Globally, tuberculosis (TB) remains a major public health crisis, which has been dramatically fueled by the HIV epidemic. Clinically, Mycobacterium tuberculosis is the most important opportunistic pathogen in AIDS patients, and infection of the central nervous system (CNS) is the most devastating complication of TB. As in the case of HIV infection, drug abuse has been regarded as a potential cofactor in the pathogenesis of M. tuberculosis. While there have been numerous studies on the effects of opiates on the pathogenesis of other intracellular microbes, little is known about the influence of opiates on lymphocyte trafficking and nothing is known about the impact of opiates on defense of the CNS against M. tuberculosis. Within the CNS, M. tuberculosis elicits a neuroinflammatory response, but the cells and mediators involved in this response are largely undefined. Although sensitized T lymphocytes play a critical role in defense against many CNS infections, the process of T lymphocyte entry into the brain in response to infectious agents, including M. tuberculosis, has not been delineated. Recently, a novel imaging system utilizing transgenic mice expressing luciferase was developed allowing researchers to track quantitatively """"""""in vivo"""""""" the trafficking pattern of T lymphocytes into the CNS in an animal model of multiple sclerosis. The overall goal of the research proposed in this application is to adapt this innovative methodology to assess the effects of opiate dependence on T lymphocyte trafficking into the CNS in response to intracerebral challenge with tubercle bacilli. The use of this quantitative imaging system will allow us to test the central hypothesis that opiate dependence impairs the trafficking of Bacille-Calmette-Gu?rin (BCG)-sensitized T lymphocytes into the CNS thereby increasing the severity of CNS TB. To test this hypothesis, experiments have been designed which address the two specific aims outlined below:
Specific aim 1 : Adapt a novel quantitative imaging technique to determine whether BCG- sensitized T lymphocytes traffic into the CNS in response to mycobacterial infection. It is hypothesized that BCG vaccination will protect mice against CNS TB through a rapid infiltration of BCG- sensitized T lymphocytes into the CNS following ic inoculation of tubercle bacilli.
Specific aim 2 : Determine whether morphine administration enhances the neuropathogenesis of mycobacterial infection and impairs T lymphocyte trafficking into the CNS. Using the CNS TB paradigm above and T cell imagining technology, the effects of morphine administration on the neuropathogenesis will be elucidated. It is hypothesized that morphine dependence will accelerate mortality and increase CNS damage due to infection and that the trafficking of adoptive transferred BCG- sensitized T lymphocytes will be markedly impaired in morphine-dependent mice. ? ? ?
| Olin, Michael; Oh, Seunguk; Roy, Sabita et al. (2012) Morphine induces splenocyte trafficking into the CNS. J Neuroimmune Pharmacol 7:436-43 |
| Olin, Michael R; Armien, Anibal G; Cheeran, Maxim C-J et al. (2008) Role of nitric oxide in defense of the central nervous system against Mycobacterium tuberculosis. J Infect Dis 198:886-9 |
