Brain atrophy in picornavirus‐infected FVB mice is dependent on the H‐2D^bclass I molecule

Abstract

Brain atrophy is a common feature of numerous neurologic diseases in which the role of neuroinflammation remains ill-defined. In this study, we evaluated the contribution of major histocompatibility complex class I molecules to brain atrophy in Theiler's murine encephalomyelitis virus (TMEV)-infected transgenic FVB mice that express the D class I molecule. FVB/D and wild-type FVB mice were evaluated for changes in neuroinflammation, virus clearance, neuropathology, and development of brain atrophy T2-weighted MRI and subsequent 3-dimensional volumetric analysis. Significant brain atrophy and hippocampal neuronal loss were observed in TMEV-infected FVB/D mice, but not in wild-type FVB mice. Brain atrophy was observed at 1 mo postinfection and persisted through the 4-mo observation period. Of importance, virus-infected FVB/D mice elicited a strong CD8 T-cell response toward the immunodominant D-restricted TMEV-derived peptide, VP2, and cleared TMEV from the CNS. In addition, immunofluorescence revealed CD8 T cells near virus-infected neurons; therefore, we hypothesize that class I restricted CD8 T-cell responses promote development of brain atrophy. This model provides an opportunity to analyze the contribution of immune cells to brain atrophy in a system where persistent virus infection and demyelination are not factors in long-term neuropathology.-Huseby Kelcher, A. M., Atanga, P. A., Gamez, J. D., Cumba Garcia, L. M., Teclaw, S. J., Pavelko, K. D., Macura, S. I., Johnson. A. J. Brain atrophy in picornavirus-infected FVB mice is dependent on the H-2D class I molecule.

Protective and Pathological Immunity during Central Nervous System Infections

“…In the latter model, the type I IFN have a key role in priming the pathological monocyte response ( Nayak et al., 2013 ) and can lead to edema, neuronal death, and herniation ( Matullo et al., 2011 , Matullo et al., 2010 ). A similar phenotype is apparent in mice infected with picornovirus ( Huseby Kelcher et al., 2017 ) and in murine models of cerebral malaria. In the latter system, CD8 + T cell responses are associated with alterations in TJs and vascular breakdown in the meninges and parenchyma, resulting in edema, neuronal cell death within the brainstem, and cerebral herniation ( Huggins et al., 2017 , Swanson et al., 2016 ), reminiscent of the disease process observed in humans ( Seydel et al., 2015 ).…”

“…There are reports of the induction of neuronal class I during infection ( Neumann et al., 1995 ), but there remains a major knowledge gap in our understanding of whether neuronal antigen presentation influences resistance or susceptibility to infection in vivo. There is in vitro and in vivo evidence for CD8 + T cells interacting directly with infected neurons during Theiler’s virus, LCMV, Borna and picornavirus infection ( Chevalier et al., 2011 , Huseby Kelcher et al., 2017 , McDole et al., 2010 , Rall et al., 1995 ) and there is evidence that the ability of HSV to inhibit class I expression in neurons in basal ganglia is key to avoid CD8 + T cell responses ( Orr et al., 2007 ). Unexpectedly, imaging studies indicate that CD11c + cells (likely microglia or DC), but not parasite-specific CD8 + T cells, frequently interact with cysts of T. gondii ( John et al., 2011 , Schaeffer et al., 2009 ).…”

Facets of Theiler’s Murine Encephalomyelitis Virus-Induced Diseases: An Update

“…The resistance of C57BL/6 mice to the development of demyelination is linked to the H-2D MHC class I locus [25,28,211,212,213], enabling vigorous MHC class I-restricted antiviral CD8 + T cell responses. This is exemplified by the transgenic introduction of the Db class I molecule in susceptible FVB mice (FVB/D b ), resulting in robust antiviral cytotoxicity, TMEV elimination, and resistance to TMEV-IDD [214]. Similarly, the genetic ablation of CD8 + T cells in mice with a C57BL/6 background has been shown to reduce antiviral immunity, which leads to TMEV persistence and demyelination in the spinal cord [195,215,216].…”

Severe and multifaceted systemic immunosuppression caused by experimental cancers of the central nervous system requires release of non-steroid soluble mediators

“…TMEV can be cleared effectively in C57BL/6 mice whereas SJL mice experience chronic infection accompanied with demyelination (16). TMEV infection resulted in significant and severe thymic involution measurable by a reduction in thymic weight and cellularity seven days post infection in both C57BL/6 and SJL mice (Figure 7 B).…”

“…Next, we assessed thymi during TMEV infection in C57BL/6 mice. C57BL/6 mice clear TMEV infection within 21-45 days post infection (15,16,20,48). Because C57BL/6 mice mount an effective antiviral CD8 T cell response, this model allows us to determine whether thymic involution is reversible upon viral clearance (20,74).…”