Age-Dependent Effects of Immunoproteasome Deficiency on Mouse Adenovirus Type 1 Pathogenesis.

Affiliation

Department of Pediatrics, University of Michigan, Ann Arbor, Michigan, USA [Email]

Abstract

Acute respiratory infection with mouse adenovirus type 1 (MAV-1) induces activity of the immunoproteasome, an inducible form of the proteasome that shapes CD8 T cell responses by enhancing peptide presentation by major histocompatibility complex (MHC) class I. We used mice deficient in all three immunoproteasome subunits (triple-knockout [TKO] mice) to determine whether immunoproteasome activity is essential for control of MAV-1 replication or inflammatory responses to acute infection. Complete immunoproteasome deficiency in adult TKO mice had no effect on MAV-1 replication, virus-induced lung inflammation, or adaptive immunity compared to C57BL/6 (B6) controls. In contrast, immunoproteasome deficiency in neonatal TKO mice was associated with decreased survival and decreased lung gamma interferon (IFN-γ) expression compared to B6 controls, although without substantial effects on viral replication, histological evidence of inflammation, or expression of the proinflammatory cytokines tumor necrosis factor alpha and interleukin-1β in lungs or other organs. T cell recruitment and IFN-γ production was similar in lungs of infected B6 and TKO mice. In lungs of uninfected B6 mice, we detected low levels of immunoproteasome subunit mRNA and protein that increased with age. Immunoproteasome subunit expression was lower in lungs of adult IFN-γ-deficient mice compared to B6 controls. Together, these results demonstrate developmental regulation of the immunoproteasome that is associated with age-dependent differences in MAV-1 pathogenesis.IMPORTANCE MAV-1 infection is a useful model to study the pathogenesis of an adenovirus in its natural host. Host factors that control MAV-1 replication and contribute to inflammation and disease are not fully understood. The immunoproteasome is an inducible component of the ubiquitin proteasome system that shapes the repertoire of peptides presented by MHC class I to CD8 T cells, influences other aspects of T cell survival and activation, and promotes production of proinflammatory cytokines. We found that immunoproteasome activity is dispensable in adult mice. However, immunoproteasome deficiency in neonatal mice increased mortality and impaired IFN-γ responses in the lungs. Baseline immunoproteasome subunit expression in lungs of uninfected mice increased with age. Our findings suggest the existence of developmental regulation of the immunoproteasome, like other aspects of host immune function, and indicate that immunoproteasome activity is a critical protective factor early in life.

Keywords

adenovirus,immunoproteasome,interferon gamma,neonatal immunology,respiratory viruses,

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