Prostaglandin E2 Production and T Cell Function in Mouse Adenovirus Type 1 Infection following Allogeneic Bone Marrow Transplantation

Abstract

Adenovirus infections are important complications of bone marrow transplantation (BMT). We demonstrate delayed clearance of mouse adenovirus type 1 (MAV-1) from lungs of mice following allogeneic BMT. Virus-induced prostaglandin E2 (PGE2) production was greater in BMT mice than in untransplanted controls, but BMT using PGE2-deficient donors or recipients failed to improve viral clearance, and treatment of untransplanted mice with the PGE2 analog misoprostol did not affect virus clearance. Lymphocyte recruitment to the lungs was not significantly affected by BMT. Intracellular cytokine staining of lung lymphocytes demonstrated impaired production of INF-γ and granzyme B by cells from BMT mice, and production of IFN-γ, IL-2, IL-4, and IL-17 following ex vivo stimulation was impaired in lymphocytes obtained from lungs of BMT mice. Viral clearance was not delayed in untransplanted INF-γ-deficient mice, suggesting that delayed viral clearance in BMT mice was not a direct consequence of impaired IFN-γ production. However, lung viral loads were higher in untransplanted CD8-deficient mice than in controls, suggesting that delayed MAV-1 clearance in BMT mice is due to defective CD8 T cell function. We did not detect significant induction of IFN-β expression in lungs of BMT mice or untransplanted controls, and viral clearance was not delayed in untransplanted type I IFN-unresponsive mice. We conclude that PGE2 overproduction in BMT mice is not directly responsible for delayed viral clearance. PGE2-independent effects on CD8 T cell function likely contribute to the inability of BMT mice to clear MAV-1 from the lungs.

Interferon-dependent immunoproteasome activity during mouse adenovirus type 1 infection

“…Although IFN-γ does not exert a critical antiviral function during MAV-1 respiratory infection (Anderson et al, 2009; McCarthy et al, 2015b) or myocarditis (McCarthy et al, 2015a), we demonstrated that it is necessary for virus-induced inflammatory responses in the hearts of MAV-1-infected mice (McCarthy et al, 2015a). In the present study, we tested the hypothesis that IFN-γ-induced immunoproteasome activity is an important contributor to virus-induced inflammation.…”

“…CD8 T cells are recruited to the lungs, hearts, and brains of mice infected with MAV-1 (McCarthy et al, 2015a; McCarthy et al, 2015b; McCarthy et al, 2014; Procario et al, 2012; Weinberg et al, 2007). Compared to MAV-1 viral loads in wild type mice, viral loads are higher in brains of MHC class I-deficient mice following i.p.…”

“…Compared to MAV-1 viral loads in wild type mice, viral loads are higher in brains of MHC class I-deficient mice following i.p. inoculation (Moore et al, 2003), in the lungs of CD8-deficient mice (McCarthy et al, 2015b), and in hearts of CD8-depleted mice (McCarthy and Weinberg, unpublished data) following i.n. inoculation.…”

“…inoculation. CD8 T cell dysfunction in mice following allogeneic bone marrow transplantation is associated with delayed clearance of MAV-1 from the lungs (McCarthy et al, 2015b). We therefore anticipated that immunoproteasome deficiency would impair viral clearance if it was associated with effects on virus-specific CD8 T cell function due to altered presentation of virus-specific epitopes by MHC class I.…”

“…The strict species specificity of the adenoviruses precludes detailed studies of HAdV pathogenesis in mouse models. We have used mouse adenovirus type 1 (MAV-1) to study the pathogenesis of adenovirus respiratory infection in its natural host (McCarthy et al, 2013; McCarthy et al, 2015b; McCarthy et al, 2014; Procario et al, 2012; Procario et al, 2016; Weinberg et al, 2005). Recently, we used MAV-1 to establish a mouse model of adenovirus myocarditis (McCarthy et al, 2015a) in which intranasal (i.n.)…”