DESCRIPTION (provided by applicant): During an immune response bi-directional communication exists between the brain and the immune system to maintain homeostasis. Two major pathway systems are involved in this cross-communication, the hypothalamic-pituitary-adrenal (HPA) axis and the sympatho-adrenal-medullary (SAM) system. Activation of the SAM system leads to release of catecholamines from sympathetic nerve terminals and from the adrenal medulla. Both glucocorticoids and catecholamines affect immune responses and exacerbate HIV disease. Interestingly, not all AIDS patients chronically infected with Toxoplasma develop clinical disease suggesting factors in addition to low CD4 T cell counts influence pathogenesis. 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 the nor-epinephrine (N-EPI), the main mediator of the SAM system as cofactor in the intestinal pathology of mice orally infected under conditions of stress. The rationale behind this research centers in the fact that susceptible C57BI/6 mice died after peroral infection with T. gondii due to intestinal pathology driven in part by interferon (IFN)-? released by lamina propia (LP) CD4+ T cells; while cold water stress (CWS) enhanced the survival of these mice likely by decreasing CD4+ T cell-driven intestinal pathology. We hypothesize that a potential mechanism may involve adreno-sympathetic regulation of intestinal T cells activity in stressed animals, leading to altered intestinal immune responses to T. gondii infection. 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 determine ex vivo the contribution of N-EPI, the main mediators of the sympathetic nervous system (SNS) on LP dendritic cells and CD4+ T cells during CWS; and (2) to determine the contribution of N-EPI and peripheral sympathetic innervations on LP cellular responses during CWS and infection. At the completion of this research, we expect to have determined the contributions of N-EPI to the stress-induced changes in intestinal cellular responses during peroral T. gondii infection. In addition to having basic application in understanding normal physiologic and host defensive processes modulated by the central nervous system, 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||5/15/06 → 2/28/10|
- National Institutes of Health: $211,884.00
- National Institutes of Health: $179,635.00
- Immunology and Microbiology(all)