Lack of Cell Cycle Inhibitor p21 and Low CD4⁺ T Cell Suppression in Newborns After Exposure to IFN-β

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The monocyte-derived cytokine response in whole blood from preterm newborns against sepsis-related bacteria is similar to term newborns and adults

IntroductionSepsis is characterized by a dysregulated innate immune response. It is a leading cause of morbidity and mortality in newborns, in particular for newborns that are born premature. Although previous literature indicate that the pro-inflammatory response may be impaired in preterm newborns, serum levels of monocyte-derived cytokines, such as TNF-α and IL-6, vary highly between newborns and can reach adult-like concentrations during sepsis. These contradictory observations and the severe consequences of neonatal sepsis in preterm newborns highlight the need for a better understanding of the pro-inflammatory cytokine response of preterm newborns to improve sepsis-related outcomes.Methods and resultsUsing an in vitro model with multiple read outs at the transcriptional and protein level, we consistently showed that the monocyte-derived cytokine response induced by sepsis-related bacteria is comparable between preterm newborns, term newborns and adults. We substantiated these findings by employing recombinant Toll-like receptor (TLR) ligands and showed that the activation of specific immune pathways, including the expression of TLRs, is also similar between preterm newborns, term newborns and adults. Importantly, we showed that at birth the production of TNF-α and IL-6 is highly variable between individuals and independent of gestational age.DiscussionThese findings indicate that preterm newborns are equally capable of mounting a pro-inflammatory response against a broad range of bacterial pathogens that is comparable to term newborns and adults. Our results provide a better understanding of the pro-inflammatory response by preterm newborns and could guide the development of interventions that specifically modulate the pro-inflammatory response during sepsis in preterm newborns

Perinatal Infections With Ureaplasma

Ureaplasma species are increasingly recognized as relevant pathogens in prenatal, perinatal and postnatal morbidity. They are commonly found as commensals on the mucous membranes of the lower urogenital tract of pregnant women, but when ascending, they can cause bacterial vaginosis, chorioamnionitis, premature birth and postnatal morbidities such as bronchopulmonary dysplasia, and early-onset neonatal sepsis and meningitis. The detection of Ureaplasma species is challenging and is not covered by routine diagnostics, and current empiric antibiotic treatment in neonates suspected of infection is not directed against Ureaplasma species. The aim of this review is to discuss the pathophysiology of Ureaplasma infections, the clinical consequences and the current difficulties in diagnosis and treatment by providing an overview of the current literature

Siglec-1 inhibits RSV-induced interferon gamma production by adult T cells in contrast to newborn T cells.

Interferon gamma (IFN-γ) plays an important role in the antiviral immune response during respiratory syncytial virus (RSV) infections. Monocytes and T cells are recruited to the site of RSV infection, but it is unclear whether cell-cell interactions between monocytes and T cells regulate IFN-γ production. In this study, micro-array data identified the upregulation of sialic acid-binding immunoglobulin-type lectin 1 (Siglec-1) in human RSV-infected infants. In vitro, RSV increased expression of Siglec-1 on healthy newborn and adult monocytes. RSV-induced Siglec-1 on monocytes inhibited IFN-γ production by adult CD4+T cells. In contrast, IFN-γ production by RSV in newborns was not affected by Siglec-1. The ligand for Siglec-1, CD43, is highly expressed on adult CD4+T cells compared to newborns. Our data show that Siglec-1 reduces IFN-γ release by adult T cells possibly by binding to the highly expressed CD43. The Siglec-1-dependent inhibition of IFN-γ in adults and the low expression of CD43 on newborn T cells provides a better understanding of the immune response against RSV in early life and adulthood

Siglec-1 inhibits RSV-induced interferon gamma production by adult T cells in contrast to newborn T cells.

