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Expression of inflammatory cytokines and inducible nitric oxide synthase in brains of SIV-infected rhesus monkeys: applications to HIV-induced central nervous system disease.

ABSTRACT: Human immunodeficiency virus type 1 (HIV-1) infection of the central nervous system (CNS) can lead to severe impairments in cognition, behavior, and motor skills. The mechanism(s) by which HIV-1 induces CNS disease are not well understood. Recent evidence suggests that expression of inducible nitric oxide synthase (iNOS) and nitric oxide (NO) may contribute to HIV-1-induced neurologic disease. We sought to determine if these factors were present in the CNS of rhesus monkeys with simian immunodeficiency virus (SIV)-induced CNS disease.Total NO production in cerebral spinal fluid (CSF) from infected monkeys was determined by measuring nitrite (NO2-) and nitrate (NO3-) (stable NO degradation products) utilizing Greiss reagents. In situ hybridization revealed iNOS, interferon-gamma (IFNgamma), and interleukin 1 beta (IL-1 beta) mRNA in the brains of SIV-infected monkeys. Microglia were isolated from animals infected with SIV. Following stimulation with LPS, induction of iNOS mRNA in isolated microglia was analyzed by reverse transcriptase-polymerase chain reaction.Serial CSF samples from an SIV-infected monkey reveal increased levels of NO2-/NO3-. In situ hybridization demonstrated iNOS, IFN gamma, and IL-1 beta mRNAs in post-mortem brain tissue of SIV-infected monkeys. Furthermore, stimulated microglia from an SIV-infected monkey could produce iNOS mRNA.The presence of iNOS in the brain and NO2-/NO3- in the CSF indicates that NO is produced in the CNS of SIV-infected monkeys. The data suggest that iNOS and NO may be contributing to SIV-induced CNS disease.

SUBMITTER: Lane TE

PROVIDER: S-EPMC2230039 | biostudies-other | 1996 Jan

REPOSITORIES: biostudies-other

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Expression of inflammatory cytokines and inducible nitric oxide synthase in brains of SIV-infected rhesus monkeys: applications to HIV-induced central nervous system disease.

Lane T E TE Buchmeier M J MJ Watry D D DD Fox H S HS

Molecular medicine (Cambridge, Mass.) 19960101 1

<h4>Background</h4>Human immunodeficiency virus type 1 (HIV-1) infection of the central nervous system (CNS) can lead to severe impairments in cognition, behavior, and motor skills. The mechanism(s) by which HIV-1 induces CNS disease are not well understood. Recent evidence suggests that expression of inducible nitric oxide synthase (iNOS) and nitric oxide (NO) may contribute to HIV-1-induced neurologic disease. We sought to determine if these factors were present in the CNS of rhesus monkeys wi ...[more]

PMID: 8900532

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Project description:BackgroundThe factors contributing to chronic Chagas' heart disease remain unknown. High nitric oxide (NO) levels have been shown to be associated with cardiomyopathy severity in patients. Further, NO produced via inducible nitric oxide synthase (iNOS/NOS2) is proposed to play a role in Trypanosoma cruzi control. However, the participation of iNOS/NOS2 and NO in T. cruzi control and heart injury has been questioned. Here, using chronically infected rhesus monkeys and iNOS/NOS2-deficient (Nos2(-/-)) mice we explored the participation of iNOS/NOS2-derived NO in heart injury in T. cruzi infection.MethodologyRhesus monkeys and C57BL/6 and Nos2(-/-) mice were infected with the Colombian T. cruzi strain. Parasite DNA was detected by polymerase chain reaction, T. cruzi antigens and iNOS/NOS2(+) cells were immunohistochemically detected in heart sections and NO levels in serum were determined by Griess reagent. Heart injury was assessed by electrocardiogram (ECG), echocardiogram (ECHO), creatine kinase heart isoenzyme (CK-MB) activity levels in serum and connexin 43 (Cx43) expression in the cardiac tissue.ResultsChronically infected monkeys presented conduction abnormalities, cardiac inflammation and fibrosis, which resembled the spectrum of human chronic chagasic cardiomyopathy (CCC). Importantly, chronic myocarditis was associated with parasite persistence. Moreover, Cx43 loss and increased CK-MB activity levels were primarily correlated with iNOS/NOS2(+) cells infiltrating the cardiac tissue and NO levels in serum. Studies in Nos2(-/-) mice reinforced that the iNOS/NOS2-NO pathway plays a pivotal role in T. cruzi-elicited cardiomyocyte injury and in conduction abnormalities that were associated with Cx43 loss in the cardiac tissue.ConclusionT. cruzi-infected rhesus monkeys reproduce features of CCC. Moreover, our data support that in T. cruzi infection persistent parasite-triggered iNOS/NOS2 in the cardiac tissue and NO overproduction might contribute to CCC severity, mainly disturbing of the molecular pathway involved in electrical synchrony. These findings open a new avenue for therapeutic tools in Chagas' heart disease.

Dataset Information

Expression of inflammatory cytokines and inducible nitric oxide synthase in brains of SIV-infected rhesus monkeys: applications to HIV-induced central nervous system disease.

Publications

Expression of inflammatory cytokines and inducible nitric oxide synthase in brains of SIV-infected rhesus monkeys: applications to HIV-induced central nervous system disease.

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