Chronic drug users account for approximately a third of all cases of AIDS in the USA and recent data indicate that progression to AIDS dementia is markedly accelerated in this population. A frequent occurrence in the HIV positive opioid abusing population is the incidence of infection with S. pneumoniae. In chronic neurodegenerative diseases such as Alzheimer's frequent episodes or persistent systemic infection lead to progressive decline in cognitive function and accelerate the process of neurodegeneration through activation of proinflammatory cytokines. Furthermore, and of relevance to this proposal, in HIV patients, clinical studies reveal that elevated proinflammatory cytokines and activated microglia consistently correlated with HIV associated dementia (HAD) than viral load or viral protein. Pathogens are recognized by Toll like receptors which are distinct pattern recognition receptors. Ligation of TLRs by different pathogen-associated molecules has the capacity to engage specific downstream intracellular signaling cascades and thus tailor the innate response to the activation stimulus. Recent studies demonstrate the expression of TLRs in the CNS. Although there is some evidence that S. pneumoniae activates Toll like receptors 2, 4 and 9 in peripheral immune cells, there are no studies clearly delineating the role of TLR's in S. pneumoniae induced glial activation and its contribution to HIV neuropathogenesis. In preliminary studies we demonstrate that chronic morphine treatment in the presence of TAT synergistically increases susceptibility to S. pneumoniae infection with increased dissemination of bacteria into the CNS. In addition we observed a synergistic increase in proinflammatory response with concurrent increase in neuronal apoptosis. We hypothesize that although opioid drug abuse and HIV-proteins can either independently or synergistically modulate neuropathogenesis, co-infection with S. pneumoniae reduces the threshold for proinflammatory cytokines synthesis and significantly accelerates the neuropathogenic process. We further hypothesize that activation of Toll like receptors may be a potential mechanism for the synergistic increase in neuropathogenesis in opioid drug abusers that are co-infected with HIV and S. pneumoniae. To test our hypothesis we will in Specific Aim 1: Determine the role of Toll like receptor (TLR2, TLR4 and TLR9) activation on glial cells as a potential mechanism for the synergistic induction in proinflammatory cytokine synthesis by morphine and TAT in a murine model of S. pneumonia.
Specific Aim 2 : Determine the molecular and cellular mechanism by which morphine and TAT synergistically amplify S. pneumoniae induced TLR 2, 4 and 9 signaling.
Specific Aim 3 : Determine the role of Toll like receptor activation on peripheral immune cells as a potential mechanism for the increased recruitment of peripheral immune cells to the CNS following infection with S. pneumoniae in a chronic morphine TAT transgenic mouse model. These studies will reveal important information about the role of Toll like receptors in neuropathogenesis following persistent systemic infection. This will pave the way for future studies targeting Toll like receptors as potential therapeutic approach to ameliorate neuroinflammation associated with microgial activation.

Public Health Relevance

The latest statistics on the world epidemic of AIDS &HIV (UNAIDS/WHO, November 2005) report that at least 40 million people are infected with HIV with nearly 6 million cases of AIDS world-wide. There is a strong correlation between chronic drug use and increase susceptibility to HIV infection. Chronic drug users accounts for approximately a third of all cases of AIDS in the USA and the progression to AIDS dementia is markedly accelerated in opiate drug abusers. Our studies show chronic morphine and opioid withdrawal following chronic use increase susceptibility to S. Pneumonia. We propose that morphine and morphine withdrawal synergizes with HIV proteins in the context of S. pneumonia infection to potentiate and exacerbate neuronal damage. We propose to determine the mechanisms by which morphine contributes to neuronal dysfunction in HIV-infected individuals.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA012104-13
Application #
8234091
Study Section
NeuroAIDS and other End-Organ Diseases Study Section (NAED)
Program Officer
Avila, Albert
Project Start
1999-05-01
Project End
2014-02-28
Budget Start
2012-03-01
Budget End
2013-02-28
Support Year
13
Fiscal Year
2012
Total Cost
$332,956
Indirect Cost
$106,786
Name
University of Minnesota Twin Cities
Department
Surgery
Type
Schools of Medicine
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
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Ramakrishnan, S; Anand, Vidhu; Roy, Sabita (2014) Vascular endothelial growth factor signaling in hypoxia and inflammation. J Neuroimmune Pharmacol 9:142-60
Ninkovi?, Jana; Roy, Sabita (2014) High throughput fluorometric technique for assessment of macrophage phagocytosis and actin polymerization. J Vis Exp :e52195
Ma, J; Wan, J; Meng, J et al. (2014) Methamphetamine induces autophagy as a pro-survival response against apoptotic endothelial cell death through the Kappa opioid receptor. Cell Death Dis 5:e1099
Ninkovic, Jana; Roy, Sabita (2013) Role of the mu-opioid receptor in opioid modulation of immune function. Amino Acids 45:9-24
Meng, Jingjing; Yu, Haidong; Ma, Jing et al. (2013) Morphine induces bacterial translocation in mice by compromising intestinal barrier function in a TLR-dependent manner. PLoS One 8:e54040
Olin, Michael; Oh, Seunguk; Roy, Sabita et al. (2012) Morphine induces splenocyte trafficking into the CNS. J Neuroimmune Pharmacol 7:436-43
Ninkovi?, Jana; Roy, Sabita (2012) Morphine decreases bacterial phagocytosis by inhibiting actin polymerization through cAMP-, Rac-1-, and p38 MAPK-dependent mechanisms. Am J Pathol 180:1068-79
Chanakira, Alice; Dutta, Raini; Charboneau, Richard et al. (2012) Hypoxia differentially regulates arterial and venous smooth muscle cell proliferation via PDGFR-? and VEGFR-2 expression. Am J Physiol Heart Circ Physiol 302:H1173-84
Roy, Sabita (2011) Drugs of abuse effects on immunity and microbial pathogenesis. J Neuroimmune Pharmacol 6:435-8

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