The OM-85 bacterial lysate inhibits SARS-CoV-2 infection of epithelial cells by downregulating SARS-CoV-2 receptor expression.

BACKGROUND: Treatments for coronavirus disease 2019, which is caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), are urgently needed but remain limited. SARS-CoV-2 infects cells through interactions of its spike (S) protein with angiotensin-converting enzyme 2 (ACE2) and transmembrane protease serine 2 (TMPRSS2) on host cells. Multiple cells and organs are targeted, particularly airway epithelial cells. OM-85, a standardized lysate of human airway bacteria with strong immunomodulating properties and an impeccable safety profile, is widely used to prevent recurrent respiratory infections. We found that airway OM-85 administration inhibits Ace2 and Tmprss2 transcription in the mouse lung, suggesting that OM-85 might hinder SARS-CoV-2/host cell interactions. OBJECTIVES: We sought to investigate whether and how OM-85 treatment protects nonhuman primate and human epithelial cells against SARS-CoV-2. METHODS: ACE2 and TMPRSS2 mRNA and protein expression, cell binding of SARS-CoV-2 S1 protein, cell entry of SARS-CoV-2 S protein-pseudotyped lentiviral particles, and SARS-CoV-2 cell infection were measured in kidney, lung, and intestinal epithelial cell lines, primary human bronchial epithelial cells, and ACE2-transfected HEK293T cells treated with OM-85 in vitro. RESULTS: OM-85 significantly downregulated ACE2 and TMPRSS2 transcription and surface ACE2 protein expression in epithelial cell lines and primary bronchial epithelial cells. OM-85 also strongly inhibited SARS-CoV-2 S1 protein binding to, SARS-CoV-2 S protein-pseudotyped lentivirus entry into, and SARS-CoV-2 infection of epithelial cells. These effects of OM-85 appeared to depend on SARS-CoV-2 receptor downregulation. CONCLUSIONS: OM-85 inhibits SARS-CoV-2 epithelial cell infection in vitro by downregulating SARS-CoV-2 receptor expression. Further studies are warranted to assess whether OM-85 may prevent and/or reduce the severity of coronavirus disease 2019.

Surfactant Protein-A Protects against IL-13-Induced Inflammation in Asthma.

The lung surfactant proteins are recognized as critical not only for their role in lowering lung surface tension but also in innate host defense. Reports have shown that some asthmatic patients have decreased levels of one member of this protein family in particular, surfactant protein-A (SP-A). Our studies set out to determine the contribution of SP-A to the response of a key effector cytokine in asthma, IL-13. Our studies employ both animal models sufficient and deficient in SP-A challenged with IL-13 and primary epithelial cells from participants with asthma that are exogenously treated with SP-A in the context of IL-13 challenge. The inflammatory response and mucin production were assessed in both model systems. As compared with WT mice, we show that the activity of IL-13 is dramatically augmented in SP-A-/- mice, which have significantly increased neutrophil and eosinophil recruitment, mucin production and asthma-associated cytokines in the bronchoalveolar lavage fluid. In parallel, we show asthma-associated factors are attenuated in human cells from asthma subjects when exogenous SP-A is added during IL-13 challenge. Although many of these phenotypes have previously been associated with STAT6 signaling, SP-A inhibited IL-13-induced STAT3 phosphorylation in mice and in human epithelial cells while having little effect on STAT6 phosphorylation. In addition, when either STAT3 or IL-6 were inhibited in mice, the phenotypes observed in SP-A-/- mice were significantly attenuated. These studies suggest a novel mechanism for SP-A in asthma as a modulator of IL-13-induced inflammation via mediating downstream IL-6/STAT3 signaling.

Type 2 inflammation modulates ACE2 and TMPRSS2 in airway epithelial cells.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has dramatically changed our world, country, communities, and families. There is controversy regarding risk factors for severe COVID-19 disease. It has been suggested that asthma and allergy are not highly represented as comorbid conditions associated with COVID-19. OBJECTIVE: Our aim was to extend our work in IL-13 biology to determine whether airway epithelial cell expression of 2 key mediators critical for SARS-CoV-2 infection, namely, angiotensin-converting enzyme 2 (ACE2) and transmembrane protease, serine 2 (TMPRSS2), are modulated by IL-13. METHODS: We determined effects of IL-13 treatment on ACE2 and TMPRSS2 expression ex vivo in primary airway epithelial cells from participants with and without type 2 asthma obtained by bronchoscopy. We also examined expression of ACE2 and TMPRSS2 in 2 data sets containing gene expression data from nasal and airway epithelial cells from children and adults with asthma and allergic rhinitis. RESULTS: IL-13 significantly reduced ACE2 and increased TMPRSS2 expression ex vivo in airway epithelial cells. In 2 independent data sets, ACE2 expression was significantly reduced and TMPRSS2 expression was significantly increased in the nasal and airway epithelial cells in type 2 asthma and allergic rhinitis. ACE2 expression was significantly negatively associated with type 2 cytokines, whereas TMPRSS2 expression was significantly positively associated with type 2 cytokines. CONCLUSION: IL-13 modulates ACE2 and TMPRSS2 expression in airway epithelial cells in asthma and atopy. This deserves further study with regard to any effects that asthma and atopy may render in the setting of COVID-19 infection.

