent upon copper product and disinfectant) compared to carbon steel. MNV-1 demonstrated an 87–99% reduction on each copper surfaces at 1 h and 99% reduction at 2 h compared to carbon steel. Similarly, coronavirus 229E exhibited a 97–99% reduction after 1 h and 90–99% after 2 h. Simulated use with artificial sweat did not hinder the antiviral nor the antibacterial activity of Cu surfaces. Self-sanitizing copper surfaces maintained antibacterial and antiviral activity after 200 rounds of simulated cleaning.

Normalization of deviance is a term first coined by sociologist Diane Vaughan when reviewing the Challenger disaster. Vaughan noted that the root cause of the Challenger disaster was related to the repeated choice of NASA officials to fly the space shuttle despite a dangerous design flaw with the O-rings. Vaughan describes this phenomenon as occurring when people within an organization become so insensitive to deviant practice that it no longer feels wrong. Insensitivity occurs insidiously and sometimes over years because disaster does not happen until other critical factors line up. In clinical practice, failing to do time outs before procedures, shutting off alarms, and breaches of infection control are deviances from evidence-based practice. As in other industries, health care workers do not make these choices intending to set into motion a cascade toward disaster and harm. Deviation occurs because of barriers to using the correct process or drivers such as time, cost, and peer pressure. As in other industries, operators will often adamantly defend their actions as necessary and justified. Although many other high-risk industries have embraced the normalization of deviance concept, it is relatively new to health care. It is urgent that we explore the impact of this concept on patient harm. We can borrow this concept from other industries and also the steps these other high-risk organizations have found to prevent it.

Respiratory virus infections initiate and transmit from the upper respiratory tract (URT). Coronaviruses, including OC43, are a major cause of respiratory infection and disease. Failure to mount an effective antiviral immune response in the nasal mucosa increases the risk of severe disease and person-to-person transmission, highlighting the need for URT infection models to support the development of nasal treatments that improve coronavirus antiviral immunity. We aimed to determine if OC43 productively infected the mouse URT and would therefore be a suitable model to assess the efficacy and mechanism of action of nasal-targeting immune-modifying treatments. We administered OC43 via intranasal inoculation to wild-type Balb/c mice and assessed virus airway tropism (by comparing total respiratory tract vs. URT-only virus exposure) and characterized infection-induced immunity by quantifying specific antiviral cytokines and performing gene array assessment of immune genes. We then assessed the effect of immune-modulating therapies, including an immune-stimulating TLR2/6 agonist (INNA-X) and the immune-suppressing corticosteroid fluticasone propionate (FP). OC43 replicated in nasal respiratory epithelial cells, with peak viral RNA observed 2 days after infection. Prophylactic treatment with INNA-X accelerated expression of virus-induced IFN-λ and IFN-stimulated genes. In contrast, intranasal FP treatment increased nasal viral load by 2.4 fold and inhibited virus-induced IFN and IFN-stimulated gene expression. Prior INNA-X treatment reduced the immune-suppressive effect of FP. We demonstrate that the mouse nasal epithelium is permissive to OC43 infection and strengthen the evidence that TLR2 activation is a β-coronavirus innate immune determinant and therapeutic target.

Background Specific microRNAs (miRNAs) play essential roles in airway remodeling in asthma. Infection with influenza A virus (IAV) may also magnify pre-existing airway remodeling leading to asthma exacerbation. However, these events remain to be fully defined. We investigated the expression of miRNAs with diverse functions including proliferation (miR-20a), differentiation (miR-22) or innate/adaptive immune responses (miR-132) in primary bronchial epithelial cells (pBECs) of asthmatics following infection with the H1N1 strain of IAV. Methods pBECs from subjects ( n  = 5) with severe asthma and non-asthmatics were cultured as submerged monolayers or at the air-liquid-interface (ALI) conditions and incubated with IAV H1N1 (MOI 5) for up to 24 h. Isolated miRNAs were subjected to Taqman miRNAs assays. We confirmed miRNA targets using a specific mimic and antagomir. Taqman mRNAs assays and immunoblotting were used to assess expression of target genes and proteins, respectively. Results At baseline, these miRNAs were expressed at the same level in pBECs of asthmatics and non-asthmatics. After 24 h of infection, miR-22 expression increased significantly which was associated with the suppression of CD147 mRNA and HDAC4 mRNA and protein expression in pBECs from non-asthmatics, cultured in ALI. In contrast, miR-22 remained unchanged while CD147 expression increased and HDAC4 remained unaffected in cells from asthmatics. IAV H1N1 mediated increases in SP1 and c-Myc transcription factors may underpin the induction of CD147 in asthmatics. Conclusion The different profile of miR-22 expression in differentiated epithelial cells from non-asthmatics may indicate a self-defense mechanism against aberrant epithelial responses through suppressing CD147 and HDAC4, which is compromised in epithelial cells of asthmatics.

