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

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.

The Immunoproteasome Subunits LMP2, LMP7 and MECL-1 Are Crucial Along the Induction of Cerebral Toxoplasmosis

“…Notably, using the LCMV infection model, Nussbaum et al, observed that although LMP2 -/or LMP7 -/mice had fewer CD8 + T cells, these animals were able to mount strong CD8 + anti-viral immune responses demonstrated by similar kinetics of viral clearance compared to WT mice (57). In addition, analyzing the role of mouse adenovirus type 1 infection in pathogenesis of TKO mice the authors detected age-dependent differing effects (58). All these studies demonstrate that the role of the IP during infection is multifaceted and most likely pathogen specific.…”

Murine adenoviruses: tools for studying adenovirus pathogenesis in a natural host

“…MAdV‐1 also causes myocarditis that is accompanied by myocyte and endothelial necrosis when inoculated intraperitoneally or intranasally . Many mouse primary cell types, cell strains, and established cell lines can support MAdV‐1 replication in vitro , including fibroblasts (3T6, 3T12 and L929) , endothelial cells (MBMEC) , preadipocyte cells (3T3‐L1) , epithelial cells (LA‐4, MLE‐12 and MLE‐15; J.B. Weinberg, unpublished), cardiac myocytes macrophages/monocytes , and tumor cells such as lung adenoma (LA‐4), renal adenocarcinoma (RAG) , and rectal carcinoma (CMT‐93) cells .…”

“…Intranasal inoculation of MAdV‐1 results in significantly increased immunoproteasome activity in the lung and heart compared to uninfected mice , and this is dependent on IFNγ. The immunoproteasome is important for survival of neonatal mice infected with MAdV‐1 .…”

“…MAdV‐1 has recently been examined as a model to study oral replication‐competent AdV vaccines in vivo in a natural host . Intranasal, intraperitoneal, and natural MAdV‐1 infection generate neutralizing antibodies . Oral infection of C57BL/6 mice, which have intermediate susceptibility to MAdV‐1 , leads to a systemic infection with moderate bowel pathogenesis and antiviral neutralizing antibody responses .…”

Acute adenoviral infection elicits an arrhythmogenic substrate prior to myocarditis

“…Unlike CVB3 however, many HAdVs cannot replicate effectively in mice, resulting in a dearth of understanding regarding adenoviral cardiotropism and virus-specific effects on the heart due to this stringent adenoviral speciesspecificity 46,54 . Mouse adenovirus type 1 (MAdV-1) has historically been employed in modeling respiratory disease and encephalitis, and while not a 'cardiotropic' virus, additional studies have successfully modeled adenoviral myocarditis in mice using MAdV-1, with an emphasis on inflammation [55][56][57][58] . In 2008, mouse adenovirus type-3 (MAdV-3) was isolated as distinct from the previously described MAdV-1 and MAdV-2, and reported to be cardiotropic 59,60 .…”