Tumour necrosis factor-alpha mediates blood-brain barrier damage in HIV-1 infection of the central nervous system

The pathogenesis of brain inflammation and damage by human immunodeficiency virus (HIV) infection is unclear. Because blood-brain barrier damage and impaired cerebral perfusion are common features of HIV-1 infection, we evaluated the role of tumour necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) in mediating disruption of the blood-brain barrier. Levels of TNF-alpha were more elevated in cerebrospinal fluid (CSF) than in serum of HIV-1 infected patients and were mainly detected in those patients who had neurologic involvement. Intrathecal TNF-alpha levels correlated with signs of blood-brain barrier damage, manifested by high CSF to serum albumin quotient, and with the degree of barrier impairment. In contrast, intrathecal IL-1beta levels did not correlate with blood-brain barrier damage in HIV-1 infected patients. TNF-alpha seems to be related to active neural inflammation and to blood-brain barrier damage. The proinflammatory effects of TNF-alpha in the nervous system are dissociated from those of IL-1beta.     

Neuronal fractalkine expression in HIV-1 encephalitis: roles for macrophage recruitment and neuroprotection in the central nervous system

HIV-1 infection of the brain results in chronic inflammation, contributing to the neuropathogenesis of HIV-1 associated neurologic disease. HIV-1-infected mononuclear phagocytes (MP) present in inflammatory infiltrates produce neurotoxins that mediate inflammation, dysfunction, and neuronal apoptosis. Neurologic disease is correlated with the relative number of MP in and around inflammatory infiltrates and not viral burden. It is unclear whether these cells also play a neuroprotective role. We show that the chemokine, fractalkine (FKN), is markedly up-regulated in neurons and neuropil in brain tissue from pediatric patients with HIV-1 encephalitis (HIVE) compared with those without HIVE, or that were HIV-1 seronegative. FKN receptors are expressed on both neurons and microglia in patients with HIVE. These receptors are localized to cytoplasmic structures which are characterized by a vesicular appearance in neurons which may be in cell-to-cell contact with MPs. FKN colocalizes with glutamate in these neurons. Similar findings are observed in brain tissue from an adult patient with HIVE. FKN is able to potently induce the migration of primary human monocytes across an endothelial cell/primary human fetal astrocyte trans-well bilayer, and is neuroprotective to cultured neurons when coadministered with either the HIV-1 neurotoxin platelet activating factor (PAF) or the regulatory HIV-1 gene product Tat. Thus focal inflammation in brain tissue with HIVE may up-regulate neuronal FKN levels, which in turn may be a neuroimmune modulator recruiting peripheral macrophages into the brain, and in a paracrine fashion protecting glutamatergic neurons.     

Coronavirus infection of the central nervous system: host-virus stand-off

Several viruses infect the mammalian central nervous system (CNS), some with devastating consequences, others resulting in chronic or persistent infections associated with little or no overt pathology. Coronavirus infection of the murine CNS illustrates the contributions of both the innate immune response and specific host effector mechanisms that control virus replication in distinct CNS cell types. Despite T-cell-mediated control of acute virus infection, host regulatory mechanisms, probably designed to protect CNS integrity, contribute to the failure to eliminate virus. Distinct from cytolytic effector mechanisms expressed during acute infection, non-lytic humoral immunity prevails in suppressing infectious virus during persistence.     

HIV-1 replication in the central nervous system occurs in two distinct cell types

Human immunodeficiency virus type 1 (HIV-1) infection of the central nervous system (CNS) can lead to the development of HIV-1-associated dementia (HAD). We examined the virological characteristics of HIV-1 in the cerebrospinal fluid (CSF) of HAD subjects to explore the association between independent viral replication in the CNS and the development of overt dementia. We found that genetically compartmentalized CCR5-tropic (R5) T cell-tropic and macrophage-tropic HIV-1 populations were independently detected in the CSF of subjects diagnosed with HIV-1-associated dementia. Macrophage-tropic HIV-1 populations were genetically diverse, representing established CNS infections, while R5 T cell-tropic HIV-1 populations were clonally amplified and associated with pleocytosis. R5 T cell-tropic viruses required high levels of surface CD4 to enter cells, and their presence was correlated with rapid decay of virus in the CSF with therapy initiation (similar to virus in the blood that is replicating in activated T cells). Macrophage-tropic viruses could enter cells with low levels of CD4, and their presence was correlated with slow decay of virus in the CSF, demonstrating a separate long-lived cell as the source of the virus. These studies demonstrate two distinct virological states inferred from the CSF virus in subjects diagnosed with HAD. Finally, macrophage-tropic viruses were largely restricted to the CNS/CSF compartment and not the blood, and in one case we were able to identify the macrophage-tropic lineage as a minor variant nearly two years before its expansion in the CNS. These results suggest that HIV-1 variants in CSF can provide information about viral replication and evolution in the CNS, events that are likely to play an important role in HIV-associated neurocognitive disorders.     

