Viral Infections of the Human Nervous System

Central nervous system viral disease

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Animals also presented a reduction of tight junction protein ZO-1, suggesting other effects into BBB, and exhibited augment in lipid peroxidation in the brain [ 29 ]. GSH is related with the transport of endogenous and exogenous molecules to extracellular medium. ABCC1 is expressed in tumor cells [ 30 ] and normal tissues, such as the brain [ 31 ] and lymphocytes [ 32 ]. ABCC1 expression depends on Nrf2 activation and translocation to the nucleus [ 33 ].

It was already described in this charter; JC virus was detected in CNS tumors, such as glioblastomas. This brain tumor is highly proliferative and invasive and presents mechanisms of multidrug resistance MDR. On the other hand, the redox state disequilibrium or down modulation of GSH made these MDR cells more sensitive to chemotherapy [ 9 ]. However, the influence of proteins from virus in MDR mechanisms expression remains unknown.

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This result was directly correlated to the proviral load; a lower expression of ABCC1 was observed in patients with higher proviral load [ 34 ]. The pharmacological inhibition of ABCC induced a proliferation increase induced by mitogen of lymphocytes obtained from HTLVinfected individuals [ 19 ]. It was suggested that dysregulations of ABC efflux transporters were implicated with the BBB breakdown during neurological diseases [ 35 ].

In infectious diseases this phenomenon can be involved in virus entrance in the CNS. Together these results suggested that the balancing of oxidative cellular status involves the increase in active GSH efflux to extracellular medium [ 36 ]. The cell phenotype is related with a group of cytokines and other immune products produced by T cell, generating inflammatory or anti-inflammatory cells.

INTRODUCTION

During viral infections the activation of inflammatory T-cell phenotype can be associated with virus eradication. However, in the CNS the exacerbation of inflammatory response is related with neurodegeneration [ 37 ]. This GSH down modulation was followed by change in cytokine profile. The infection induced generation of M2 macrophages and T lymphocytes with Th2 phenotype.

Macrophages and dendritic cells are an important group of APCs. During infections macrophages can acquire specialized functional phenotypes. Macrophages classic activated are involved in inflammatory responses and are denominated M1. Macrophages alternative activated exhibit an antagonic inflammatory profile and named M2 [ 37 ]. In addition, low intracellular levels of GSH were correlated with defective processing of antigens in APCs, indicating that GSH may be a critical factor in antigen processing [ 39 ].

During the LP-BM5 infection, macrophage polarization into alternative profile was observed, suggesting that M2 cells were driving the T-cell phenotype.

Viral Infections of the Human Nervous System

LP-BM5-infected mice treatment with GSH replacement changed the macrophage polarization to M1 profile, inducing an increase in Th1 cytokine production and augmented antiviral response [ 38 ]. Thus, GSH modulation causes immune response phenotype alteration, leading to an important impact in virus elimination Figure 2.

The neurodegeneration is associated with decontrolled inflammatory responses into the CNS. Inflammatory cytokines induce nitric oxide NO and ROS production for innate immune cells and microglial cells. The incubation of microglia cells in the presence of viral protein gp was observed to increase in ROS production [ 36 ].

The inflammatory microenvironment reduces the glutamate uptake, inducing accumulation of this excitatory amino acid and excitotoxic neurodegeneration. Although, any study has not related the viral infection, GSH intracellular levels, and excitotoxic neurodegeneration, the literature suggested that antioxidant responses can prevent the neuron death directly or indirectly. This is an acyclic deoxyguanosine nucleoside analogue [ 41 ]. Moreover, the results suggested that antiviral therapy suppressed the oxidative damage by downregulation of malondialdehyde and upregulation of GSH levels in mice serum [ 42 ].

No antiviral treatment intervention exists for HTLV-1 infection. Usually, symptomatic patients are treated with corticosteroid pulse therapy. The h ighly a ctive a ntiretroviral t herapy HAART is started with the combination of two nucleoside analogue transcriptase reverse inhibitors and one non-analogue nucleoside transcriptase reverse inhibitor or protease inhibitor plus ritonavir-boosted.

In this study the patients received one protease inhibitor indinavir or ritonavir in combination with two nucleoside analogs lamivudine plus zidovudine or plus stavudine , suggesting that the HAART ameliorates the oxidative alterations related with HIV-1 infection [ 43 ]. After the HAART treatment, T-lymphocyte cell adhesion on human aortic endothelial cell monolayer increases significantly. However, the addition of NAC or GSH induced the inhibition of these effects, suggesting that the modulation of antioxidant levels activated the endothelium [ 44 ].

