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Patients with an influenza virus infection can be complicated by acute encephalopathy and encephalitis. To investigate the immune reactions involved in the neurocomplication, mouse microglia and astrocytes were isolated, infected with human H1N1 and avian H5N1 influenza viruses, and examined for their immune responses. We observed homogeneously distributed viral receptors, sialic acid (SA)-alpha2,3-Galactose (Gal) and SA-alpha2,6-Gal, on microglia and astrocytes. Both viruses were replicative and productive in microglia and astrocytes. Virus-induced apoptosis and cytopathy in infected cells were observed at 24 h post-infection (p.i.). Expression of IL-1beta, IL-6 and TNF-alpha mRNA examined at 6 h and 24 h p.i. was up-regulated, and their expression levels were considerably higher in H5N1 infection. The amounts of secreted proinflammatory IL-1beta, IL-6 and TNF-alpha at 6 h and 24 h p.i. were also induced, with greater induction by H5N1 infection. This study is the first demonstration that both human H1N1 and avian H5N1 influenza viruses can infect mouse microglia and astrocytes and induce apoptosis, cytopathy, and proinflammatory cytokine production in them in vitro. Our results suggest that the direct cellular damage and the consequences of immunopathological injury in the CNS contribute to the influenza viral pathogenesis.
Cell Mol Immunol 2008 Apr
PMID:Apoptosis and proinflammatory cytokine responses of primary mouse microglia and astrocytes induced by human H1N1 and avian H5N1 influenza viruses. 1844 41

Flaviviruses are a group of positive-stranded RNA viruses that cause a spectrum of severe illnesses globally in more than 50 million individuals each year. While effective vaccines exist for three members of this group (yellow fever, Japanese encephalitis, and tick-borne encephalitis viruses), safe and effective vaccines for several other flaviviruses of clinical importance, including West Nile and dengue viruses, remain in development. An effective humoral immune response is critical for protection against flaviviruses and an essential goal of vaccine development. The effectiveness of virus-specific antibodies in vivo reflects their capacity to inhibit virus entry and spread through several mechanisms, including the direct neutralisation of virus infection. Recent advances in our understanding of the structural biology of flaviviruses, coupled with the use of small-animal models of flavivirus infection, have promoted significant advances in our appreciation of the factors that govern antibody recognition and inhibition of flaviviruses in vitro and in vivo. In this review, we discuss the properties that define the potency of neutralising antibodies and the molecular mechanisms by which they inhibit virus infection. How recent advances in this area have the potential to improve the development of safe and effective vaccines and immunotherapeutics is also addressed.
Expert Rev Mol Med 2008 May 12
PMID:Molecular mechanisms of antibody-mediated neutralisation of flavivirus infection. 1847 42

To confirm studies suggesting that HIV-1 infects neurons and to determine whether CD8(+) T lymphocytes traffic to HIV-1-infected neurons, we used laser capture microdissection to remove hippocampal neurons with and without perineuronal CD8(+) T cells from AIDS patients with HIV-1 encephalitis (HIVE) or without HIVE and from normal controls. We used hyperbranched multidisplacement amplification for whole gene amplification (MDA-WGA) plus two rounds of PCR to amplify housekeeping sequences (HK(+)) and, in HK(+) samples, to amplify HIV-1 gag, nef, and pol sequences. Sample size and, in single neurons, MDA-WGA correlated with housekeeping gene amplification (P < 0.05), whereas patient group and postmortem interval did not (P > 0.05). Neuronal viral sequences correlated with HIVE (43% vs. 13% and 0 in non-HIVE and controls, respectively) and, in HIVE cases, with perineuronal CD8(+) T lymphocytes (70% in CD8(+) samples vs. 37% of CD8(-) samples). Our results suggest that MDA-WGA is a useful technique when analyzing DNA from single cells from autopsy brains, supporting prior studies that show that neurons may contain HIV-1 neuronal sequences in vivo. The association between neuronal infection and perineuronal CD8(+) T cells supports our hypothesis that these cells specifically traffic to infected neurons but raises the possibility that CD8(+) T cells, if infected, could transmit virus to neurons.
J Mol Diagn 2008 Jul
PMID:Successful application of hyperbranched multidisplacement genomic amplification to detect HIV-1 sequences in single neurons removed from autopsy brain sections by laser capture microdissection. 1855 69

