Maternal-fetal immunologic response to SARS-CoV-2 infection in a symptomatic vulnerable population: A prospective cohort

Background: COVID-19 disproportionally affects pregnant women and their newborn, yet little is known about the variables that modulate the maternal-fetal immune response to infection.Methods: We prospectively studied socioeconomic, biologic and clinical factors affecting humoral immunity in 87 unvaccinated pregnant women admitted to hospital in the Buenos Aires metropolitan area for symptoms consistent with COVID-19 disease.Results: The number of days between symptom onset and childbirth predicted maternal and newborn virus Spike protein Receptor Binding Domain (RBD)-specific IgG. These findings suggest newborns may benefit less when mothers deliver soon after COVID-19 infection. Similarly, a longer time between symptom onset and birth predicted higher in utero transfer of maternal IgG and its concentration in cord blood. Older gestational ages at birth were associated with lower maternal IgG: cord blood IgG ratios. Eighty seven percent of women with confirmed SARS-CoV-2 infection developed RBD-specific IgA responses in breast milk within 96 h of childbirth. IgA was not significantly associated with time from infection but correlated with maternal serum IgG and placental transfer.Conclusions: These results demonstrate the combined role of biologic, clinical and socioeconomic variables associated with maternal SARS-CoV-2 RBD-specific antibodies and supports early vaccination strategies for COVID-19 in socioeconomically vulnerable pregnant women.Fil: Larcade, Ramon. No especifíca;Fil: DeShea, Lise. Oklahoma State University; Estados UnidosFil: Lang, Gillian A.. Oklahoma State University; Estados UnidosFil: Caballero, Mauricio Tomás. Fundación para la Investigación en Infectología Infantil; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Ferretti, Adrian. Fundación para la Investigación en Infectología Infantil; ArgentinaFil: Beasley, William H.. Oklahoma State University; Estados UnidosFil: Tipple, Trent E.. Oklahoma State University; Estados UnidosFil: Vain, Néstor Eduardo. No especifíca;Fil: Prudent, Luis. No especifíca;Fil: Lang, Mark L.. Oklahoma State University; Estados UnidosFil: Polack, Fernando Pedro. Fundación para la Investigación en Infectología Infantil; ArgentinaFil: Ofman, Gaston. Fundación para la Investigación en Infectología Infantil; Argentin

The discovery BPD (D-BPD) program: Study protocol of a prospective translational multicenter collaborative study to investigate determinants of chronic lung disease in very low birth weight infants

Background: Premature birth is a growing and serious public health problem affecting more than one of every ten infants worldwide. Bronchopulmonary dysplasia (BPD) is the most common neonatal morbidity associated with prematurity and infants with BPD suffer from increased incidence of respiratory infections, asthma, other forms of chronic lung illness, and death (Day and Ryan, Pediatr Res 81: 210-213, 2017; Isayama et la., JAMA Pediatr 171:271-279, 2017). BPD is now understood as a longitudinal disease process influenced by the intrauterine environment during gestation and modulated by gene-environment interactions throughout the neonatal and early childhood periods. Despite of this concept, there remains a paucity of multidisciplinary team-based approaches dedicated to the comprehensive study of this complex disease. Methods: The Discovery BPD (D-BPD) Program involves a cohort of infants < 1,250 g at birth prospectively followed until 6 years of age. The program integrates analysis of detailed clinical data by machine learning, genetic susceptibility and molecular translation studies. Discussion: The current gap in understanding BPD as a complex multi-trait spectrum of different disease endotypes will be addressed by a bedside-to-bench and bench-to-bedside approach in the D-BPD program. The D-BPD will provide enhanced understanding of mechanisms, evolution and consequences of lung diseases in preterm infants. The D-BPD program represents a unique opportunity to combine the expertise of biologists, neonatologists, pulmonologists, geneticists and biostatisticians to examine the disease process from multiple perspectives with a singular goal of improving outcomes of premature infants. Trial registration: Does not apply for this study.Fil: Ofman, Gaston. University of Alabama at Birmingahm; Estados UnidosFil: Caballero, Mauricio Tomás. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Álvarez Paggi, Damián Jorge. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Marzec, Jacqui. National Institute of Environmental Health Sciences; Estados UnidosFil: Nowogrodzki, Florencia. No especifíca;Fil: Cho, Hye Youn. National Institute of Environmental Health Sciences; Estados UnidosFil: Sorgetti, Mariana. No especifíca;Fil: Colantonio, Guillermo. No especifíca;Fil: Bianchi, Alejandra. No especifíca;Fil: Prudent, Luis M.. Fundación para la Salud Materno Infantil; ArgentinaFil: Vain, Néstor Eduardo. Fundación para la Salud Materno Infantil; Argentina. Sanatorio de la Trinidad Palermo.; ArgentinaFil: Mariani, Gonzalo Luis. Hospital Italiano; ArgentinaFil: Digregorio, Jorge. Sanatorio de la Trinidad Palermo.; ArgentinaFil: Lopez Turconi, Elba. No especifíca;Fil: Osio, Cristina. Sanatorio "Otamendi y Miroli S. A."; ArgentinaFil: Galletti, Maria Fernanda. Hospital Italiano; ArgentinaFil: Quiros, Mariangeles. Clinica y Maternidad Suizo Argentina; ArgentinaFil: Brum, Andrea. Sanatorio de la Trinidad Palermo.; ArgentinaFil: Lopez Garcia, Santiago. No especifíca;Fil: Garcia, Silvia. Sanatorio "Otamendi y Miroli S. A."; ArgentinaFil: Bell, Douglas. National Institute of Environmental Health Sciences; Estados UnidosFil: Jones, Marcus H.. Pontificia Universidade Católica do Rio Grande do Sul; BrasilFil: Tipple, Trent E.. University of Alabama at Birmingahm; Estados UnidosFil: Kleeberger, Steven R.. National Institute of Environmental Health Sciences; Estados UnidosFil: Polack, Fernando Pedro. University of Alabama at Birmingahm; Estados Unido

