transforming-growth-factor-beta and Encephalitis--Viral

Viral infections of the central nervous system (CNS) are important causes of worldwide morbidity and mortality, and understanding how viruses perturb host cell signaling pathways will facilitate identification of novel antiviral therapies. We now show that reovirus infection activates transforming growth factor beta (TGF-beta) and bone morphogenetic protein (BMP) signaling in a murine model of encephalitis in vivo. TGF-beta receptor I (TGF-beta RI) expression is increased and its downstream signaling factor, SMAD3, is activated in the brains of reovirus-infected mice. TGF-beta signaling is neuroprotective, as inhibition with a TGF-beta RI inhibitor increases death of infected neurons. Similarly, BMP receptor I expression is increased and its downstream signaling factor, SMAD1, is activated in reovirus-infected neurons in the brains of infected mice in vivo. Activated SMAD1 and SMAD3 were both detected in regions of brain infected by reovirus, but activated SMAD1 was found predominantly in uninfected neurons in close proximity to infected neurons. Treatment of reovirus-infected primary mouse cortical neurons with a BMP agonist reduced apoptosis. These data provide the first evidence for the activation of TGF-beta and BMP signaling pathways following neurotropic viral infection and suggest that these signaling pathways normally function as part of the host's protective innate immune response against CNS viral infection.

Topics: Animals; Apoptosis; Bone Morphogenetic Protein Receptors, Type I; Bone Morphogenetic Proteins; Brain; Cells, Cultured; Central Nervous System; Encephalitis, Viral; Mice; Reoviridae; Reoviridae Infections; Signal Transduction; Smad1 Protein; Smad3 Protein; Transforming Growth Factor beta

Cytomegalovirus (CMV) encephalitis is well documented in immunosuppressed persons, but its pathogenesis has received little investigative attention. The examination of brain tissue from 2 patients with acquired immunodeficiency syndrome who had CMV encephalitis showed colocalization of CMV inclusions and transforming growth factor (TGF)-beta in cells that contained astrocyte-specific glial filaments. To investigate the relationship between CMV and TGF-beta in the brain, an ex vivo murine model of CMV-infected astrocytes was established. Cultures of primary murine (strain FVB/N) astrocytes inoculated with murine (Smith strain) CMV expressed, over time, increasing amounts of infectious CMV in parallel with increasing levels of TGF-beta mRNA and peptide. Astrocyte release of CMV declined in the presence of antibody to TGF-beta and increased substantially after the addition of exogenous TGF-beta. These findings suggest that CMV infection of astrocytes induces the production of TGF-beta, which in turn enhances productive CMV expression.

Topics: AIDS-Related Opportunistic Infections; Animals; Astrocytes; Brain; Cells, Cultured; Cytomegalovirus; Cytomegalovirus Infections; Disease Models, Animal; Encephalitis, Viral; HIV-1; Humans; Male; Mice; RNA, Messenger; Transforming Growth Factor beta; Virus Replication

Canine distemper virus (CDV) infection in dogs is commonly associated with demyelinating leukoencephalitis (DL). Although the mechanism of primary demyelination in distemper remains undetermined recent studies showed a direct virus-induced cytolysis in early non-inflammatory and immune-mediated mechanisms in inflammatory lesions. To further investigate the pathogenesis of this morbillivirus-induced demyelination the expression of a variety of cytokine mRNA species (interleukin (IL)-1beta, IL-2, IL-6, IL-10, IL-12, tumor necrosis factor (TNF)-alpha, transforming growth factor (TGF)-beta1, and interferon (IFN)-gamma in cerebrospinal fluid cells of 12 dogs with CDV encephalitis was investigated employing reverse transcription-polymerase chain reaction (RT-PCR) and these findings were correlated to the type of CNS lesions. Neuropathology revealed the whole spectrum of distemper DL lesions from acute to chronic alterations, however, most plaques lacked active demyelination. Three control animals were devoid of any cytokine expression, whereas in distemper animals IL-10 transcripts were found in nine dogs with acute and chronic lesions. IL-6, TNF, and TGF mRNA was found in six, four, and three animals, respectively. IL-12 and IFN-gamma, suggestive of a TH1-like dominated immune response, were detected only in one animal with chronic lesions. Summarized, TNF and IL-6, associated with disease exacerbation, and IL-10 and TGF, indicative of remission, were often observed simultaneously in distemper DL and could not be assigned to a specific disease stage. However IL-10 mRNA remained the most frequently detected cytokine indicating a stage of inactivity in most animals investigated.

Topics: Animals; Brain; Demyelinating Diseases; Disease Models, Animal; Distemper; Distemper Virus, Canine; DNA Primers; Dogs; Encephalitis, Viral; Gene Expression; Interferon-gamma; Interleukin-1; Interleukin-10; Interleukin-12; Interleukin-2; Interleukin-6; Multiple Sclerosis; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

HIV-1-infected brain macrophages participate in neurologic dysfunction through their continual secretion of neurotoxins. We previously demonstrated that astroglial cells activate HIV-1-infected monocytes to produce such neurotoxic activities. In this study, the mechanism underlying these monocyte secretory activities was unraveled and found dependent on HIV-1's ability to prime monocytes for activation. LPS stimulation of HIV-1-infected monocytes resulted in an overexpression of eicosanoids, platelet-activating factor (PAF), and TNF-alpha. This was dependent on the level of HIV-1 infection and monocyte stimulation. Cell to cell interactions between activated virus-infected monocytes and primary human astrocytes reduced monocyte secretions. The capacity of astrocytes to deactivate monocytes was, notably, TGF-beta independent. Although astrocytes constitutively produced latent TGF-beta 2, HIV-1-infected monocytes neither affected TGF-beta 2 production nor converted it into a bioactive molecule. Furthermore, addition of rTGF-beta 1 or rTGF-beta 2 or its Abs to LPS-stimulated monocyte-astrocyte mixtures had no effect on monokine production. In contrast, addition of rIL-10 to LPS-stimulated monocytes produced a dose-dependent decrease in TNF-alpha. IL-10 mRNAs were detected in monocytes, but not astrocytes, following LPS treatment. These results suggest that macrophage activation, a major component of HIV-1 infection in the brain, precipitates neuronal injury by causing virus-infected cells to synthesize neurotoxins. The neurotoxins produced by monocytes are then regulated by astrocytes. Astrocytes therefore, can play either positive or negative roles for disease depending on prior macrophage activation. These findings begin to unravel the cellular control mechanisms that influence cognitive and motor dysfunctions in HIV-1-infected individuals.

Topics: Astrocytes; Base Sequence; Cells, Cultured; Down-Regulation; Eicosanoids; Encephalitis, Viral; HIV Infections; HIV-1; Humans; Lipopolysaccharides; Macrophage Activation; Molecular Sequence Data; Monocytes; Platelet Activating Factor; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha