a-controlled-mouse-model-for-neonatal-polymicrobial-sepsis

A Controlled Mouse Model for Neonatal Polymicrobial Sepsis

Neonatal sepsis remains a global burden. A preclinical model to screen effective prophylactic or therapeutic interventions is needed. Neonatal mouse ...

probiotic-studies-in-neonatal-mice-using-gavage

Probiotic Studies in Neonatal Mice Using Gavage

Adult mouse models have been widely used to understand the mechanism behind disease progression in humans. The applicability of studies done in adult ...

University of British Columbia

The burden of newborn infectious disease has long been recognized as the highest across the entire human life span. The precise underlying cause is unfortunately still far from clear. A substantial body of data derived mostly from in vitro experimentation indicates "lower" host immune responses in early vs. adult life and is briefly summarized within this review. However, emerging data derived mostly from in vivo experimentation reveal that the newborn host also exhibits an exuberant immune and inflammatory response following infection when compared to the adult. In this context, it is important to emphasize that "infection" does not equate "infectious disease," as for many infections it is the host response to the infection that causes disease. This simple insight readily arranges existing evidence into cause-effect relationships that explain much of the increase in clinical suffering from infection in early life. We here briefly summarize the evidence in support of this paradigm and highlight the important implications it has for efforts to ameliorate the suffering and dying from infection in early life.

Newborn susceptibility to infection vs. disease depends on complex in vivo interactions of host and pathogen.

Newborns suffer high rates of mortality due to infectious disease-this has been generally regarded to be the result of an "immature" immune system with a diminished disease-fighting capacity. However, the immaturity dogma fails to explain (i) greater pro-inflammatory responses than adults  and (ii) the ability of neonates to survive a significantly higher blood pathogen burden than of adults. To reconcile the apparent contradiction of clinical susceptibility to disease and the host immune response findings when contrasting newborn to adult, it will be essential to capture the entirety of available host-defense strategies at the newborn's disposal. Adults focus heavily on the disease resistance approach: pathogen reduction and elimination. Newborn hyperactive innate immunity, sensitivity to immunopathology, and the energetic requirements of growth and development (immune and energy costs), however, preclude them from having an adult-like resistance response. Instead, newborns also may avail themselves of disease tolerance (minimizing immunopathology without reducing pathogen load), as a disease tolerance approach provides a counterbalance to the dangers of a heightened innate immunity and has lower-associated immune costs. Further, disease tolerance allows for the establishment of a commensal bacterial community without mounting an unnecessarily dangerous immune resistance response. Since disease tolerance has its own associated costs (immune suppression leading to unchecked pathogen proliferation), it is the maintenance of homeostasis between disease tolerance and disease resistance that is critical to safe and effective defense against infections in early life. This paradigm is consistent with nearly all of the existing evidence.

Outgrowing the Immaturity Myth: The Cost of Defending From Neonatal Infectious Disease.

Bacterial sepsis is one of the leading causes of death in newborns. In the face of growing antibiotic resistance, it is crucial to understand the pathology behind the disease in order to develop effective interventions. Neonatal susceptibility to sepsis can no longer be attributed to simple immune immaturity in the face of mounting evidence that the neonatal immune system is tightly regulated and well controlled. The neonatal immune response is consistent with a "disease tolerance" defense strategy (minimizing harm from immunopathology) whereas adults tend toward a "disease resistance" strategy (minimizing harm from pathogens). One major advantage of disease tolerance is that is less energetically demanding than disease resistance, consistent with the energetic limitations of early life. Immune effector cells enacting disease resistance responses switch to aerobic glycolysis upon TLR stimulation and require steady glycolytic flux to maintain the inflammatory phenotype. Rapid and intense upregulation of glucose uptake by immune cells necessitates an increased reliance on fatty acid metabolism to (a) fuel vital tissue function and (b) produce immunoregulatory intermediates which help control the magnitude of inflammation. Increasing disease resistance requires more energy: while adults have fat and protein stores to catabolize, neonates must reallocate resources away from critical growth and development. This understanding of sepsis pathology helps to explain many of the differences between neonatal and adult immune responses. Taking into account the central role of metabolism in the host response to infection and the severe metabolic demands of early life, it emerges that the striking clinical susceptibility to bacterial infection of the newborn is at its core a problem of metabolism. The evidence supporting this novel hypothesis, which has profound implications for interventions, is presented in this review.

Danny Harbeson

Department of Experimental Medicine

University of British Columbia

A Controlled Mouse Model for Neonatal Polymicrobial Sepsis

Probiotic Studies in Neonatal Mice Using Gavage

Danny Harbeson

.css-o250i3{font-size:18px;font-family:Open Sans,sans-serif;line-height:21.6px;}Department of Experimental Medicine

University of British Columbia

A Controlled Mouse Model for Neonatal Polymicrobial Sepsis

Probiotic Studies in Neonatal Mice Using Gavage

Department of Experimental Medicine