The Elite Athlete and Strenuous Exercise in Pregnancy.

Highly trained women continue to exercise during pregnancy, but there is little information available to guide them, and their health care providers, in how to maximize performance without jeopardizing the maternal-fetal unit. Available evidence focusing on average women who perform regular vigorous exercise suggests that this activity is helpful in preventing several maladies of pregnancy, with little to no evidence of harm. However, some studies have shown that there may be a limit to how intense an elite performer should exercise during pregnancy. Health care providers should monitor these women athletes carefully, to build trust and understanding.

Location, Location, Location: Accelerometer Placement Affects Steps-Based Physical Activity Outcomes During Pregnancy and Postpartum.

As pregnancy progresses, physical changes may affect physical activity (PA) measurement validity. n = 11 pregnant women (30.1 ± 3.8 years) wore ActiGraph GT3X+ accelerometers on the right hip, right ankle, and non-dominant wrist for 3-7 days during the second and third trimesters (21 and 32 weeks, respectively) and 12 weeks postpartum. Data were downloaded into 60-second epochs from which stepping cadence was calculated; repeated-measures analysis of variance was used to determine significant differences among placements. At all time points, the wrist accelerometer measured significantly more daily steps (9930-10 452 steps/d) and faster average stepping cadence (14.5-14.6 steps/min) than either the hip (4972-5944 steps/d, 7.1-8.6 steps/min) or ankle (7161-8205 steps/d, 10.3-11.9 steps/min) placement, while moderate- to vigorous-intensity activity at the wrist (1.2-1.7 min/d) was significantly less than either hip (3.0-5.9 min/d) or ankle (6.1-7.3 min/d). Steps, cadence, and counts were significantly lower for the hip than the ankle at all time points. Kappa calculated for agreement in intensity classification between the various pairwise comparisons ranged from .06 to .41, with Kappa for hip-ankle agreement (.34-.41) significantly higher than for wrist-ankle (.09-.11) or wrist-hip (.06-.16). These data indicate that wrist accelerometer placement during pregnancy likely results in over counting of PA parameters and should be used with caution.

Ultrathin planar graphene supercapacitors.

With the advent of atomically thin and flat layers of conducting materials such as graphene, new designs for thin film energy storage devices with good performance have become possible. Here, we report an "in-plane" fabrication approach for ultrathin supercapacitors based on electrodes comprised of pristine graphene and multilayer reduced graphene oxide. The in-plane design is straightforward to implement and exploits efficiently the surface of each graphene layer for energy storage. The open architecture and the effect of graphene edges enable even the thinnest of devices, made from as grown 1-2 graphene layers, to reach specific capacities up to 80 µFcm(-2), while much higher (394 µFcm(-2)) specific capacities are observed multilayer reduced graphene oxide electrodes. The performances of devices with pristine as well as thicker graphene-based structures are examined using a combination of experiments and model calculations. The demonstrated all solid-state supercapacitors provide a prototype for a broad range of thin-film based energy storage devices.

Small Peptide Derivatives Within the Carbohydrate Recognition Domain of SP-A2 Modulate Asthma Outcomes in Mouse Models and Human Cells.

