title: Morphine modulation of toll-like receptors in microglial cells potentiates neuropathogenesis in a HIV-1 model of coinfection with pneumococcal pneumoniae.
abstract: Chronic drug users account for a third of all cases of AIDS in the United States and the progression to AIDS dementia is accelerated in opiate drug abusers. Clinically, microglial activation better correlates with HIV-associated neurocognitive disorders (HAND) than productive HIV-1 infection in the CNS. Moreover, pneumococcal pneumonia is the most common opportunistic infection in individuals with HAND. We show that coinfection with Streptococcus pneumoniae may be a contributing factor in the increased prevalence of HAND in the opioid-dependent population. To date, there have been no studies published implicating the Toll-like receptors (TLR) in the neurocognitive disorders associated with NeuroAIDS in the context of opportunistic infection. Our studies show for the first time, in a morphine-dependent model, synergistic increase and activation of TLR expression in the presence of HIV-1 protein TAT and S. pneumoniae with a significant increase in proinflammatory cytokines (IL-6, TNF-α) levels. Furthermore, concurrent increases in reactive oxygen species and nitric oxide production leading to increased caspase 3 activation are also observed in both murine and human microglial cells. These effects are recapitulated with TLR 2, 4, and 9 cognate ligands (Pam3CSK4, LPS, and CpG) and significantly attenuated in TLR 2 and 4 knock-out mice and TLR2/4 double knock-out mice. Therefor, our findings clearly suggest for the first time that activation of TLRs on microglia cells by morphine and TAT in the context of S. pneumoniae infection may be a potential mechanism for the increased prevalence of HAND in HIV-infected opioid-dependent patients.
authors: Department of Surgery, University of Minnesota, Minneapolis, Minnesota 55455, USA.
authors: Raini
authors: R
authors: Dutta
authors: Anitha
authors: A
authors: Krishnan
authors: Jingjing
authors: J
authors: Meng
authors: Subash
authors: S
authors: Das
authors: Jing
authors: J
authors: Ma
authors: Santanu
authors: S
authors: Banerjee
authors: Jinghua
authors: J
authors: Wang
authors: Richard
authors: R
authors: Charboneau
authors: Om
authors: O
authors: Prakash
authors: Roderick A
authors: RA
authors: Barke
authors: Sabita
authors: S
authors: Roy
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D060085:Coinfection / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism; D015658:HIV Infections / Q000150:complications / Q000378:metabolism*; D015497:HIV-1; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D017628:Microglia / Q000187:drug effects* / Q000378:metabolism; D009020:Morphine / Q000494:pharmacology*; D011018:Pneumonia, Pneumococcal / Q000150:complications / Q000378:metabolism*; D017450:Receptors, Opioid, mu / Q000235:genetics / Q000378:metabolism; D013296:Streptococcus pneumoniae; D051193:Toll-Like Receptors / Q000235:genetics / Q000378:metabolism*
chemical_list: D016207:Cytokines; D017450:Receptors, Opioid, mu; D051193:Toll-Like Receptors; D009020:Morphine