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Saturday, May 17, 2008
Champagne Terrace/Bordeaux (Novotel London West)
Background: Although viral infections have been proposed as etiological triggers for certain central nervous system (CNS) disorders, including autism, the identification of specific, causative pathogens--and determination of how such infections contribute to CNS disease--have been largely unsuccessful.
Objectives: To determine if peripheral infections can contribute to neuropathogenic disease, we developed a model in which mice are infected with two, concomitant viral infections: one restricted to the CNS, and the other restricted to the periphery.
Methods: In this model, mice are infected with CNS-restricted measles virus (MV; Edmonston strain, 5000 plaque forming units; PFU), and peripherally restricted lymphocytic choriomeningitis virus (LCMV; Armstrong strain, 5000 PFU).
Results: While infection by either virus alone results in no illness, simultaneous co-infection with both viruses causes neuropathology and consequent disease in ~50% of infected mice. Moreover, in 100% of doubly-challenged animals, a greater than 10-fold increase in the number of CD8+ T cells in the CNS is observed by flow cytometry, as compared to single infection alone. A substantial proportion (~40%) of these CNS infiltrating CD8+ T-cells are of LCMV-specificity, as shown by GP33 and NP396 epitope tetramer staining and chromium release assays, implying that LCMV-specific T cells are being "mis-recruited" to the MV-infected CNS. Despite no apparent cross-reactivity between the viruses, T cell-mediated CNS disease is MHC-I dependent, and appears to be due to severe edema and neuroinflammation, resulting in brainstem herniation.
Conclusions: These results indicate that concurrent immune challenges can result in novel pathogenic outcomes as compared to either challenge alone. We propose that immune cell misrecruitment may be a novel mechanism by which CNS disease can occur.
This work was supported by a grant from the NIH (NS 40500), and a Basic Science award from Autism Speaks.
Objectives: To determine if peripheral infections can contribute to neuropathogenic disease, we developed a model in which mice are infected with two, concomitant viral infections: one restricted to the CNS, and the other restricted to the periphery.
Methods: In this model, mice are infected with CNS-restricted measles virus (MV; Edmonston strain, 5000 plaque forming units; PFU), and peripherally restricted lymphocytic choriomeningitis virus (LCMV; Armstrong strain, 5000 PFU).
Results: While infection by either virus alone results in no illness, simultaneous co-infection with both viruses causes neuropathology and consequent disease in ~50% of infected mice. Moreover, in 100% of doubly-challenged animals, a greater than 10-fold increase in the number of CD8+ T cells in the CNS is observed by flow cytometry, as compared to single infection alone. A substantial proportion (~40%) of these CNS infiltrating CD8+ T-cells are of LCMV-specificity, as shown by GP33 and NP396 epitope tetramer staining and chromium release assays, implying that LCMV-specific T cells are being "mis-recruited" to the MV-infected CNS. Despite no apparent cross-reactivity between the viruses, T cell-mediated CNS disease is MHC-I dependent, and appears to be due to severe edema and neuroinflammation, resulting in brainstem herniation.
Conclusions: These results indicate that concurrent immune challenges can result in novel pathogenic outcomes as compared to either challenge alone. We propose that immune cell misrecruitment may be a novel mechanism by which CNS disease can occur.
This work was supported by a grant from the NIH (NS 40500), and a Basic Science award from Autism Speaks.