Abstract
Background: There is a need to prevent and treat infection in newborns. One approach is administration of antimicrobial proteins and peptides (APPs) such as LL-37, a membrane-active cathelicidin antimicrobial peptide, and mannose-binding lectin (MBL), a pattern-recognition protein that binds to microbial surface polysaccharides resulting in opsonization and complement activation. Low plasma/serum levels of LL-37 and of MBL have been correlated with infection and exogenous administration of these agents may enhance host defense. Methods: The antimicrobial activity of LL-37 (15 µg/ml) or rMBL (0.5, 2 and 10 µg/ml) was tested in hirudin-anticoagulated preterm and term human cord blood (N = 12-14) against Staphylococcus aureus (SA) USA 300 (2x10 4 CFU/ml), Staphylococcus epidermis (SE) 1457 (2x10 4 CFU/ml) and Candida albicans (CA) SC5314 (1x10 4 CFU/ml). After incubation (1, 45, or 180 min), CFUs were enumerated by plating blood onto agar plates. Supernatants were collected for measurement of MBL via ELISA. Results: Preterm cord blood demonstrated impaired endogenous killing capacity against SA and SE compared to term blood. Addition of LL-37 strongly enhanced antimicrobial/antifungal activity vs SA, SE and CA in term blood and SE and CA in preterm blood. By contrast, rMBL showed modest fungistatic activity vs CA in a sub-analysis of term newborns with high basal MBL levels. Baseline MBL levels varied within preterm and term cohorts with no correlation to gestational age. In summary, exogenous LL-37 demonstrated significant antimicrobial activity against SA, SE and CA in term and SE and CA in preterm human blood tested in vitro. rMBL demonstrated modest antifungal activity in term cord blood of individuals with high baseline MBL levels. Conclusions: To the extent that our in vitro results predict the effects of APPs in vivo, development of APPs for prevention and treatment of infection should take into account host age as well as the target pathogen.
Highlights
Neonatal sepsis is a major contributor to neonatal morbidity and mortality; efforts to ease the burden of this disease are crucial[1]
In the present study we focused on the potential utility of two APPs with distinct modes of action: (a) the α-helical LL-37 cationic cathelicidin[8] is a broad spectrum membrane-active antimicrobial peptide that induces microbial lysis, blocks endotoxin activity, synergizes with other host defense systems,[9] and modulates inflammatory responses[9,10]; and (b) mannose-binding lectin (MBL), a host pattern recognition receptor that recognizes and binds to sugar moieties on the surface of bacteria and fungi, enhances opsonophagocytosis, and forms complexes with MBL-associated serine proteases that trigger complement activation[11]
To characterize the activity of LL-37 and recombinant MBL (rMBL) in neonatal blood, we evaluated antimicrobial activity towards three pathogens commonly associated with late-onset sepsis (LOS) in newborns: (a) Staphylococcus epidermidis (SE), that accounts for 78% of cases of LOS due to coagulase-negative staphylococci, (b) Staphylococcus aureus (SA), a less common pathogen associated with a high rate of mortality; and Candida albicans (CA) the most common fungal pathogen associated with LOS
Summary
Neonatal sepsis is a major contributor to neonatal morbidity and mortality; efforts to ease the burden of this disease are crucial[1]. Early-onset sepsis (EOS) is most commonly differentiated from late-onset sepsis (LOS) by the onset occurring before or after the first 72 h of life, respectively[3]. Of note, both the clinical features and pathophysiology of sepsis varies markedly by age, such that adult, pediatric and neonatal sepsis criteria are distinct[1]. While screening and prophylaxis for Group B Streptococcus has reduced rates of EOS (i.e., within the first 3 days of life), LOS in the preterm infant has increased in frequency as a higher number of premature infants have survived, resulting in invasive procedures and prolonged hospital stays, as well as increased pathogen exposure[3,4].
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