We have previously demonstrated safety of G207, a doubly mutated (deletion of both gamma(1)34.5 loci, insertional inactivation of U(L)39) herpes simplex virus (HSV) for patients stereotactically inoculated in enhancing portions of recurrent malignant gliomas. We have now determined safety of two inoculations of G207, before and after tumor resection. Inclusion criteria were histologically proven recurrent malignant glioma, Karnofsky score >or=70, and ability to resect the tumor without ventricular system breach. Patients received two doses of G207 totaling 1.15 x 10(9) plaque-forming units with 13% of this total injected via a catheter placed stereotactically in the tumor. Two or five days later, tumor was resected en bloc with catheter in place. The balance of G207 dose was injected into brain surrounding the resection cavity. Six patients with recurrent glioblastoma multiforme were enrolled. Two days after the second G207 inoculation, one patient experienced transient fever, delirium, and hemiparesis, which entirely resolved on high-dose dexamethasone. No patient developed HSV encephalitis or required treatment with acyclovir. Radiographic and neuropathologic evidence suggestive of antitumor activity is reported. Evidence of viral replication was demonstrated. G207 appears safe for multiple dose delivery, including direct inoculation into the brain surrounding tumor resection cavity.
Mol Ther 2009 Jan
PMID:Phase Ib trial of mutant herpes simplex virus G207 inoculated pre-and post-tumor resection for recurrent GBM. 1911 35

Listeria monocytogenes is the causative agent of human listeriosis, a potentially fatal foodborne infection. Clinical manifestations range from febrile gastroenteritis to more severe invasive forms including meningitis, encephalitis, abortions, and perinatal infections. This Gram-positive facultative intracellular pathogen has evolved multiple strategies to face extracellular innate defense mechanisms of the host and to invade and multiply intracellularly within macrophages and nonphagocytic cells. This chapter provides an updated panorama of recent advances in the characterization of L. monocytogenes virulence determinants in the postgenomic era.
Int Rev Cell Mol Biol 2008
PMID:New insights into determinants of Listeria monocytogenes virulence. 1908 33

The mosquito-borne Japanese encephalitis (JE) virus is the major etiological agent of viral encephalitis in children living in South-East Asia, causing comas, seizures and Parkinson's disease-like movement disorders. Travelers and military personnel visiting the region are also highly susceptible to the disease. As the population in South-East Asia increases, more land is irrigated to produce rice paddies (the ideal breeding habitat for mosquitoes), and pig breeding (a zoonotic host for mosquitoes) becomes more widespread. Given the exponential growth in tourism to the region and the globalization of business and commerce, an enhanced requirement for mass vaccination exists. In the West, the current licensed vaccine against JE, JE-VAX, has been highly effective; however, the use of mouse brain-derived virus has been linked to cases of acute disseminated encephalomyelitis. Intercell AG, under license from VaccGen International LLC, is developing IC-51, a formalin-inactivated vaccine derived from cell culture-based attenuated virus that has been adapted to grow in Vero cells (African green monkey kidney cells). In extensive clinical trials performed to date, IC-51 was safe, with mild to moderate adverse events reported. In terms of immunogenicity, IC-51 was highly effective, demonstrating rapid seroconversion rates and long-term maintenance of geometric mean titers that exceeded the protective titer. The results suggests that IC-51 is fully compliant with the stringent regulatory requirements set by the WHO, has an acceptable safety profile and is non-inferior to JE-VAX.
Curr Opin Mol Ther 2009 Feb
PMID:IC-51, an injectable vaccine for the prevention of Japanese encephalitis virus infection. 1916 64

