Stress-induced immunomodulation is mediated, in part, through products of the hypothalamic-pituitary-adrenal (HPA) axis and the autonomic nervous system. Stress activates the HPA axis and the sympathetic nervous system leading to the release of glucocorticoids (corticosterone) from the adrenal cortex, and release of catecholamines (epinephrine, nor-epinephrine) from sympathetic nerve terminals and the adrenal medulla. These effects are mediated through interaction with specific receptors known to be present on the surface of immune cells. Our long-range goal is to understand how stress hormones and neuropeptides regulate infection by the opportunistic parasite Toxoplasma gondii. The objective of this application is to investigate the role of stress and infection on Toll-like receptor (TLR) reactivity in intestinal epithelial cells (IEC). TLRs are part of the innate immune system of recognition receptors that sense invading pathogens through recognition of pathogen-associated molecular patterns. TLRs differ in their pathogen recognition, but they seem to act through a common signaling pathway leading to activation of nuclear factor kappa B (NF-kappaB) and expression of inflammatory cytokines. The rationale behind this research centers in the fact that susceptible C57BL/6 mice died after peroral T. gondii infection due to intestinal pathology driven by interferon (IFN)-gamma released by CD4+ T cells. We have demonstrated that cold water stress (CWS) or beta-agonists enhance survival of mice orally infected with T. gondii likely by decreasing intestinal pathology. We hypothesize that increased mortality in susceptible C57BL/6 mice after infection is in part due to high expression of TLR by IEC from contact with gut bacteria and their inability to control inflammatory cytokines. The regulated exposure of lEC to specific cytokines during infection may be importantto the generation of functional TLR reactivity. To accomplish the objectives of this application, we will employ a mild physical stressor, CWS and a low virulent strain of T. gondii (ME49 strain). Two specific aims will be pursued: (1) to evaluate in vivo the intestinal expression and regulation of TLR2, TLR4, and TLR9 during CWS and T. gondii infection; (2) to determine in vitro, the contribution of TLR agonists and catecholamines in the expression and regulation of TLR2, TLR4, and TLR9 in IEC lines during infection. We expect at the completion of these studies to have demonstrated a cross-talk between the innate and adaptive immune systems during stress and infection in a mucosal environment. In addition to having basic application in understanding normal physiologic and host defensive processes modulated by the CNS, these results will be of great value in designing new therapeutic strategies aimed at curbing pathology induced by enhanced inflammatory responses.
|Effective start/end date||4/1/04 → 7/31/07|
- National Institutes of Health: $151,412.00
- National Institutes of Health: $176,412.00
- Immunology and Microbiology(all)