Infections and inflammatory diseases during childhood cause growth failure. Chronic and simultaneous infection with multiple enteropathogens such as Campylobacter spp. and Escherichia coli is a regular aspect of childhood in many parts of the world. Children suffering from these infections, even when they are asymptomatic for diarrhea, exhibit reduced linear growth. Similarly, children with inflammatory diseases such as juvenile idiopathic arthritis or Crohn's disease are smaller than healthy children. Reduced childhood growth is linked to impaired cognitive function, a complication seen in children with chronic enteropathogen infections and in patients with loss-of-function mutations in the insulin-like growth factor-1 (Igf1) gene. Childhood infections and inflammatory diseases that lead to growth failure are associated with low IGF-1 and elevated growth hormone (GH) levels, indicating GH resistance. However, the signaling events that lead to GH resistance in response to infection and inflammation are not understood. The principal investigator's laboratory recently made the discovery that activation of the innate immune Toll signaling pathway in the larval stage of the genetic model organism Drosophila melanogaster leads to growth failure. Reduced growth caused by active Toll signaling stems from a potent reduction in circulating levels of Drosophila insulin-like peptide 6 (Dilp6), the fly homolog of IGF-1. In this application, genomic and genetic approaches in the mouse and the fruit fly will be used to investigate the negative regulation of animal growth by innate immune and inflammatory signaling.
In Aim 1, the molecular mechanisms underlying reduced Dilp6 mRNA levels will be investigated. The principal investigator's lab will determine whether Dif, a homolog of NF-kB, binds directly to the Dilp6 promoter to inhibit its expression and will use a forward genetics approach to find additional transcriptional regulators that contribute to the negative regulation of whole-animal growth and/or Dilp6 downstream of Toll signaling.
In Aim 2, molecular mechanisms underlying GH resistance during infection will be investigated. The principal investigator's lab will identify transcriptional mechanisms linking endotoxin and pro-inflammatory cytokine signaling to reduced expression of components of the GH signaling pathway in primary mouse hepatocytes and will use a tissue-specific genetic approach to determine whether MyD88, a common component of the TLR4 and IL-1 signaling pathways is required in liver to inhibit GH signaling, IGF-1 production and growth in response to Campylobacter infection. Successful completion of the Specific Aims will identify signaling mechanisms underlying a widespread but poorly understood consequence of infection and inflammation: endocrine dysfunction leading to growth failure. The work proposed here will contribute to our understanding of hormone regulation and the control of non-immune functions by innate immune and inflammatory signaling. Furthermore, this work may lead to new therapies for treatment of growth failure and prevention of cognitive impairment in children suffering from chronic infections or inflammatory diseases.
Sustained activation of the innate immune system during periods of rapid growth leads to growth failure, whether in children suffering from chronic enteropathogen infection or in the model organism Drosophila melanogaster. In young children and in fruit fly larvae, innate immune signaling leads to insufficient circulating levels of homologous growth-promoting hormones: liver-derived insulin-like growth factor-1 and fat body-derived Drosophila insulin-like peptide 6. How infection impairs the endocrine control of growth is poorly understood, and the studies proposed here will use genetic approaches in flies and mammals to identify molecular mechanisms that link innate immune signaling with disrupted endocrine function and growth impairment.