Interferon gamma (IFN-γ) plays an important role in the antiviral immune response during respiratory syncytial virus (RSV) infections. Monocytes and T cells are recruited to the site of RSV infection, but it is unclear whether cell-cell interactions between monocytes and T cells regulate IFN-γ production. In this study, micro-array data identified the upregulation of sialic acid-binding immunoglobulin-type lectin 1 (Siglec-1) in human RSV-infected infants. In vitro, RSV increased expression of Siglec-1 on healthy newborn and adult monocytes. RSV-induced Siglec-1 on monocytes inhibited IFN-γ production by adult CD4+T cells. In contrast, IFN-γ production by RSV in newborns was not affected by Siglec-1. The ligand for Siglec-1, CD43, is highly expressed on adult CD4+T cells compared to newborns. Our data show that Siglec-1 reduces IFN-γ release by adult T cells possibly by binding to the highly expressed CD43. The Siglec-1-dependent inhibition of IFN-γ in adults and the low expression of CD43 on newborn T cells provides a better understanding of the immune response against RSV in early life and adulthood

Characteristics of RSV-Specific Maternal Antibodies in Plasma of Hospitalized, Acute RSV Patients under Three Months of Age.

Respiratory syncytial virus (RSV) is the leading cause for respiratory illness that requires hospitalization in infancy. High levels of maternal antibodies can protect against RSV infection. However, RSV-infected infants can suffer from severe disease symptoms even in the presence of high levels of RSV-specific antibodies. This study analyzes several serological characteristics to explore potential deficiencies or surpluses of antibodies that could relate to severe disease symptoms. We compare serum antibodies from hospitalized patients who suffered severe symptoms as well as uninfected infants. Disease severity markers were oxygen therapy, tachypnea, oxygen saturation, admission to the intensive care unit and duration of hospitalization. Antibodies against RSV G protein and a prefusion F epitope correlated with in vitro neutralization. Avidity of RSV-specific IgG antibodies was lower in RSV-infected infants compared to uninfected controls. Severe disease symptoms were unrelated to RSV-specific IgG antibody titers, avidity of RSV-IgG, virus neutralization capacity or titers against pre- and postfusion F or G protein ectodomains and the prefusion F antigenic site Ø. In conclusion, the detailed serological characterization did not indicate dysfunctional or epitope-skewed composition of serum antibodies in hospitalized RSV-infected infants suffering from severe disease symptoms. It remains unclear, whether specific antibody fractions could diminish disease symptoms

Study population.

<p>Study population.</p

Antibody properties do not correlate with disease severity parameters.

<p>Antibody properties do not correlate with disease severity parameters.</p

RSV-specific IgG against F protein antigenic sites Ø and I not correlate with disease severity.

<p>The abundance of antibodies in human infant plasma that bind to the prefusion F protein antigenic site Ø or the postfusion F protein antigenic site I was determined by competition with site-specific monoclonal antibodies in ELISA. (A-B) Median (± IQR) IgG titer that blocks 25% binding of D25 (site Ø) were compared between healthy and RSV-infected infants as well as between RSV patients with and without oxygen therapy. (C-D) Median (± IQR) IgG titer that blocks 15% binding of 131-2A (site I) were compared between healthy and RSV-infected infants as well as between RSV patients with and without oxygen therapy. No significant differences were observed by Mann Whitney <i>U</i> test.</p

RSV-specific IgG titer and RSV-IgG avidity do not correlate with disease severity.

<p>RSV-specific IgG levels in plasma of infants was determined by ELISA using virus particles. RSV-IgG avidity was assessed by supplementing NaSCN during ELISA. (A) RSV-specific IgG levels were displayed versus age. (B-C) Median RSV-specific IgG levels (± IQR) were compared between healthy and RSV-infected infants as well as between RSV patients with and without oxygen therapy. (D-E) Median (± IQR) avidity of RSV-IgG in healthy infants was compared to RSV-infected infants or between RSV patients with or without oxygen therapy. Associations were assessed by Spearman correlation test. Statistical analyses employed Mann Whitney U test. (**P<0.01).</p