Of mice and men: correlations between microRNA-17∼92 cluster expression and promoter methylation in severe bronchopulmonary dysplasia

We previously demonstrated that decreased miR-17∼92 cluster expression was 1) present in lungs from human infants who died with bronchopulmonary dysplasia (BPD); 2) inversely correlated with DNA methyltransferase (DNMT) expression and promoter methylation; and 3) correlated with a subsequent diagnosis of BPD at 36 wk gestational age. We tested the hypothesis that plasma miR-17 levels would be lowest in infants who ultimately develop severe BPD. Secondly, we utilized our well-characterized murine model of severe BPD that combines perinatal inflammation with postnatal hyperoxia to test the hypothesis that alterations in lung miR-17∼92, DNMT, and promoter methylation in our model would mirror our findings in tissues from premature human infants. Plasma was obtained during the first 5 days of life from premature infants born ≤32 wk gestation. Lung tissues were harvested from mice exposed to maternal inflammation and neonatal hyperoxia for 14 days after birth. miR-17∼92 cluster expression and DNA methyltransferase expression were measured by qRT-PCR, and promoter methylation was assessed by Methyl-Profiler assay. Plasma miR-17 levels are significantly lower in the first week of life in human infants who develop severe BPD compared with mild or moderate BPD. Data from our severe BPD murine model reveal that lung miR-17∼92 cluster expression is significantly attenuated, and levels inversely correlated with DNMT expression and miR-17∼92 cluster promoter methylation. Collectively, our data support a plausible role for epigenetically altered miR-17∼92 cluster in the pathogenesis of severe BPD

Alterations in VASP phosphorylation and profilin1 and cofilin1 expression in hyperoxic lung injury and BPD

Abstract Background Hyperoxia is a frequently employed therapy for prematurely born infants, induces lung injury and contributes to development of bronchopulmonary dysplasia (BPD). BPD is characterized by decreased cellular proliferation, cellular migration, and failure of injury repair systems. Actin binding proteins (ABPs) such as VASP, cofilin1, and profilin1 regulate cell proliferation and migration via modulation of actin dynamics. Lung mesenchymal stem cells (L-MSCs) initiate repair processes by proliferating, migrating, and localizing to sites of injury. These processes have not been extensively explored in hyperoxia induced lung injury and repair. Methods ABPs and CD146+ L-MSCs were analyzed by immunofluorescence in human lung autopsy tissues from infants with and without BPD and by western blot in lung tissue homogenates obtained from our murine model of newborn hyperoxic lung injury. Results Decreased F-actin content, ratio of VASPpS157/VASPpS239, and profilin 1 expression were observed in human lung tissues but this same pattern was not observed in lungs from hyperoxia-exposed newborn mice. Increases in cofilin1 expression were observed in both human and mouse tissues at 7d indicating a dysregulation in actin dynamics which may be related to altered growth. CD146 levels were elevated in human and newborn mice tissues (7d). Conclusion Altered phosphorylation of VASP and expression of profilin 1 and cofilin 1 in human tissues indicate that the pathophysiology of BPD involves dysregulation of actin binding proteins. Lack of similar changes in a mouse model of hyperoxia exposure imply that disruption in actin binding protein expression may be linked to interventions or morbidities other than hyperoxia alone

