Our long term goal is to understand how the mammalian host protects itself from viral infections of the CNS. More often than not, mammalian virus infections are cleared from the CNS without unusual signs of clinical illness. Only immunosuppressed hosts, such as with chemotherapy, AIDS and old age, or newborns with ‘immature’ immune/nervous systems have a high risk of complications from viral CNS infections. In addition to the general effects of encephalitis and meningitis, viral infections could cause long lasting damage of the host if there is neuronal depletion.
Currently, the laboratory’s main focus is to determine the molecular and cellular players in the scenario where a competent adult immune response successfully clears virus from neurons of the CNS. One way in which we study this is by employing a transgenic mouse model of human measles virus infection (Dr. G.F. Rall, PNAS 1997, 94 (9)4659-63). These mice are susceptible to viral infection of CNS neurons exclusively, with adult mice mounting an impressive CD4 and CD8 T cell response in the brain. The immune response fully protects these animals from illness, without cell death of targeted neurons. It is important to gain an understanding of whether the noncytolytic virus clearance observed is governed by the character of the immune cell infiltrate, the accessibility of the immune response to infected cells, or the nature of the infected target cells. Projects will continue with measles to study the adult anti-viral responses to brain infection.
To enable a study of innate signals of the immune response separated from an adaptive immune response to virus infection of neurons, we have established long-term brain slice cultures. All lab members are pioneering in the effort to use organotypic and primary culture of brain tissue and cells. We are evaluating the role of chemokines in the attraction of an immune response as well as the functions of T cell interactions we have seen.
West Nile virus is also being used to apply to challenge the principles we try to understand in our measles virus model. Our hypothesis is that certain ‘truths’ should apply to all viruses and immune responses in the brain. Thus, as a starting point, measurements and effects of chemokines and cytokines during the adaptive and innate immune response are being compared for pathogenic and non-pathogenic strains of West Nile virus. The brain slices and primary cultures are being employed for these studies.
Measles virus projects in the Patterson lab are also working towards determining the mode of transynaptic spread between transgenic neurons. Transmission of virus does not require a classical H:receptor interaction but can be blocked with a paramyxovirus fusion inhibitor.
Through use of mouse models - in vivo, brain slices – ex vivo and establishment of primary neuron cultures - in vitro, there are themes that have emerged from our virology studies:
- Virus infected neurons could directly alter the response of immune cells: for example, virus infection of neurons results in synthesis of proinflammatory chemokines (Patterson 2003)
- Neurons can be ‘preserved’ during an aggressive anti-viral immune response: virus infection of CNS neurons can be noncytolytically cleared by cytokines (Patterson 2002)
- Specialized host cell types can limit virus load by alteringthe viral life cycle: measles virus spread in neurons is transynaptic and depends on the MV fusion protein (Makhortova 2007)
Selected Publications
Patterson CE, John K. Daley, Lisa A. Echols, Thomas E. Lane and Glenn F. Rall. 2003. Measles virus infection induces chemokine synthesis by neurons. J. Immunology, 171(6): 3102-9. [PubMed]
Patterson CE, Diane M.P. Lawrence, Lisa A. Echols and Glenn F. Rall. 2002. Immune-Mediated Protection from Measles Virus-Induced CNS Disease is Non-Cytolytic and Gamma Interferon Dependent. J. Virology, 76: 4497-4506. [PubMed]
Evans CF, Redwine JM, Patterson CE , Askovic S, Rall GF. 2002. LCMV and the central neervous system: uncovering basic principles of CNS physiology and virus-induced disease. Curr Top Microbiol Immunol. 263: 177-95. [PubMed]
Diane M.P. Lawrence, Patterson CE, Tracy L. Gales, Melinda M. Vaughn and Glenn Rall. 2000. Measles virus spread between neurons requires cell contact but not CD46 expression, syncytia fonnation or extracellular virus production. J. Virology, 74: 1908-1918. [PubMed]
Rall GF, Lawrence DM, Patterson CE. 2000. The application of transgenic and knockout mouse technology for the study of viral pathogenesis. Virology. 271 (2): 220-6. [PubMed]
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