The interplay of type-2 inflammation and antiviral immunity underpins asthma exacerbation pathogenesis. Virus infection induces type-2 inflammation–promoting chemokines CCL17 and CCL22 in asthma; however, mechanisms regulating induction are poorly understood. By using a human rhinovirus (RV) challenge model in human airway epithelial cells in vitro and mice in vivo, we assessed mechanisms regulating CCL17 and CCL22 expression. Subjects with mild to moderate asthma and healthy volunteers were experimentally infected with RV and airway CCL17 and CCL22 protein quantified. In vitro airway epithelial cell- and mouse-RV infection models were then used to define STAT6- and NF-κB–mediated regulation of CCL17 and CCL22 expression. Following RV infection, CCL17 and CCL22 expression was higher in asthma, which differentially correlated with clinical and immunological parameters. Air–liquid interface–differentiated primary epithelial cells from donors with asthma also expressed higher levels of RV-induced CCL22. RV infection boosted type-2 cytokine–induced STAT6 activation. In epithelial cells, type-2 cytokines and STAT6 activation had differential effects on chemokine expression, increasing CCL17 and suppressing CCL22, whereas NF-κB promoted expression of both chemokines. In mice, RV infection activated pulmonary STAT6, which was required for CCL17 but not CCL22 expression. STAT6-knockout mice infected with RV expressed increased levels of NF-κB–regulated chemokines, which was associated with rapid viral clearance. Therefore, RV-induced upregulation of CCL17 and CCL22 was mediated by NF-κB activation, whereas expression was differentially regulated by STAT6. Together, these findings suggest that therapeutic targeting of type-2 STAT6 activation alone will not block all inflammatory pathways during RV infection in asthma.

Background People with substance use disorders smoke cigarettes at much higher rates than the general population in the United States and are disproportionately affected by tobacco-related diseases. Many substance use treatment centers do not provide evidence-based tobacco cessation treatment or maintain comprehensive tobacco-free workplace policies. The goal of the current work is to identify barriers and facilitators to a successful and sustainable implementation of a tobacco-free workplace program, which includes a comprehensive tobacco-free policy and evidence-based cessation treatment services, in a substance use treatment center. Methods This study is based on an ethnographic approach and uses a qualitative case study design. Data were collected via interviews with staff ( n  = 6) and clients ( n  = 16) at the substance use treatment center and site visits ( n  = 8). Data were analyzed using thematic analysis guided by the extended Normalization Process Theory designed to inform the implementation of innovations in healthcare practice. Results Staff at the substance use treatment center supported the implementation of the program and shared a good understanding of the purpose of the intervention and its potential benefits. However, the study identified significant challenges faced by the center during implementation, including widespread tobacco use among clients, contributing to attitudes among staff that tobacco cessation was a low-priority problem due to a perceived lack of interest in quitting and inability to quit among their clients. We identified several factors that contributed to changing this attitude, including provision of tobacco training to staff, active leadership support, low number of staff members who smoked, and access to material resources, including nicotine replacement products. The implementation and active enforcement of a comprehensive tobacco-free workplace program contributed to a gradual change in attitudes and improved the provision of evidence-based tobacco cessation care at the substance use treatment center. Conclusions Substance use treatment centers can integrate tobacco cessation practices in their daily operations, despite multiple challenges they face due to the complex behavioral health and socioeconomic needs of their clients. With proper support, substance use treatment centers can provide much needed tobacco cessation care to their clients who are disproportionately affected by tobacco-related health conditions and systemic health inequities.

Asthma is a global health problem with increasing prevalence. The airway epithelium is the initial barrier against inhaled noxious agents or aeroallergens. In asthma, the airway epithelium suffers from structural and functional abnormalities and as such, is more susceptible to normally innocuous environmental stimuli. The epithelial structural and functional impairments are now recognised as a significant contributing factor to asthma pathogenesis. Both genetic and environmental risk factors play important roles in the development of asthma with an increasing number of genes associated with asthma susceptibility being expressed in airway epithelium. Epigenetic factors that regulate airway epithelial structure and function are also an attractive area for assessment of susceptibility to asthma. In this review we provide a comprehensive discussion on genetic factors; from using linkage designs and candidate gene association studies to genome-wide association studies and whole genome sequencing, and epigenetic factors; DNA methylation, histone modifications, and non-coding RNAs (especially microRNAs), in airway epithelial cells that are functionally associated with asthma pathogenesis. Our aims were to introduce potential predictors or therapeutic targets for asthma in airway epithelium. Overall, we found very small overlap in asthma susceptibility genes identified with different technologies. Some potential biomarkers are IRAKM , PCDH1 , ORMDL3 / GSDMB , IL - 33 , CDHR3 and CST1 in airway epithelial cells. Recent studies on epigenetic regulatory factors have further provided novel insights to the field, particularly their effect on regulation of some of the asthma susceptibility genes (e.g. methylation of ADAM33 ). Among the epigenetic regulatory mechanisms, microRNA networks have been shown to regulate a major portion of post-transcriptional gene regulation. Particularly, miR-19a may have some therapeutic potential.