Alterations of the Thioredoxin System by Hyperoxia: Implications for Alveolar Development

Alterations in vascular endothelial growth factor (VEGF) contribute to alveolar simplification seen in animal models of bronchopulmonary dysplasia, and VEGF expression is redox regulated by thioredoxin (Trx)-1 in other diseases. The present studies tested the hypothesis that exposure to 85% O2 negatively impacts the Trx1 system and VEGF expression in the lungs of newborn mice. There was no effect of fraction of inspired oxygen on lung Trx1 or Trx reductase-1 protein levels; however, lung Trx1 protein was predominantly oxidized in the lungs of newborn mice exposed to 85% O2 by 24 hours of exposure. In room air (RA), lung Trx interacting protein (Txnip) levels decreased developmentally through Day 7 (1.0 ± 0.06 [Day 1] vs. 0.49 ± 0.10 [Day 3] vs. 0.29 ± 0.03 [Day 7]; P < 0.01), whereas VEGF expression increased (1.25 ± 0.16 [Day 1] vs. 4.35 ± 1.51 [Day 3] vs. 13.23 ± 0.37 [Day 7]; P < 0.01). Newborn mice exposed to 85% O2 had no developmental decrease in Txnip protein levels and a delayed increase in VEGF protein levels. Lung Txnip and VEGF protein levels were different than in corresponding RA controls at Day 3, before the detection of lung morphologic abnormalities in our model. Txnip and VEGF protein levels were inversely correlated in both the RA and hyperoxia-exposed groups (n = 18; R = −0.66; P = 0.003). In conclusion, oxidation of Trx1 and sustained Txnip expression in the lungs of newborn mice exposed to 85% oxygen is likely to severely attenuate normal Trx1 function. The inverse correlation of Txnip with VEGF expression suggests that decreased Trx1 function contributes to the observed lung developmental abnormalities

Selenium supplementation of lung epithelial cells enhances nuclear factor E2-related factor 2 (Nrf2) activation following thioredoxin reductase inhibition

The trace element selenium (Se) contributes to redox signaling, antioxidant defense, and immune responses in critically ill neonatal and adult patients. Se is required for the synthesis and function of selenoenzymes including thioredoxin (Trx) reductase-1 (TXNRD1) and glutathione peroxidases (GPx). We have previously identified TXNRD1, primarily expressed by airway epithelia, as a promising therapeutic target to prevent lung injury, likely via nuclear factor E2-related factor 2 (Nrf2)-dependent mechanisms. The present studies utilized the TXNRD1 inhibitor auranofin (AFN) to test the hypothesis that Se positively influences Nrf2 activation and selenoenzyme responses in lung epithelial cells. Murine transformed Club cells (mtCCs) were supplemented with 0, 10, 25, or 100 nM Na2SeO3 to create a range of Se conditions and were cultured in the presence or absence of 0.5 μM AFN. TXNRD1 and GPX2 protein expression and enzymatic activity were significantly greater upon Se supplementation (p < 0.05). AFN treatment (0.5 μM AFN for 1 h) significantly inhibited TXNRD1 but not GPx activity (p < 0.001). Recovery of TXNRD1 activity following AFN treatment was significantly enhanced by Se supplementation (p < 0.041). Finally, AFN-induced Nrf2 transcriptional activation was significantly greater in mtCCs supplemented in 25 or 100 nM Na2SeO3 when compared to non-supplemented controls (p < 0.05). Our novel studies indicate that Se levels positively influence Nrf2 activation and selenoenzyme responses following TXNRD1 inhibition. These data suggest that Se status significantly influences physiologic responses to TXNRD1 inhibitors. In conclusion, correction of clinical Se deficiency, if present, will be necessary for optimal therapeutic effectiveness of TXNRD1 inhibitors in the prevention of lung disease