HIV-1, macrophages, glial cells, and cytokines in AIDS nervous system disease

Hallmarks of central nervous system (CNS) disease in AIDS patients are headaches, fever, subtle cognitive changes, abnormal reflexes, and ataxia. Dementia and severe sensory and motor dysfunction characterize more severe disease. Autoimmune-like peripheral neuropathies, cerebrovascular disease, and brain tumors are also observed. Histological changes include inflammation, astrocytosis, microglial nodule formation, and diffuse de- or dysmyelination. Focal demyelination can also be seen. It is clear that AIDS-associated neurological diseases are correlated with greater levels of HIV-1 antigen or genome in tissues. In AIDS dementia, macrophages and microglial cells of the CNS are the predominant cell types infected and producing HIV-1. However, manifestations of the disease make it unlikely that direct infection by HIV-1 is responsible. It seems more likely that the effects are mediated through secretion of viral proteins or viral induction of cytokines that bind to glial cells and neurons. HIV-1 induction of such cytokines as interleukin 1 (IL 1) and tumor necrosis factor-alpha (TNF alpha) may lead to an autocrine feedback loop involving further productive virus replication and induction of other cytokines such as interleukin 6 (IL 6) and granulocyte-macrophage colony-stimulating factor (GMCSF). Interleukin 1 and TNF alpha in combination with IL 6 and GMCSF could account for many clinical and histopathological findings in AIDS nervous system diseases. As HIV-1 infected patients produce elevated levels of IL 1, TNF alpha, and IL 6, it will be important to make a formal connection between the presence of these factors in the CNS, which are all products of activated macrophages, astroglia, and microglia, their in vivo induction directly by virus or indirectly by virus-induced intermediates, and the clinical and pathological conditions seen in the nervous system in this disease.     

Peripheral Taenia infection increases immunoglobulins in the central nervous system

Human cysticercosis is a disease caused by larvae of the cestode Taenia solium. It is an important common cause of adult-onset seizures world-wide where it exacts a debilitating toll on the health and well-being of affected communities. It is commonly assumed that the major symptoms associated with cysticercosis are a result of the direct presence of larvae in the brain. As a result, the possible effects of peripherally located larvae on the central nervous system are not well understood. To address this question, we utilised the Taenia crassiceps intra-peritoneal murine model of cysticercosis, where larvae are restricted to the peritoneal cavity. In this model, previous research has observed behavioural changes in rodents but not the development of seizures. Here we used ELISAs, immunoblotting and the Evans Blue test for blood–brain barrier permeability to explore the central effects of peripheral infection of mice with T. crassiceps. We identified high levels of parasite-targeting immunoglobulins in the sera of T. crassiceps-infected mice. We show that the T. crassciceps larvae themselves also contain and release host immunoglobulins over time. Additionally, we describe, for the first known time, significantly increased levels of IgG within the hippocampi of infected mice, which are accompanied by changes in blood–brain barrier permeability. However, these T. crassiceps-induced changes were not accompanied by alterations to the levels of proinflammatory, pro-seizure cytokines in the hippocampus. These findings contribute to the understanding of systemic and neuroimmune responses in the T. crassiceps model of cysticercosis, with implications for the pathogenesis of human cysticercosis.     