Surfactant Protein-A (SP-A) is an innate immune modulator that regulates a variety of pulmonary host defense functions. We have shown that SP-A is dysfunctional in asthma, which could be partly due to genetic heterogeneity. In mouse models and primary bronchial epithelial cells from asthmatic participants, we evaluated the functional significance of a particular single nucleotide polymorphism of SP-A2, which results in an amino acid substitution at position 223 from glutamine (Q) to lysine (K) within the carbohydrate recognition domain (CRD). We found that SP-A 223Q humanized mice had greater protection from inflammation and mucin production after IL-13 exposure as compared to SP-A-2 223K mice. Likewise, asthmatic participants with two copies the major 223Q allele demonstrated better lung function and asthma control as compared to asthmatic participants with two copies of the minor SP-A 223K allele. In primary bronchial epithelial cells from asthmatic participants, full-length recombinant SP-A 223Q was more effective at reducing IL-13-induced MUC5AC gene expression compared to SP-A 223K. Given this activity, we developed 10 and 20 amino acid peptides of SP-A2 spanning position 223Q. We show that the SP-A 223Q peptides reduce eosinophilic inflammation, mucin production and airways hyperresponsiveness in a house dust mite model of asthma, protect from lung function decline during an IL-13 challenge model in mice, and decrease IL-13-induced MUC5AC gene expression in primary airway epithelial cells from asthmatic participants. These results suggest that position 223 within the CRD of SP-A2 may modulate several outcomes relevant to asthma, and that short peptides of SP-A2 retain anti-inflammatory properties similar to that of the endogenous protein.

Longitudinal changes in walking cadence across pregnancy and postpartum.

BACKGROUND: Physical activity during pregnancy has many health benefits yet few pregnant women meet US guidelines for physical activity. Traditionally, physical activity has been measured as time spent in moderate and/or vigorous intensity activity, but quantifying intensity is challenging. There is increasing interest in measuring both daily steps and stepping rate, or cadence, as an indicator of physical activity overall and intensity of that activity. RESEARCH QUESTION: Does free-living step cadence change across pregnancy (from 20 weeks to 32 weeks) and postpartum (12 weeks postpartum) when data is collected via hip-worn ActiGraph (ActiGraph Corp., Pensacola, FL) accelerometers? METHODS: A total of n = 32 pregnant women were enrolled in a longitudinal study of physical activity during pregnancy; these women wore accelerometers on their right hip for one week at 20 weeks gestation, again at 32 weeks gestation, and at 12 weeks postpartum. Data were used to determine total daily steps, time spent (min/day) in various cadence ranges, minutes spent at >100 and >130 steps/min as well as mean, median, maximum, and peak cadences. RESULTS: Pregnant women accumulated significantly fewer steps per day in the third trimester compared to second (1164 steps/day less) or postpartum (1397 steps/day less) time points. Third trimester women also spent significantly fewer minutes/day in MVPA (cadences ≥100 steps/minute; 4.1 min/day less) and had a significantly lower peak cadence (10.6 steps/min less), compared to second trimester only. SIGNIFICANCE: These data indicate that pregnant women take fewer steps and walk at slower cadences in the third trimester compared to second and to postpartum, which indicates that total PA as well as absolute intensity of PA are altered during pregnancy.

Physical Activity Device Reliability and Validity during Pregnancy and Postpartum.

Current physical activity (PA) recommendations for women experiencing a normal pregnancy reflect recent research showing numerous health benefits for mother and offspring. However, few studies have evaluated PA devices' reliability and validity during pregnancy, because anatomical and physiological changes throughout gestation could affect an instrument's accuracy. PURPOSE: This study aimed to determine the reliability and validity of PA devices worn on the hip, ankle, and triceps during pregnancy and postpartum. METHODS: Thirty-three women performed six activities of daily living and one treadmill walk at approximately 21 and 32 wk of pregnancy, and 12 wk postpartum. There were two visits at each time period, 1 wk apart. Energy expenditure (oxygen consumption) was measured by using indirect calorimetry (IC; criterion measure), whereas PA was quantified by using accelerometers and pedometers placed at the right hip and ankle and left triceps. Interclass reliability and monitor validity compared with IC in relative (mL·kg·min) terms were calculated using Pearson correlation. Both multitrial and single-trial intraclass reliabilities (ICC) were estimated using ANOVA to assess monitor reliability at each time period. SEM values were calculated in relative terms for each time period. RESULTS: The reliability of the devices was moderate/strong because 66% of the Pearson correlations were between 0.6 and 1.0. Multitrial ICC values were largely in the moderate/strong range because 38% of the ICC values were between 0.6 and 0.79 and 50% were between 0.8 and 1.0. The SEM values for each device between visits ranged from 7% to 23% of the mean values. Comparison between IC and devices showed that 40% and 46% of the validity coefficients were between 0.4 and 0.59 and between 0.6 and 0.79, respectively. CONCLUSIONS: PA devices show moderate/strong reliability and moderate validity for measuring PA during pregnancy and postpartum.