Immunological Defects in Neonatal Sepsis and Potential Therapeutic Approaches

Abstract

Despite advances in critical care medicine, neonatal sepsis remains a major cause of morbidity and mortality worldwide, with the greatest risk affecting very low birth weight, preterm neonates. The presentation of neonatal sepsis varies markedly from its presentation in adults, and there is no clear consensus definition of neonatal sepsis. Previous work has demonstrated that when neonates become septic, death can occur rapidly over a matter of hours or days and is generally associated with inflammation, organ injury, and respiratory failure. Studies of the transcriptomic response by neonates to infection and sepsis have led to unique insights into the early proinflammatory and host protective responses to sepsis. Paradoxically, this early inflammatory response in neonates, although lethal, is clearly less robust relative to children and adults. Similarly, the expression of genes involved in host protective immunity, particularly neutrophil function, is also markedly deficient. As a result, neonates have both a diminished inflammatory and protective immune response to infection which may explain their increased risk to infection, and their reduced ability to clear infections. Such studies imply that novel approaches unique to the neonate will be required for the development of both diagnostics and therapeutics in this high at-risk population.

Keywords: genomics; host response; infection; inflammation; innate immunity; shock; transcriptomics.

Figure 1

Distinct features of the neonatal immunity.

Figure 2

Pathway analysis of gene expression from blood leukocytes of neonates and young adults subjected to sepsis. Modified from Gentile et al. (30). Copyright 2014. The American Association of Immunologists, Inc. Heat maps show the gene expression of the functional category hematological systems development and function. Blue represents pathways with an overexpression of genes leading to downregulation of the pathway, whereas orange represents pathways with an overexpression of genes whose activation will lead to upregulation of the pathway. The corresponding tables show the top 10 pathways and their corresponding z-score within the functional category. Blue indicates the pathway is significantly downregulated, and red indicates the pathway is significantly upregulated.