Background and objectives Because of its beneficial off‐target effects against non‐mycobacterial infectious diseases, bacillus Calmette–Guérin (BCG) vaccination might be an accessible early intervention to boost protection against novel pathogens. Multiple epidemiological studies and randomised controlled trials (RCTs) are investigating the protective effect of BCG against coronavirus disease 2019 (COVID‐19). Using samples from participants in a placebo‐controlled RCT aiming to determine whether BCG vaccination reduces the incidence and severity of COVID‐19, we investigated the immunomodulatory effects of BCG on in vitro immune responses to SARS‐CoV‐2. Methods This study used peripheral blood taken from participants in the multicentre RCT and BCG vaccination to reduce the impact of COVID‐19 on healthcare workers (BRACE trial). The whole blood taken from BRACE trial participants was stimulated with γ‐irradiated SARS‐CoV‐2‐infected or mock‐infected Vero cell supernatant. Cytokine responses were measured by multiplex cytokine analysis, and single‐cell immunophenotyping was made by flow cytometry. Results BCG vaccination, but not placebo vaccination, reduced SARS‐CoV‐2‐induced secretion of cytokines known to be associated with severe COVID‐19, including IL‐6, TNF‐α and IL‐10. In addition, BCG vaccination promoted an effector memory phenotype in both CD4+ and CD8+ T cells, and an activation of eosinophils in response to SARS‐CoV‐2. Conclusions The immunomodulatory signature of BCG’s off‐target effects on SARS‐CoV‐2 is consistent with a protective immune response against severe COVID‐19.
The inositol 1,4,5-trisphosphate receptor (InsP 3 R), an intracellular calcium channel, has three isoforms with >65% sequence homology, yet the isoforms differ in their function and regulation by post-translational modifications. We showed previously that
Background: Postnatal infection with cytomegalovirus (CMV) in verypreterm and very-low-birth-weight infants, transmitted through breast milk (BM), is potentially associated with adverse outcomes. This study aimed to investigate the incidence and clinical significance of postnatal CMV infection in a tertiary neonatal intensive care unit. Methods: Infants of CMV-seropositive mothers born in a neonatal intensive care unit in Melbourne, Australia, were observed for 14 weeks from birth in a prospective cohort study. Maternal BM and infant urine were tested weekly for CMV by culture and polymerase chain reaction, respectively. Clinical and laboratory data were collected and analyzed in relation to the infants' CMV infection status. Results: Data from 65 infants of 56 CMV-seropositive mothers were available for analysis. Of these mothers, 88% (49/56) shed CMV in their BM. Of the 58 infants exposed to CMV-positive BM, 27 (47%) became urine polymerase chain reaction CMV-positive. There was no significant difference in gestational age, birth weight, incidence of bronchopulmonary dysplasia, or necrotizing enterocolitis between the CMV-positive and CMV-negative groups. However, CMV-positive infants had a longer length of hospital stay and more episodes of prolonged neutropenia. Of the CMV-positive infants, 30% (8/27) remained asymptomatic, 48% (13/27) had symptoms categorized as mild and 22% (6/27) as severe. Conclusions: About half of preterm and very-low-birth-weight infants exposed to CMV-positive BM become infected, and a fifth develop significant clinical symptoms. Future studies should address the maternal and neonatal factors that determine the risk of mother-to-infant CMV transmission, as well as those leading to clinical deterioration and long-term sequelae.
as ''quantal'' Ca2þ release. Such quantal behavior of IP3R is thought to be due to the feedback regulation of the channel by luminal Ca2þ. A high level of luminal Ca2þ enhances the sensitivity of IP3R to IP3, while a reduced luminal Ca2þ level desensitizes IP3R. Despite its importance, the molecular basis underling the regulation of IP3R by luminal Ca2þ is unknown. Ryanodine receptors (RyRs), another family of intracellular Ca2þ release channels, also exhibit quantal Ca2þ release in response to agonists, and are regulated by luminal Ca2þ. We have recently demonstrated that mutations in the TM10 helix (the pore inner helix) of the RyR2 channel markedly alter the sensitivity of the channel to activation by luminal Ca2þ. Given the high degree of sequence homology in the channel pore-forming region between RyR and IP3R, we hypothesize that the TM6 helix in IP3R, corresponding to TM10 in RyR, is also important for luminal Ca2þ regulation of IP3R. To test this hypothesis, we have generated a number of mutations in the TM6 of IP3R and established stable, inducible HEK293 cell lines expressing these mutants. By monitoring the ER luminal Ca2þ level using a fluorescent ER Ca2þ sensor protein, D1ER, we found that mutations in TM6 either increase or decrease the rate of IP3-induced Ca2þ release in permeablized mutant cells. These mutations also affect the sensitivity of ATP-triggered Ca2þ release in intact cells. Further studies at the single channel level should provide new insights into the role of the pore-forming region in the luminal Ca2þ regulation of IP3R.
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