transforming-growth-factor-beta and Encephalitis--Herpes-Simplex

Herpes simplex virus type-1 (HSV-1) initially infects mucoepithelial tissues of the orofacial region, the eye and to a lesser extent the genitalia. Subsequently, the virus is retrogradely transported through the axons of the sensory and sympathetic neurons to their nuclei, where the virus establishes a life-long latent infection. During this latency period, the viral genome is transcriptionally silent except for a single region encoding the latency-associated transcript (LAT). LAT has been shown to affect apoptosis, but little else is known regarding its effects on neurons. To understand how HSV-1 latency might affect dendrites in sympathetic neurons, we transfected primary cultures of sympathetic neurons obtained from rat embryos, with LAT expressing plasmids. LAT inhibited initial dendritic growth and induced dendritic retraction in sympathetic neurons. Latent HSV-1 infection of cultured sympathetic neurons inhibited dendritic growth indicating that this is likely also a consequence of natural infection.

Topics: Animals; Bone Morphogenetic Protein 7; Bone Morphogenetic Proteins; Cell Differentiation; Cells, Cultured; Dendrites; Encephalitis, Herpes Simplex; Ganglia, Sympathetic; Gene Expression Regulation, Viral; Genetic Vectors; Green Fluorescent Proteins; Herpes Simplex; Herpesvirus 1, Human; MicroRNAs; Rats; Rats, Sprague-Dawley; Signal Transduction; Transfection; Transforming Growth Factor beta; Viral Proteins; Virus Latency

Infection of the central nervous system (CNS) with herpes simplex virus (HSV)-1 initiates a rapidly progressive, necrotizing, and fatal encephalitis in humans. Even with the advent of antiviral therapy, effective treatments for HSV-1 brain infection are limited because the cause of the resulting neuropathogenesis is not completely understood. We previously reported that human microglial cells, while nonproductively infected, respond to HSV-1 by producing robust amounts of pro-inflammatory mediators, such as tumor necrosis factor(TNF), interleukin (IL)-1beta, CCL5 (RANTES), and CXCL10 (IP-10). Although initiation of immune responses by glial cells is an important protective mechanism in the CNS, unrestrained inflammatory responses may result in irreparable brain damage. To elucidate the potential immunomodulatory role of anti-inflammatory cytokines, we investigated the effects of IL-4, IL-10, and transforming growth factor (TGF)-beta on microglial cell cytokine and chemokine production in response to HSV-1. Results from these studies demonstrated a consistent IL-10-mediated suppression of TNF-alpha (60% +/- 2%), IL-1beta (68% +/- 3%), CCL5 (62 +/- 4%), but not CXCL10 production by HSV-1-infected microglial cells. This inhibition was associated with decreased HSV-1-induced activation of NF-kappaB. These results suggest that IL-10 has the ability to regulate microglial cell production of immune mediators and thereby, dampen the pro-inflammatory response to HSV-1.

Topics: Adjuvants, Immunologic; Cells, Cultured; Chemokine CCL5; Chemokine CXCL10; Chemokines, CC; Chemokines, CXC; Encephalitis, Herpes Simplex; Fetus; Herpesvirus 1, Human; Humans; Inflammation Mediators; Interleukin-1; Interleukin-10; Interleukin-4; Microglia; NF-kappa B; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha