Defective innate immunity predisposes murine neonates to poor sepsis outcome but is reversed by TLR agonists

Abstract

Neonates exhibit an increased risk of sepsis mortality compared with adults. We show that in contrast to adults, survival from polymicrobial sepsis in murine neonates does not depend on an intact adaptive immune system and is not improved by T cell-directed adaptive immunotherapy. Furthermore, neonates manifest an attenuated inflammatory and innate response to sepsis, and have functional defects in their peritoneal CD11b ؉ cells. Activation of innate immunity with either a Toll-like receptor 4 (TLR4) or TLR7/8 agonist, but not a TLR3 agonist, increased the magnitude, but abbreviated the early systemic inflammatory response, reduced bacteremia, and improved survival to polymicrobial sepsis. TLR4 agonist pretreatment enhanced peritoneal neutrophil recruitment with increased oxidative burst production, whereas the TLR7/8 agonist also enhanced peritoneal neutrophil recruitment with increased phagocytic ability. These benefits were independent of the adaptive immune system and type I interferon signaling. Improving innate immune function with select TLR agonists may be a useful strategy to prevent neonatal sepsis mortality. IntroductionSepsis causes profound defects in innate and acquired immunity. In septic adults, circulating leukocytes fail to mount an attenuated inflammatory response, monocytes have defective antigen presentation in part due to reduced MHC class II expression, and dendritic cells and lymphocytes exhibit increased apoptosis. [1][2][3][4] These deficiencies contribute to a failure to clear primary pathogens, an increased propensity to develop superinfections, and an inability to mount adaptive immune responses. Considerable progress has been made in understanding the pathogenesis of and identifying potential immunomodulatory therapies for treating sepsis in adult animals. For example, MyD88 and type I interferon signaling pathways 5,6 are important requisites for innate and inflammatory host defense responses to pathogens. 7,8 Stimulating the innate immune system with Toll-like receptor (TLR) agonists improves survival in adult animal models of sepsis. 9,10 Similarly, absence of the adaptive immune system 11 or an inability of B cells to produce antibodies 12 predisposes adult mice to a poor outcome in sepsis. Correction of adaptive immune dysfunction by prevention of lymphocyte apoptosis or treatment with agonistic glucocorticoid-induced tumor necrosis factor (TNF) receptor antibody (anti-GITR) to stimulate effector T-cell function, improves survival in animal models of adult sepsis. 11,13 These studies highlight the importance of both the innate and adaptive immune systems in eliminating invading pathogens in adult mammals. However, the mechanisms of protective immunity in neonates that do not possess a fully intact immune system, and who develop sepsis at increased rates, 14 are less clear.More than 1 million babies die each year worldwide within the first 4 weeks of life from sepsis. 15 Neonatal sepsis mortality is higher than in children and adults, 16,17 peaking in premature infants, where r...

An Immunological Perspective on Neonatal Sepsis

“…These models have confirmed the limited myelopoietic capacity of the newborn and its impact on survival of newborn mice during sepsis [96]. Using a poly-microbial infection model, Wynn and Moldawer demonstrated that rodent neonates rely heavily on innate immune defense during sepsis [97]. Moreover, the brain of a developing newborn is also particularly vulnerable to inflammation, and neonatal infections carry an important risk of major longterm neurological disability in premature infants [98].…”

Lipopolysaccharide Clearance, Bacterial Clearance, and Systemic Inflammatory Responses Are Regulated by Cell Type–Specific Functions of TLR4 during Sepsis

“…It was shown that TLR4 stimulation leads to enhanced phagocytosis of bacteria by macrophages (15). Furthermore, other investigators showed that agonists of TLR4 (33,46) or other TLRs (46), given either as a pretreatment or early postinfection, enhance bacterial clearance and survival in models of sepsis. We confirm in our current work that LPS given 1 h after CLP improves bacterial clearance.…”

The developing human preterm neonatal immune system: A case for more research in this area

“…However, the evolutionary advantage of attenuated innate immune defenses in utero clearly becomes a major clinical disadvantage following a preterm birth. Nonetheless, direct evidence for the implication of specific innate immune deficits in increasing preterm infants' risk of infection in humans is lacking and inference from data in mice is complicated by significant functional differences across species [52]. Moreover, the presence of compensatory mechanisms (i.e.…”