Neonatal bacterial infection alters fever to live and simulated infections in adulthood
Introduction
Fever is an evolutionarily conserved and critical component of the host immune response to infection (Steiner et al., 2006b). Fever in mammals is a highly regulated change in body temperature homeostasis that is initiated and maintained by the host via endogenous mediators. In response to proinflammatory cytokines (e.g., TNFα, interleukin (IL)-6) or other pyrogenic molecules (e.g., LPS), the activation of the arachidonic acid cascade leads to the biosynthesis of prostaglandins (i.e., PGE2) within both the periphery and the brain, primarily within the pre-optic area (POA) of the anterior hypothalamus, which are then responsible for fever induction (Ivanov and Romanovsky, 2004, Steiner et al., 2006b). Evidence suggests that the early phase of fever is initiated via PGE2 synthesis within peripheral macrophages, whereas later phases are mediated centrally, via PGE2 synthesis within perivascular macrophages and resident nonhematopoietic cells (e.g., endothelial cells, microglia) (Steiner et al., 2006a). Inducible cyclooxygenase (COX)-2 is a critical enzyme in each phase of prostaglandin synthesis, and preventing its induction also prevents fever (Cao et al., 1995, Quan et al., 1998).
Despite its benefits, excessive or prolonged fever and its associated catabolic changes may be damaging or lethal to the host (Berczi, 1998), and sepsis remains a major problem in Westernized countries (Adib-Conquy and Cavaillon, 2002). Tolerance to repeated exposures of infectious molecules may be an adaptive response aimed at preventing excessive fever and inflammation (Arbibe and Sansonetti, 2007). LPS-tolerant animals survive otherwise lethal doses of LPS (Broad et al., 2006). Tolerance is characterized by reduced fever, changes in cytokine production (e.g., decreased TNFα), and altered gene expression in peripheral macrophages (e.g., decreased NF-kB expression) (West and Heagy, 2002, Fan and Cook, 2004). The principal cell surface receptor for LPS on innate immune cells, TLR 4, is required for fever expression (Steiner et al., 2006a), and is functionally altered in tolerant cells (West and Heagy, 2002). There is also evidence for central mediators of tolerance; intact vagal innervation of the liver is required for the development of LPS tolerance in rats, although the mechanism is unknown (Ivanov et al., 2000). Notably, augmented immune responses and increased resistance to infection often accompany tolerance, strong evidence of its adaptive function (Rayhane et al., 2000, Lehner et al., 2001, Foster et al., 2007). Indeed, tolerance has recently been described as a “critical feature of homeostasis”, and not simply a brake system for inflammation (Arbibe and Sansonetti, 2007).
The majority of investigations on tolerance have involved homotypic challenges (e.g., repeated doses of LPS acting on TLR 4). However, an important clinical question is whether tolerance, and its protective mechanisms, applies more broadly to heterotypic challenges that work via multiple or disparate TLRs (e.g., CpG DNA via TLR 9; Viruses via TLR 3), or whether such challenges may instead be synergistic and ultimately result in increased inflammation and poorer outcome. For instance, viral infection often augments the subsequent response to LPS (Nansen and Randrup Thomsen, 2001, Fejer et al., 2005). In contrast, low dose peptidoglycan (gram-positive bacteria) or cytokines alone can protect from subsequent high dose LPS, and vice versa (Cavaillon, 1995). Similarly, TLR 2, 4, and 9 agonists induce cross-tolerance to subsequent heterotypic challenge to macrophages in vitro, although responses in vivo often differ (Dalpke et al., 2005). In sum, there is evidence for both sensitization and cross-tolerance in the literature (reviewed in Broad et al., 2006), but the mechanisms are largely unknown.
The developmental history of the individual may be a critical overlooked factor in the host response to serial or repeated infections. For instance, several groups have now demonstrated that early-life challenge with LPS significantly alters subsequent LPS-induced fever and cytokine expression in adulthood (Boisse et al., 2004, Ellis et al., 2005, Walker et al., 2006). Interestingly, this outcome depends on exposure to the same (homotypic) antigen (LPS in both cases), as fever in response to poly IC, a viral mimetic which acts on TLR 3, is not significantly altered as a consequence of early-life challenge with LPS (Ellis et al., 2006). These data suggest the possibility of specific changes in the TLR pathways underlying each outcome.
From these data, an important question is whether early-life infection with a live pathogen (e.g., E. coli) will alter fever/sickness responses to immune challenges in adulthood, which has potential implications for infection resistance and disease outcomes. Notably, although TLR 4 remains the primary receptor for recognition of LPS molecules on E. coli, this replicating pathogen may stimulate via multiple TLRs (e.g., TLR 2/4/5/9; Hemmi et al., 2000, Hayashi et al., 2001, Steiner et al., 2005), making this an important comparison from both a clinical and mechanistic standpoint. Thus, the goal of the current study was to characterize whether fever to both LPS and E. coli in adulthood is altered as a consequence of neonatal infection with live E. coli, and to explore some of the potential mechanisms.
Section snippets
Animals
Adult male and female Sprague–Dawley rats (70 days) were obtained from Harlan (Indianapolis, IN) and housed in same sex pairs in individually ventilated, microisolator polypropylene cages, with ad libitum access to food and filtered water. The colony was maintained at 22 °C on a 12:12-h light:dark cycle (lights on at 0500 h). Following acclimation to laboratory conditions, males and females were paired into breeders. Sentinel animals were housed in the colony room and screened periodically for
Low dose LPS-induced fever and weight loss do not differ as a consequence of early-life infection
There were no neonatal group differences in body temperature in response to an injection of saline (SAL) on P60. Fever in response to P61 LPS also did not significantly differ by group (p > 0.05; Fig. 2a). Activity levels dropped significantly in all rats in response to LPS compared to saline (F(1,287) = 36.5, p < 0.001), but did not differ by neonatal treatment (data not shown). Both activity and fever responses returned to normal by Day 2. All rats lost weight on Day 1 post-LPS, and this was
Discussion
Several groups have demonstrated that early-life exposure to infectious agents may have significant consequences for the development and function of physiological systems throughout the lifespan, a phenomenon known as “perinatal programming” (Barker et al., 1995). We explored whether fever to infectious stimuli in adulthood is altered as a consequence of neonatal infection with bacteria. Fever and weight loss to a single low dose of LPS in adult rats infected early in life were each slightly
Conclusions
The role of infectious events occurring early in life, and susceptibility to neuroinflammation or disease later in life, has become a topic of immense interest in recent years (Hornig et al., 1999, Shanks et al., 2000, Breivik et al., 2002, Shi et al., 2003). Taken together, our data indicate that early-life infection is associated with marked changes in host temperature regulation to repeat immune challenges in adulthood, which may have implications for infection resistance and ultimately
Role of funding source
The NIH did not support this study, and had no role in study design, in the collection, analysis and interpretation of data, in the writing of the report, or in the decision to submit the paper for publication to this journal.
Conflict of interest
All authors declare that they have no conflicts of interest.
Acknowledgements
The authors thank Alexis Northcutt and Andrea Eads for technical assistance.
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