Abstract
Staphylococcus epidermidis (SE) causes late onset sepsis and significant morbidity in catheterized preterm newborns. Animal models of SE infection are useful in characterizing disease mechanisms and are an important approach to developing improved diagnostics and therapeutics. Current murine models of neonatal bacterial infection employ intraperitoneal or subcutaneous routes at several days of age, and may, therefore, not accurately reflect distinct features of innate immune responses to bacteremia. In this study we developed, validated, and characterized a murine model of intravenous (IV) infection in neonatal mice <24 hours (h) old to describe the early innate immune response to SE. C57BL/6 mice <24 h old were injected IV with 106, 107, 108 colony-forming units (CFU) of SE 1457, a clinical isolate from a central catheter infection. A prospective injection scoring system was developed and validated, with only high quality injections analyzed. Newborn mice were euthanized between 2 and 48 h post-injection and spleen, liver, and blood collected to assess bacterial viability, gene expression, and cytokine production. High quality IV injections demonstrated inoculum-dependent infection of spleen, liver and blood. Within 2 h of injection, SE induced selective transcription of TLR2 and MyD88 in the liver, and increased systemic production of plasma IL-6 and TNF-α. Despite clearance of bacteremia and solid organ infection within 48 h, inoculum-dependent impairment in weight gain was noted. We conclude that a model of IV SE infection in neonatal mice <24 h old is feasible, demonstrating inoculum-dependent infection of solid organs and a pattern of bacteremia, rapid and selective innate immune activation, and impairment of weight gain typical of infected human neonates. This novel model can now be used to characterize immune ontogeny, evaluate infection biomarkers, and assess preventative and therapeutic modalities.
Highlights
Human neonates express a distinct, but incompletely characterized, immune response to infection
There is a specific pattern of Toll-like receptors (TLRs)-mediated cytokine production by neonatal mononuclear cells, monocytes and antigen-presenting cells that is skewed toward low production of pro-inflammatory Th1-polarizing cytokines (e.g., TNF-a) and high production of cytokines with anti-inflammatory or Th2polarizing activities (e.g., IL-6) [2,3,7,8,9,10,11]
Feasibility of a newborn IV Staphylococcus epidermidis (SE) infection model We developed a novel model of IV SE infection in newborn mice less than 24 h old, incorporating techniques developed by Kienstra et al describing intravascular injection of fluorescent dextran into newborn mice [45]
Summary
Human neonates express a distinct, but incompletely characterized, immune response to infection. This response is heavily dependent on innate immunity due to early qualitative and quantitative deficiencies in the adaptive immune system [1,2]. Innate immune function is itself dependent on both gestational and postnatal age, and is essential for host defense against infection [2,3,4]. Preterm newborns are susceptible to invasive bacteria. In addition to this age-dependent activity, neonatal immune responses rely heavily on the expression of pattern recognition receptors such as Toll-like receptors (TLRs) [2,5,6]. A number of recent studies have shed light on the distinct responses of newborns to TLR agonists in vitro [12,13], but much remains to be learned regarding interactions of the newborn with live bacterial pathogens in vivo
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