NIAID Director Tony Fauci (top) and NIMH Director Tom Insel set the stage for the workshop

Advances in neuroscience and immunology that underpin treatment strategies for shock and tissue damage can be quickly adapted to targeted biodefense strategies, investigators agreed at a workshop sponsored by the Integrative Neural Immune Program, NIMH, and NIAID. Other participants hailed from NINDS, NIAAA, NIA, NCI, NCCAM, and the extramural community.

Setting the stage for the business of the workshop, NIAID Director Anthony Fauci described the NIAID Biodefense Research Agenda and emphasized the nationwide infrastructure designed to translate basic research insights into targeted diagnostic, therapeutic, and vaccine strategies for biodefense^1,2.

Talking Points

Following are some of the salient issues discussed during the workshop.

NIAID’s Charles Hackett addressed the rationale for targeting innate immune responses as a first line of defense against unknown pathogens and supported the focus on innate immune components for management of shock and tissue damage resulting from infection or toxins.

Reviewing the role of adenosine and adenosine receptors in shock and tissue damage, NIAID’s Michail Sitkovsky highlighted the interplay between hypoxia and adenosine release in initiating and amplifying shock and tissue damage, as well as the protective effects of adenosine agonists.

Joel Linden, of the University of Virginia, Charlottesville, reported on his studies of adenosine agonists in the treatment of septic shock.

NIMH’s Esther Sternberg reviewed neuroendocrine and neural pathways (hypothalamic-pituitary-adrenal axis, sympathetic and parasympathetic nervous system, and endocannabinoids) known to regulate both inflammation and cardiovascular tone in shock and tissue damage.

Cox Terhorst, of Harvard University, Boston, offered insights from his studies of experimental colitis.

NIAID’s Mahtab Moayeri presented observations from animal models of anthrax lethal toxin-induced shock.

Jane Welsh, of the University of Texas A&M, College Station, discussed the glucocorticoid responses in protecting against and exacerbating postviral shock.

NIMH’s Jeanette Webster elaborated on glucocorticoid receptor repression by anthrax lethal toxin.

NIAAA’s George Kunos reported on endocannabinoid receptors in septic shock.

Kevin Tracey, of the North Shore–Long Island Jewish Research Institute, Manhasset, N.Y., explored the role of the vagus nerve and cholinergic agonists in the treatment of sepsis and shock.

Dualities

Several common themes emerged from these presentations and the subsequent panel discussion, moderated by NINDS’ Audrey Penn and Richard Johnson, of Johns Hopkins University, Baltimore.

Much like overenhancement of adaptive immunity, overstimulation of innate immunity is a double-edged sword.

Similarly, mediators that regulate both inflammation and cardiovascular tone (hypotension) can either protect from or enhance shock and tissue damage.

As an inducer of mediator release, hypoxia generates more hypoxia and tissue damage.

Neural and neuroendocrine factors deserve study both as potential molecular therapeutic targets and as factors contributing to individual variability in host susceptibility in the general population.

Directions

It was agreed that several agents already shown to be effective in treating shock and tissue damage in animal models exposed to known pathogens might well be quickly applied to treating shock and tissue damage from unknown biotoxins.

It was also agreed that fully effective management of patients exposed to biotoxins would include evaluation of responsiveness and activity of neural and neuroendocrine pathways that could contribute to individual variability related to age, sex, associated illness, concurrent medications, physical training, stress, nutritional deprivation, and other physiological stressors.

Investigators emphasized the importance of considering sex hormones and interactions between the hypothalamic-pituitary-gonadal axis and other neuroendocrine systems as variables that could modulate the effects of neural agents in the treatment of shock and tissue damage.

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1. A.S. Fauci. "Biodefence on the research agenda. Commentary." Nature 421: 787 (2003).

2. NIAID Biodefense Research Agenda for CDC Category A Agents. Progress Report, Aug. 2003: click onto title to download 41-page PDF file of the progress report.

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