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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21AI060401-01
Application #
6798863
Study Section
AIDS-associated Opportunistic Infections and Cancer Study Section (AOIC)
Program Officer
Wali, Tonu M
Project Start
2004-04-01
Project End
2006-03-31
Budget Start
2004-04-01
Budget End
2005-03-31
Support Year
1
Fiscal Year
2004
Total Cost
$176,412
Indirect Cost
Name
Northern Arizona University
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
806345542
City
Flagstaff
State
AZ
Country
United States
Zip Code
86011
Johnson, Stacy L; Gopal, Radha; Enriquez, Amber et al. (2014) Role of glucocorticoids and Toxoplasma gondii infection on murine intestinal epithelial cells. Parasitol Int 63:687-94
Gopal, R; Birdsell, D; Monroy, F P (2011) Regulation of chemokine responses in intestinal epithelial cells by stress and Toxoplasma gondii infection. Parasite Immunol 33:12-24
Aviles, Hernan; Stiles, Jonathan; O'Donnell, Phyllis et al. (2008) Kinetics of systemic cytokine and brain chemokine gene expression in murine toxoplasma infection. J Parasitol 94:1282-8
Gopal, R; Birdsell, D; Monroy, F P (2008) Regulation of toll-like receptors in intestinal epithelial cells by stress and Toxoplasma gondii infection. Parasite Immunol 30:563-76
Monroy, Fernando P (2008) Toxoplasma gondii: effect of infection on expression of 14-3-3 proteins in human epithelial cells. Exp Parasitol 118:134-8
Thompson, Eric G; Aviles, Hernan O; Monroy, Fernando P (2008) Antibodies in cold stressed mice recognize a surface protein in Toxoplasma gondii tachyzoites. J Parasitol 94:114-8