Increased peroxynitrite activity in AIDS dementia complex: implications for the neuropathogenesis of HIV-1 infection

Oxidative stress is suggested to be involved in several neurodegenerative diseases. One mechanism of oxidative damage is mediated by peroxynitrite, a neurotoxic reaction product of superoxide anion and nitric oxide. Expression of two cytokines and two key enzymes that are indicative of the presence of reactive oxygen intermediates and peroxynitrite was investigated in brain tissue of AIDS patients with and without AIDS dementia complex and HIV-seronegative controls. RNA expression of IL-1beta, IL-10, inducible nitric oxide synthase, and superoxide dismutase (SOD) was found to be significantly higher in demented compared with nondemented patients. Immunohistochemical analysis showed that SOD was expressed in CD68-positive microglial cells while inducible nitric oxide synthase was detected in glial fibrillary acidic protein (GFAP)-positive astrocytes and in equal amounts in microglial cells. Approximately 70% of the HIV p24-Ag-positive macrophages did express SOD, suggesting a direct HIV-induced intracellular event. HIV-1 infection of macrophages resulted in both increased superoxide anion production and elevated SOD mRNA levels, compared with uninfected macrophages. Finally, we show that nitrotyrosine, the footprint of peroxynitrite, was found more intense and frequent in brain sections of demented patients compared with nondemented patients. These results indicate that, as a result of simultaneous production of superoxide anion and nitric oxide, peroxynitrite may contribute to the neuropathogenesis of HIV-1 infection.     

Insulin and the central nervous system

Data from literature concerning the neurobiological, electrical and metabolic effects of insulin are reviewed. Emphasis is laid on insulin distribution in the CNS, on distribution and localization of the insulin brain receptors, on insulin transport through the hemato-encephalic barrier. Data concerning insulin effect on the electrical activity of various CNS neurons, particularly, on those of the feeding and satiety centres. The effects of insulin on the brain metabolism are discussed. Insulin shares many properties with the nerve growth factor and may be considered as specific neurotransmitter and neuromodulator.     

中枢神经系统隐球菌感染动物模型的研究

目的 构建中枢神经系统隐球菌感染的动物模型。方法 给予小鼠脑内接种隐球菌构建中枢神经系统隐球菌感染的动物模型。小鼠被随机地分为实验组和对照组,给予实验组小鼠脑内接种隐球菌菌悬液,对照组小鼠脑内接种生理盐水。结果 从组织病理方面观察到,实验组小鼠脑组织中的蛛网膜下腔、软脑膜表面、脑实质内、侧脑室脉络丛组织内均可见隐球菌菌体,脑膜轻度增生,侧脑室轻度扩大,脉络丛血管轻度扩张充血。对照组小鼠脑组织可见侧脑室轻度扩大,蛛网膜下腔血管、脑实质内血管、脉络丛血管均有轻度扩张充血,而蛛网膜下腔、软脑膜表面、脑实质内及侧脑室和室旁均未见隐球菌浸润。从组织病理观察结果两组具有一定的对比性。结论 小鼠脑内接种隐球菌构建其中枢神经系统隐球菌感染的模型,为研究人中枢神经系统隐球菌病提供了一个工具。     

HIV-1 variation: consequences for disease progression and vaccine strategies

HIV-1 displays a high degree of biological heterogeneity in vitro, differing in tropism, kinetics of replication, cytopathogenicity, resistance to antiviral drugs and susceptibility to serum neutralization. Some of these properties can be linked to pathogenesis in the host. HIV variation is a major challenge to the development of effective vaccine or antiviral therapies.     

Flunarizine and verapamil: Effects on central nervous system and peripheral consequences of cytotoxic hypoxia in rats

Flunarizine is a calcium entry blocking drug possessing antihypoxic activity in animal models of cerebral and peripheral ischemia-anoxia and has clinical usefulness in circulatory disorders of both central and peripheral origin. This report compares the activity of flunarizine and verapamil, another calcium entry blocking drug, on the central nervous system (CNS) and peripheral consequences of cytotoxic hypoxia induced by high and low doses of KCN. The lethal effect of KCN (6 mg/kg, i.p.) in rats was prevented by orally administered flunarizine (ED₅₀ = 12 mg/kg with four-hr pretreatment) but not by verapamil (at oral doses up to 80 mg.kg with one-hr pretreatment). Since the lethal effect of KCN involves failure of respiration at the CNS level, these results suggest that flunarizine protects against the hypoxic effect of the cyanide ion by an action in brain tissue. We found also that the stimulant effect of low intravenous doses (0.5 mg/kg/min) of KCN upon respiration rate was not altered in pentobarbital- and chloralose-anesthetized rats treated with oral doses of flunarizine up to 80 mg/kg (with four hr pretreatment). In contrast, KCN-stimulated respiration rate in pentobarbital anesthetized rats was significantly attenuated by verapamil (20 and 40 mg/kg, p.o. with one hr pretreatment). Since low doses of the cyanide ion render respiration quicker and deeper by an action on chemoreceptive cells in peripheral arteries, the effect of verapamil against the hypoxic effect of KCN is mediated by an action in the periphery. In summary, we have shown that the physiological consequences of cytotoxic hypoxia can be affected by calcium entry blocking drugs having site-specific activities. Based on our results, flunarizine is more effective than verapamil against cellular anoxia involving the CNS.     

