Chronic mental health disorders, including AIDS-related cognitive impairment, schizophrenia, and chronic fatigue syndrome, have been associated with neurotropic viruses that infect and persist in the brain. More data are needed to understand how neurons are changed by viral infection, and how these changes contribute to mental health disorders. The long term objective of the proposed research is to produce cellular and molecular data that will advance our understanding of how neurons influence, and are influenced by viral infections. Within this framework, it will be determined how neuronal regulatory transcription factors control the establishment of viral latency. Secondly, it will be determined if the neural-immune response; specifically cytokines, can modulate neuronal regulatory transcription factor activity during the viral infection. Central to the proposed research plan are two model systems: (1) events the occur during viral brain infections will be elucidated in mice infected with herpes simplex virus (HSV), (2) cytokine regulation of neuronal regulatory transcription factor activities will be determined in neuronal cell cultures. Using electrophoretic mobility shift assays (EMSA), the investigators will determine how regulatory transcription factor activities change during establishment of latent HSV brain infections, and during cytokine treatment of neuronal cells. With the complementation of animal and neuronal cell culture studies, specific neuronal regulatory transcription factors that interact with promoter elements of critical HSV genes will be identified. These studies will include (i) immunoblot analysis of UV-crosslinked neuronal or brain regulatory transcription factors to HSV DNA; (ii) in vitro transcription assays to determine if HSV gene transcription is attenuated by nuclear extracts from HSV-infected brains and cytokine-treated neuronal cells; (iii) immunohistochemical localization (cellular and subcellular) of identified regulatory transcription factors in HSV-infected brains and cytokine-treated cells. Data accumulated from these studies aim to provide novel insights into how neurons convert productive viral infections into latent or persistent infections. Moreover, these studies aim to further elucidate how neuronal-immune interactions during viral infections contribute to chronic neuronal disorders.
| Lewandowski, G; Zimmerman, M N; Denk, L L et al. (2002) Herpes simplex type 1 infects and establishes latency in the brain and trigeminal ganglia during primary infection of the lip in cotton rats and mice. Arch Virol 147:167-79 |