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 (gamma)HV-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-alpha, interleukin 1beta, 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.
Mol Cells 2009 Jan 31
PMID:Age-dependent pathogenesis of murine gammaherpesvirus 68 infection of the central nervous system. 1921 40

The infiltration of monocytes into the CNS represents one of the early steps to inflammatory events in AIDS-related encephalitis and dementia. Increased activity of selected matrix metalloproteinases (MMPs) such as MMP-9 impairs the integrity of blood-brain barrier leading to enhanced monocyte infiltration into the CNS. In this study, we examined the effect of HIV-1 Tat on the expression of MMP-9 in CRT-MG human astroglioma cells. Treatment of CRT-MG cells with HIV-1 Tat protein significantly increased protein levels of MMP-9, as measured by Western blot analysis, zymography and an ELISA. Treatment of CRT-MG cells with HIV-1 Tat protein markedly increased mRNA levels of MMP-9, as analyzed by RT-PCR. Pretreatment of CRT-MG cells with NF-kappaB inhibitors led to decrease in Tat-induced protein and mRNA expression of MMP-9. Pretreatment of CRT-MG cells with MAPK inhibitors suppressed Tat-induced MMP-9 expression. Furthermore, HIV-1 Tat-induced expression of MMP-9 was significantly inhibited by neutralization of TNF-alpha, but not IL-1beta and IL-6. Taken together, our results indicate that HIV-1 Tat can up-regulate expression of MMP-9 via MAPK-NF-kappaB-dependent mechanisms as well as Tat-induced TNF-alpha production in astrocytes.
Exp Mol Med 2009 Feb 28
PMID:Extracellular HIV-1 Tat up-regulates expression of matrix metalloproteinase-9 via a MAPK-NF-kappaB dependent pathway in human astrocytes. 1928 89

Toll-like receptors (TLRs) form a large family of pattern recognition receptors with at least 11 members in human and 13 in mouse. TLRs recognize a wide variety of microbial components and potential host-derived agonists that have emerged as key mediators of innate immunity. TLR signaling also plays an important role in the activation of the adaptive immune system by inducing proinflammatory cytokines and upregulating costimulatory molecules of antigen presenting cells. The dysregulation of TLR signaling may cause autoimmunity. This review discusses the contribution of TLR signaling to the initiation and progression of autoimmune diseases, such as rheumatoid arthritis, experimental autoimmune encephalitis, myocarditis, hepatitis, kidney disease, systemic lupus erythematosus, diabetes, obesity, and experimental autoimmune uveitis as well as aging. The involvement of TLR signaling in the pathogenesis of autoimmune diseases may provide novel targets for the development of therapeutics.
Curr Mol Med 2009 Apr
PMID:The critical role of Toll-like receptor signaling pathways in the induction and progression of autoimmune diseases. 1935 17

Since its first description, experimental autoimmune encephalomyelitis, originally designated experimental allergic encephalitis (EAE), has been proposed as animal model to investigate pathogenetic hypotheses and test new treatments in the field of central nervous system inflammation and demyelination, which has become, in the last 30 years, the most popular animal model of multiple sclerosis (MS). This experimental disease can be obtained in all mammals tested so far, including nonhuman primates, allowing very advanced preclinical studies. Its appropriate use has led to the development of the most recent treatments approved for MS, also demonstrating its predictive value when properly handled. Some of the most exciting experiments validating the use of neural precursor cells (NPCs) as a potential therapeutic option in CNS inflammation have been performed in this model. We review here the most relevant immunological features of EAE in the different animal species and strains, and describe detailed protocols to obtain the three most common clinical courses of EAE in mice, with the hope to provide both cultural and practical basis for the use of this fascinating animal model.
Methods Mol Biol 2009
PMID:Animal models of multiple sclerosis. 1937 2


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