Age-dependent pathogenesis of murine gammaherpesvirus 68 infection of the central nervous system

Gammaherpesvirus infection of the central nervous system (CNS) has been linked to various neurological diseases, including meningitis, encephalitis, and multiple sclerosis. However, little is known about the interactions between the virus and the CNS in vitro or in vivo. Murine gammaherpesvirus 68 (MHV-68 or _γHV-68) is genetically related and biologically similar to human gammaherpesviruses, thereby providing a tractable animal model system in which to study both viral pathogenesis and replication. In the present study, we show the successful infection of cultured neuronal cells, microglia, and astrocytes with MHV-68 to various extents. Upon intracerebroventricular injection of a recombinant virus (MHV-68/LacZ) into 4–5-week-old and 9–10-week-old mice, the 4–5-week-old mice displayed high mortality within 5–7 days, while the majority of the 9–10-week-old mice survived until the end of the experimental period. Until a peak at 3–4 days post-infection, viral DNA replication and gene expression were similar in the brains of both mouse groups, but only the 9–10-week-old mice were able to subdue viral DNA replication and gene expression after 5 days post-infection. Pro-inflammatory cytokine mRNAs of tumor necrosis factor-α, interleukin 1β, and interleukin 6 were highly induced in the brains of the 4–5-week-old mice, suggesting their possible contributions as neurotoxic factors in the agedependent control of MHV-68 replication of the CNS. These authors contributed equally to this work.     

Mycoplasma hominis infection of the central nervous system in a neonate.

A newborn infant with group B streptococcal sepsis responded to the intravenous administration of antibiotics within 3 days, but then began to show signs of central nervous system infection. Routine cultures of cerebrospinal fluid samples were negative, but others done for Mycoplasma hominis yielded that organism. After 3 more days of antibiotic therapy, cultures for M. hominis were negative, and the child''s recovery was uneventful.     

Tenascin-R: role in the central nervous system

Tenascin-R (TN-R), a member of the tenascin family of extracellular matrix glycoproteins, is exclusive to the nervous system. It affects cell migration, adhesion and differentiation, although no remarkable clinical consequences have been shown in knock-out animal models. TN-R's expression pattern suggests a possible primary or secondary role in certain neurological problems including malformations, tumors and neurodegenerative disorders. This review summarizes the structure and molecular interactions of this molecule and discusses its function and possible roles in the central nervous system.     

Endothelin-1 modulates cardiorespiratory control by the central nervous system

In urethane-anesthetized, vagotomized and immobilized rats under artificial ventilation, an intracisternal injection of 0.1 pmol of endothelin-1 resulted in immediate increases, lasting for 3–15 min, in arterial pressure, heart rate and renal sympathetic nerve activity. Phrenic nerve activity and the rate of its burst activity (burst rate) also increased initially but subsequently decreased for 5–20 min. At doses of 1 or 10 pmol, the initial increases (phase I) were followed by a period of decreases in all variables, that lasted for 20–80 min, below the pre-injection level (phase II). Phrenic nerve activity often disappeared completely. All the variables usually returned to, or often exceeded, pre-injection levels (phase III). However, arterial pressure sometimes remained below control for at least 2 h. Topical application of endothelin-1 to the ventral surface of the medulla produced the same pattern of changes as with intracisternal injection. This particular response pattern was not generated by local administration to any other brain sites examined.

In conclusion, intracisternally administered endothelin-1 modulates cardiorespiratory control by the central nervous system. The effect on the central respiratory control was especially powerful. The ventral surface of the medulla appears to play a crucial role in this modulation.