Abstract:
Almost 40% of childhood deaths occur within the first 28 days of life, with neonatal sepsis being a major contributor to morbidity and mortality, particularly among preterm infants. Newborns are highly susceptible to infections, as their immune responses, compared to those of adults, are still characterized by anti-inflammatory and immunosuppressive mechanisms originating from fetal life. On the other hand, newborns have an impaired ability to resolve inflammatory reactions once they have been initiated. Immune-checkpoint molecules (ICMs) control inflammatory responses and may contribute to immune adaptations in early life, but their role in neonatal sepsis has been poorly defined so far. The ICM CD200 and its receptor CD200R have been suggested to play an important part in regulating inflammatory responses in various murine models of inflammatory diseases and human inflammatory diseases. However, its expression pattern on many neonatal immune cells and its potential role in regulating neonatal responses in inflammatory diseases has not been described so far.
In this study, we investigated the role of CD200/CD200R for the pathogenesis of neonatal sepsis. In a murine E. coli sepsis model, neonatal mice required lower bacterial doses to reach mortality comparable to adults and showed higher bacterial burden in lungs and blood, alongside pro-inflammatory cytokine levels. Neonates displayed higher CD200R but lower CD200 expression on monocytes, while neonatal T-cells expressed more CD200 than CD200R. Additionally, neonates had elevated soluble CD200 (sCD200) levels. Recombinant CD200 (rCD200) administration significantly increased mortality in neonatal mice without affecting bacterial load, cytokine levels or immune cell composition, while CD200 blockade had no clear effect in preliminary experiments.
A cross-species analysis of CD200 and CD200R expression of mice and humans revealed notable differences between species. Human neonates (pre-term and full-term) expressed more CD200 on T-cells than adults, with similarly high CD200R expression across groups, while sCD200 levels were lower in newborns compared to adults. Functional assays were unable to elucidate the functional relevance of CD200/CD200R on neonatal immune cells.
Differential CD200/CD200R expression in neonates could reflect developmental immune adaptations that limit excessive inflammation after birth but may predispose neonates to the development of severe infections after pathogen encounter. This provides a basis for further studies on how immune checkpoint pathways shape early-life immunity and transition from fetal to postnatal life. Although rCD200 worsened sepsis outcomes in neonatal mice, immune checkpoint pathways remain a potential target for novel therapeutic approaches in neonatal inflammatory disease.
Immunology