Abstract
Although viruses have been implicated in central nervous system (CNS) diseases of unknown etiology, including multiple sclerosis and amyotrophic lateral sclerosis, the reproducible identification of viral triggers in such diseases has been largely unsuccessful. Here, we explore the hypothesis that viruses need not replicate in the tissue in which they cause disease; specifically, that a peripheral infection might trigger CNS pathology. To test this idea, we utilized a transgenic mouse model in which we found that immune cells responding to a peripheral infection are recruited to the CNS, where they trigger neurological damage. In this model, mice are infected with both CNS-restricted measles virus (MV) and peripherally restricted lymphocytic choriomeningitis virus (LCMV). While infection with either virus alone resulted in no illness, infection with both viruses caused disease in all mice, with ∼50% dying following seizures. Co-infection resulted in a 12-fold increase in the number of CD8+ T cells in the brain as compared to MV infection alone. Tetramer analysis revealed that a substantial proportion (>35%) of these infiltrating CD8+ lymphocytes were LCMV-specific, despite no detectable LCMV in CNS tissues. Mechanistically, CNS disease was due to edema, induced in a CD8-dependent but perforin-independent manner, and brain herniation, similar to that observed in mice challenged intracerebrally with LCMV. These results indicate that T cell trafficking can be influenced by other ongoing immune challenges, and that CD8+ T cell recruitment to the brain can trigger CNS disease in the apparent absence of cognate antigen. By extrapolation, human CNS diseases of unknown etiology need not be associated with infection with any particular agent; rather, a condition that compromises and activates the blood-brain barrier and adjacent brain parenchyma can render the CNS susceptible to pathogen-independent immune attack.
Highlights
Despite the exquisitely specific activation of the adaptive immune response following antigenic encounter, recruitment of immune cells to the affected site is governed by relatively nonspecific factors, including chemokine gradients and adhesion molecule induction on barrier endothelia [1,2,3]
There are many central nervous system (CNS) diseases, including multiple sclerosis and amyotrophic lateral sclerosis, which have an inflammatory component, though no direct link has been established between incidence and a CNS-resident infectious agent
We developed a viral co-infection model using measles virus (MV) as a CNS activator and recruiting signal and lymphocytic choriomeningitis (LCMV) as a peripheral immune response initiator
Summary
Despite the exquisitely specific activation of the adaptive immune response following antigenic encounter, recruitment of immune cells to the affected site is governed by relatively nonspecific factors, including chemokine gradients and adhesion molecule induction on barrier endothelia [1,2,3]. Using a mouse model of influenza infection, it was shown that primed transgenic CD4+ T cells that were specific for ovalbumin (with no cross-reactivity to flu) migrated efficiently to the infected lung. Despite such recruitment, these cells did not proliferate [4], showing that T cell recruitment and proliferation can be uncoupled. Many human and animal diseases are caused by polymicrobial exposures, including human pneumonia, otitis media, peritonitis and periodontitis Other diseases, such as hepatitis and Lyme’s disease, though caused by a single pathogen, can have exacerbated symptoms when combined with a second pathogen [5,6]. In this report, we asked whether recruitment of activated immune cells to virus-negative tissues occurs in individuals who are challenged simultaneously with multiple pathogens/antigens of differing tropism, and if so, whether this affects the pathogenic outcome
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