IL-27 neutralization with and without antibiotics as an approach to prevent and treat neonatal sepsis
Madhavi Annamanedi, Jessica M. Povroznik, Samantha Arevalo-Marcano, Cory M. Robinson
Madhavi Annamanedi, Jessica M. Povroznik, Samantha Arevalo-Marcano, Cory M. Robinson
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Research Article Immunology Infectious disease Inflammation

IL-27 neutralization with and without antibiotics as an approach to prevent and treat neonatal sepsis

Abstract

Neonatal sepsis is a predominant cause of neonatal mortality and long-term morbidity that severely affects preterm and low-birth-weight newborns. Antibiotic resistance and long-term developmental issues associated with neonatal sepsis necessitate finding new and improved treatment options. IL-27 has diverse influences on the immune response, is elevated during the neonatal period compared with adulthood, and continues to rise further during infection. Elevated levels of IL-27 early in life predispose the host to impaired control of the pathogen burden and increased mortality. This study explored the therapeutic potential of IL-27p28 antibody administration to improve treatment outcomes during murine neonatal sepsis. Sepsis was induced by subcutaneous inoculation of K1-encapsulated E. coli, and the neonatal pups were rescued with IL-27p28 monoclonal antibody. Pups that received prophylactic antibody prior to the infection demonstrated superior bacterial clearance and significant weight gain compared with controls during infection. The combination of subclinical dose of gentamicin along with IL-27p28 antibody administered 2 hours after infection, significantly improved bacterial clearance and glucose homeostasis, with reduced serum levels of IL-6 and TNF-α, vital organ damage, and improved the survival rate of infected pups compared with gentamicin alone. These findings suggest that IL-27p28 antagonization represents a promising therapeutic tool for treatment of neonatal sepsis.

Authors

Madhavi Annamanedi, Jessica M. Povroznik, Samantha Arevalo-Marcano, Cory M. Robinson

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Figure 4

IL-27 neutralization augments gentamicin to improve bacterial clearance, neonatal morbidity, and reduced systemic inflammation.

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IL-27 neutralization augments gentamicin to improve bacterial clearance,...
(A) Neonatal 4-day-old C57BL/6 mice pups (n = 2–3 per experiment) were infected subcutaneously with a range of 1 × 105 to 5 × 105 CFUs of E. coli O1:K1:H7. After 2 hours of infection, pups received no treatment, 5 μg/g gentamicin alone, or a combination with 10 μg IL-27 monoclonal antibody subcutaneously. Blood and peripheral organs were collected at 24 hours after infection. (B) Box plot with blood glucose levels for each pup is shown. (C) The stomachs of pups that received IL-27 antibody demonstrated reduced gross pathology and increased milk availability. The median (D) blood and (E) spleen CFUs are shown (total n = 32 across 4 experiments with separate litters). (F and G) Box plot showing average serum levels of IL-6 and TNF-α in the spleens of treatment groups, respectively, measured by multiplex immunoassay for each pup (total n = 20 across 3 experiments with separate litters). For all the box plots, boxes represent the median (center line) and extend from the 25th to 75th percentiles (bottom and top lines, respectively); whiskers extend from the minimum to the maximum value. Statistical significance was determined using Kruskal-Wallis’s test with Dunn’s multiple comparisons (B), ordinary 1-way ANOVA with Tukey’s multiple comparisons (D and E), and ordinary 1-way ANOVA with Holm-Šídák multiple comparisons (F and G). ns, P = 0.123; *P = 0.033; **P = 0.002.