Immune Regulation of Viral Recrudescence
Principal Investigator: Cornelia Bergmann
Abstract: DESCRIPTION (provided by applicant): The central nervous system (CNS) is a major target for acute encephalitic viral infections, as well as a reservoir of latent/persisting viruses. While effective immune control of persisting viruses in immunocompetent individuals is reflected by the absence of overt neurological deficits or pathology, this balance is highly tenuous. Studies supported by this award were the first to demonstrate that intrathecal antibody secreting cells (ASC) were critical to control CNS viral persistence even despite early T cell mediated control and presence of anti-viral serum antibody (Ab). We have also defined the regulation of ACS recruitment into the CNS by identifying the crucial chemokine receptor and chemokine. The reliance on local ASC for prolonged Ab output during neurotropic coronavirus infection is a critical observation, as it provides a potent non lytic mechanism of sustained immune control applicable to numerous neurotropic infections. Indeed, a vital local protective role of ASC is supported by other experimental CNS infections, particularly by RNA viruses such as Sindbis, Semliki Forest, and Rabies viruses. Intrathecal Ab synthesis is also well documented in humans during infections associated with neurological complications and the demyelinating disease multiple sclerosis (MS). However, virtually nothing is known about the origin, maintenance, and relevance of ASC in the CNS or other specialized microenvironments. The overall goal is to define the regulation of protective, yet minimally destructive ASC within the CNS, to combat infections where virus replicates in the CNS in the absence of overt blood brain barrier damage or inflammatory signals. The Specific Aims are to 1) determine the role of CNS resident cells in mediating ASC entry and localization within the CNS;and 2) determine the relative contribution of migratory ASC versus circulating, non Ab secreting memory B cells in maintaining ASC within the CNS. In situ hybridization combined with confocal microscopy in Aim 1 will determine the spatial relationship between chemokines, viral antigen, ASC localization and the microvasculature. The results will further reveal a central role of astrocytes in regulating ASC recruitment. Aim 2 uses transgenic mice in which germinal center derived ASC and memory B cells are phenotypically marked, to specifically test the role of virus specific B cells in contributing to ASC maintenance during chronic CNS infection. Adoptive transfers will define whether the initial burst of ASC in the CNS is sufficient to sustain local protective capacity. Non of these parameters have been studied during viral or autoimmune encephalomyelitis. The ability to trace ASC and Bmem using transgenic markers provides a versatile innovative approach to dissect humoral immunity in a non-lymphoid organ prone to persisting infection. The contribution of peripherally activated B cells rather than lymphoid tissue neogenesis, in sustaining intrathecal humoral responses during persistent infections associated with limited ongoing inflammation will be beneficial for understanding protective responses during human CNS infections caused by measles virus, rubella virus, JC virus, and HIV.
Funding Period: -------------------- - --------------------
more information: NIH RePORT
- Astrocyte-derived CXCL10 drives accumulation of antibody-secreting cells in the central nervous system during viral encephalomyelitisTimothy W Phares
Department of Neurosciences, Lerner Research Institute, The Cleveland Clinic, Cleveland, OH, USA
J Virol 87:3382-92. 2013..These results suggest that CXCL10 is critical for two phases: recruitment of ASC to the CNS vasculature and ASC entry into the CNS parenchyma...
- Intrathecal humoral immunity to encephalitic RNA virusesTimothy W Phares
Departments of Neurosciences NC30, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA
Viruses 5:732-52. 2013..The sustained Ab production by local ASC, as well as chemokines and cytokines associated with ASC recruitment and retention, are highlighted as critical components of immune control...
- IL-21 optimizes T cell and humoral responses in the central nervous system during viral encephalitisTimothy W Phares
Department of Neurosciences, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA
J Neuroimmunol 263:43-54. 2013..Viral control was already lost prior to humoral CNS responses, but demyelination remained comparable. These data demonstrate a critical role of IL-21 in regulating CNS immunity, sustaining viral persistence and preventing mortality. ..