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

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Abstract

Neonatal sepsis is a predominant cause of neonatal mortality and long-term morbidity which severely effects preterm and low birth weight newborns. Antibiotic resistance and long-term developmental issues associated with neonatal sepsis necessitates finding new and improved treatment options. Interleukin-27 (IL-27) has diverse influences on the immune response, is elevated during the neonatal period compared to 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 Escherichia 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 to controls during infection. The combination of subclinical dose of gentamicin and IL-27p28 antibody administered 2h post-infection, significantly improved bacterial clearance, glucose homeostasis, with reduced serum levels of IL-6 and TNF-α, vital organ damage and significantly improved the survival rate of infected pups compared to 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