Neonatal sepsis proteomics defines a three-pathway serum signature in newborns
Neonatal sepsis remains one of the most difficult emergencies in pediatrics because the bedside presentation is often vague while the biological injury is already advancing. In Senegal, where incidence is high and case fatality remains substantial, the need for a usable molecular signal is especially acute. This study moves directly at that problem by comparing serum proteomes from neonates and adults and then searching for protein patterns that separate confirmed infection from non-confirmed illness and healthy controls.
The investigators analyzed neat serum using data-independent acquisition proteomics on an Evosep-timsTOF HT platform. The cohort included 22 neonates with confirmed sepsis, 6 with non-confirmed sepsis, 17 healthy newborn controls, 6 unclassified neonates, 9 outliers, and 20 healthy adults. From that design came a broad map of circulating proteins rather than a single-marker strategy. In newborns, the assay identified 979 ± 20 proteins, compared with 718 ± 40 in adults.
One sentence captures the biological imbalance: newborn serum is not just smaller in scale, it is qualitatively different.
Immune immaturity and a narrower proteomic range in newborn serum
Across the neonatal samples, immune-response proteins were reduced, the dynamic range was narrower, and structural proteins such as collagens were relatively increased. That pattern fits the biology of early life, when immune defense is still maturing and tissues are undergoing active development. The serum environment in a newborn therefore reflects more than infection status; it also carries the signature of developmental physiology, which complicates any attempt to read sepsis from a single analyte.
This is exactly why the proteomic approach matters. A narrow diagnostic lens can miss the layered host response of neonatal infection, where inflammation, leukocyte mobilization, vascular injury, and tissue remodeling unfold at the same time. The study’s analytic strategy moved beyond isolated markers by using differential abundance testing, unsupervised clustering, weighted gene co-expression network analysis, and correlation analyses with clinical parameters. That design is well suited to a syndrome in which no single pathway explains the whole picture.
A 53-protein cluster separated confirmed from non-confirmed sepsis
Weighted gene co-expression network analysis produced a 53-protein cluster that discriminated confirmed sepsis from non-confirmed sepsis and healthy controls. Several proteins in the cluster had already appeared in independent neonatal or adult sepsis studies using different methods, which strengthens confidence that the signal is not an artifact of one platform alone. The broader contribution here is not only replication; it is the way the proteins sort into coherent biological themes.
The panel mapped to three major processes. The first involved pathogen sensing and acute-phase inflammation, with proteins such as LBP, CD14, CRP, SAA1/2, and ORM1/2. These molecules sit near the front line of host recognition, where microbial products trigger innate signaling and rapidly amplify the inflammatory response. In a newborn, a weak early clinical signal can hide a very active molecular response.
The second pathway centered on innate immune activation and leukocyte recruitment. Proteins including FCGR3A, CSF1R, CD163, and CD206 fit with myeloid activation and cellular trafficking into inflamed tissue. The same cluster also pointed to platelet exhaustion, with PF4, PPBP, THBS1, and GP5 appearing among the dysregulated proteins. In sepsis, platelets do more than participate in clotting; they become engaged in immune crosstalk, endothelial signaling, and microvascular injury. Exhaustion of that system is a marker of how far the inflammatory cascade has progressed.
Endothelial injury and vascular dysfunction sit at the center of severe disease
The third major process was endothelial injury and microvascular dysfunction with tissue remodeling. Proteins such as ICAM1, VCAM1, VWF, and SPARC point to injured endothelium, altered adhesion biology, and repair activity in the microcirculation. In parallel, the panel showed loss of protective lipoproteins and serpins, including APOA1, APOA2, APOM, SERPINA4, and SERPINA5. The vascular wall is not a passive bystander in neonatal sepsis; it is part of the disease process, and once endothelial integrity fails, tissue perfusion, capillary leak, and organ dysfunction follow more easily.
This pathway-level organization gives the study practical value. Neonatal sepsis is frequently managed on clinical suspicion before microbiology is definitive, and that approach saves lives but also exposes many infants to treatment without certainty. A serum panel that captures pathogen sensing, immune recruitment, and endothelial injury could help separate infants with true systemic infection from those with non-specific inflammatory illness. It may also offer a route to stratify severity rather than simply answer yes-or-no infection questions.
Why a multi-pathway panel fits neonatal diagnosis better than a single marker
The molecular architecture of this study argues against a one-protein solution. Newborns have a developing immune system, a distinct baseline proteome, and a clinical syndrome that often overlaps with respiratory, metabolic, and perinatal stress states. A biomarker that only reflects inflammation may fail when the dominant signal is vascular damage; one that only reflects endothelial leakage may miss early pathogen recognition. The 53-protein set is therefore more credible as a diagnostic framework than as a shortlist of interchangeable markers.
The cohort also included healthy adults, which helped establish a reference for the neonatal serum proteome itself. That comparison matters because adult immune biology cannot simply be projected onto newborns. The proteomic differences observed here show why neonatal diagnostics need age-specific reference ranges and age-specific biomarker discovery. Without that, a clinically important neonatal abnormality can look ordinary if judged against the wrong baseline.
The study was conducted in Senegal, a setting where the burden of neonatal infection is high and where access to advanced diagnostics is often limited. A serum-based panel designed around robust biological processes could eventually prove more practical than pathogen detection alone, especially when cultures are slow, insensitive, or unavailable. The work does not yet establish a bedside test, and it does not provide a validated cutoff for clinical use. It does, however, define a biologically coherent target set for the next stage of assay development.
No single protein will solve neonatal sepsis, but this serum map makes the disease legible in a way that routine bedside signs rarely do.