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Background: Humoral bactericidal activity was first recognized nearly a century ago. However, the extent of inter-individual heterogeneity and the mechanisms underlying such heterogeneity beyond antibody or complement systems have not been well studied., Methods: The plasma bactericidal activity of five healthy volunteers were tested against 30 strains of Gram-negative uropathogens, Klebsiella pneumoniae and Escherichia coli, associated with bloodstream infections. IgG and IgM titers specific to K. pneumoniae strains KP13883 and KPB1 were measured by ELISA, and complement inhibitor was used to measure the contribution of complement-induced killing. Furthermore, MALDI-TOF mass spectrometry was conducted to determine the metabolomic components of plasma with bactericidal properties in 25 healthy individuals using Bayesian inference of Pearson correlation between peak intensity and colony counts of surviving bacteria., Results: Plasma bactericidal activity varied widely between individuals against various bacterial strains. While individual plasma with higher IgM titers specific to K. pneumoniae strain KP13883 showed more efficient killing of the strain, both IgM and IgG titers for K. pneumoniae strain KPB1 did not correlate well with the killing activity. Complement inhibition assays elucidated that the complement-mediated killing was not responsible for the inter-individual heterogeneity in either isolate. Subsequently, using MALDI-TOF mass spectrometry on plasmas of 25 healthy individuals, we identified several small molecules including gangliosides, pediocins, or saponins as candidates that showed negative correlation between peak intensities and colony forming units of the test bacteria., Conclusion: This is the first study to demonstrate the inter-individual heterogeneity of constitutive innate humoral bactericidal function quantitatively and that the heterogeneity can be independent of antibody or the complement system., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Abe, Ram-Mohan, Zudock, Lewis, Carroll and Yang.)

Although cellular immunity has garnered much attention in the era of single-cell technologies, humoral innate immunity has receded in priority due to its presumed limited roles. Hence, despite the long-recognised bactericidal activity of serum-a functional characteristic of constitutive humoral immunity-much remains unclear regarding mechanisms underlying its inter-individual heterogeneity and clinical implications in bloodstream infections. Recent work suggests that the immediate antimicrobial effect of humoral innate immunity contributes to suppression of the excessive inflammatory responses to infection by reducing the amount of pathogen-associated molecular patterns. In this Personal View, we propose the need to re-explore factors underlying the inter-individual heterogeneity in serum antibacterial competence as a new approach to better understand humoral innate immunity and revisit the clinical use of measuring serum antibacterial activity in the management of bacterial bloodstream infections. Given the current emphasis on subtyping sepsis, a serum bactericidal assay might prove useful in defining a distinct sepsis endotype, to enable more personalised management., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)