International Meeting for Autism Research (London, May 15-17, 2008): Neuropathogenic Consequences of Dysregulated Immune Responses to Concomitant Immune Challenges

Neuropathogenic Consequences of Dysregulated Immune Responses to Concomitant Immune Challenges

Saturday, May 17, 2008
Champagne Terrace/Bordeaux (Novotel London West)
G. Rall , Fox Chase Cancer Center, Philadelphia, PA
C. Matullo , Fox Chase Cancer Center, Fox Chase Cancer Center, Philadelphia, PA
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.