The first approved antiretroviral drug was zidovudine AZT , a nucleoside reverse transcriptase inhibitor. Furthermore, AZT treatment induces a skeletal muscle mitochondrial peroxide production [ 45 ]. Similar results were observed in monocytic cell lines incubated in the presence of AZT. AZT is the antiretroviral drug with the best intracerebral penetration, however this substance virus resistance mutations in periphery and CNS [ 47 ].

However, the results suggested that AZT long-term exposure caused deletion of mitochondrial DNA and neuron death [ 48 ]. Furthermore, AZT or the combination AZT plus indinavir protease inhibitor induces oxidative stress in human brain microvascular endothelial cells. These cells represent an important model to study BBB. The combination AZT plus indinavir induced an increase in ROS production, disruption in membrane mitochondrial potential, reduction in intracellular GSH levels, augment permeability of endothelial layer, leading cell death [ 49 ].

Together these results suggested that this antiretroviral therapy compromises the BBB and could be associated with HIV-1 neurological diseases. These findings suggested that the replacement of GSH, reducing the oxidative stress in HIVinfected patients, is an interesting therapeutic approach. In this chapter we explore some aspects about neurodegenerative diseases associated with viral infection, GSH, and oxidative stress. However, studies that describe how the oxidative stress is involved in disease development remain insufficient.

The oxidative stress in the CNS is associated to many neurodegenerative diseases. ROS, including reactive nitrogen species, are important mediator of brain and spinal cord damage.

INTRODUCTION

They are related with inflammation and mitochondrial and proteasomal dysfunction. The vulnerability of the CNS is associated with the higher consumption of oxygen than other tissues. Indeed, some evidence suggests that diabetes is a risk factor for bacterial CNS disease 48 and poor outcome in tuberculous meningitis Without convalescent glucose and hemoglobin A1c assays, however, we were unable to distinguish hyperglycemia resulting from severe disease or undiagnosed diabetes that might have predisposed to CNS infection.

Intensive euglycemia management is difficult; it can lead to hypoglycemia, especially in unconscious patients, and requires skilled dedicated nursing that is not available in hospitals in rural Asia. Whether such intensive therapy would save lives remains uncertain, but the development of an inexpensive computerized algorithm technology for resource-poor settings to facilitate safe euglycemia management 50 should be a priority for investigation of efficacy.

The burgeoning global prevalence of diabetes calls for research regarding the relationship between hyperglycemia and CNS infections and optimizing their combined management Our data suggest that patient survival could be improved through 2 patient management interventions, the implementation of antibiotic use guidelines and strengthening of high-dependency units. The finding that poor outcomes were associated with a decreased GCS score at admission suggests that high-dependency units a likely cost-effective intervention could be used to enhance supportive care for unconscious patients with CNS infection.

Creating these units and incorporating them into care could improve outcomes and reduce the burden of intensive care unit treatment for these patients. More investigation is needed on the efficacy and cost-effectiveness of high-dependency units in different contexts.

Ceftriaxone is conventionally used in Laos as a first-line treatment for CNS bacterial infection but lacks efficacy for emerging rickettsial pathogens, for which doxycycline is recommended 4. Because delays in antibiotic therapy could result in severe consequences for patients, the decision for administering these drugs is made on the basis of clinical signs and laboratory results at admission. However, in Laos, we found that no variable, even in combination, could permit objective selection of appropriate antibiotics.

Therefore, the administration of early first-line empiric treatment with ceftriaxone and doxycycline for all patients with suspected CNS infection might save patient lives in Laos and elsewhere in rural Asia 4. Her main research topics of interest are the study of undifferentiated fever, dengue epidemiology, infections of the CNS, and respiratory infections. We thank the patients, Bounthaphany Bounxouei Associate Professor and Director , and staff of Mahosot Hospital, especially the microbiology laboratory staff and the ward staff for their technical help and support. We also thank Mavuto Mukaka for his help with statistical analysis and Nicholas Day for comments on the paper.

Table of Contents — Volume 25, Number 5—May Please use the form below to submit correspondence to the authors or contact them at the following address:. Highlight and copy the desired format. Section Navigation.

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Figure 1 Figure 2 Figure 3 Figure 4. Table 1 Table 2 Table 3 Table 4 Table 5. Craig, Suhella M. Dance, Stuart D. Blacksell, Xavier de Lamballerie, and Paul N. Mayxay, R.

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Phetsouvanh, S. Rattanavong, M. Vongsouvath, V. Davong, V. Chansamouth, K. Phommasone, C. Moore, S. Dittrich, O. Lattana, J. Sirisouk, P. Phoumin, P. Panyanivong, A. Sengduangphachanh, B.

Sibounheuang, A. Chanthongthip, M.

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