The role of indoleamine 2,3-dioxygenase in LP-BM5 murine retroviral disease progression

Abstract

BackgroundIndoleamine 2,3-dioxygenase (IDO) is an immunomodulatory intracellular enzyme involved in tryptophan degradation. IDO is induced during cancer and microbial infections by cytokines, ligation of co-stimulatory molecules and/or activation of pattern recognition receptors, ultimately leading to modulation of the immune response. LP-BM5 murine retroviral infection induces murine AIDS (MAIDS), which is characterized by profound and broad immunosuppression of T- and B-cell responses. Our lab has previously described multiple mechanisms regulating the development of immunodeficiency of LP-BM5-induced disease, including Programmed Death 1 (PD-1), IL-10, and T-regulatory (Treg) cells. Immunosuppressive roles of IDO have been demonstrated in other retroviral models, suggesting a possible role for IDO during LP-BM5-induced retroviral disease progression and/or development of viral load.MethodsMice deficient in IDO (B6.IDO−/−) and wildtype C57BL/6 (B6) mice were infected with LP-BM5 murine retrovirus. MAIDS and LP-BM5 viral load were assessed at termination.ResultsAs expected, IDO was un-inducible in B6.IDO−/− during LP-BM5 infection. B6.IDO−/− mice infected with LP-BM5 retrovirus succumbed to MAIDS as indicated by splenomegaly, serum hyper IgG2a and IgM, decreased responsiveness to B- and T-cell mitogens, conversion of a proportion of CD4+ T cells from Thy1.2+ to Thy1.2-, and increased percentages of CD11b+Gr-1+ cells. LP-BM5 infected B6.IDO−/− mice also demonstrated the development of roughly equivalent disease kinetics as compared to infected B6 mice. Splenic viral loads of B6 and B6.IDO−/− mice were also equivalent after infection as measured by LP-BM5-specific Def Gag and Eco Gag viral mRNA, determined by qRT-PCR.ConclusionsCollectively, these results demonstrate IDO neither plays an essential role, nor is required, in LP-BM5-induced disease progression or LP-BM5 viral load.

The Role of Myeloid-Derived Suppressor Cells in Viral Infection

“…Genetic ablation of indoleamine 2,3-deoxygenase (IDO) did not affect MDSCmediated suppression; however, IDO may function in wildtype MDSCs from LP-BM5-infected mice and be compensated for by other mechanisms in the IDO-knockout MDSCs (113). Supporting a potential role for IDO in LP-BM5, overall IDO is increased during MAIDS and may play a role in the associated pain hypersensitivity (65,69,113). Current data are conflicting as to whether increased IDO plays a role in LP-BM5 retrovirus replication and immunodeficiency (65,113).…”

“…Supporting a potential role for IDO in LP-BM5, overall IDO is increased during MAIDS and may play a role in the associated pain hypersensitivity (65,69,113). Current data are conflicting as to whether increased IDO plays a role in LP-BM5 retrovirus replication and immunodeficiency (65,113).…”

Reciprocal relationship of T regulatory cells and monocytic myeloid-derived suppressor cells in LP-BM5 murine retrovirus-induced immunodeficiency

“…MDSC expansion occurs in several microbial infections including bacterial (Delano et al, 2007;Goñi et al, 2002;Sunderkötter et al, 2004), fungal (Mencacci et al, 2002), parasitic (Giordanengo et al, 2002;Terrazas et al, 2001;Voisin et al, 2004) and viral infections, including, but not limited to, hepatitis B virus (Chen et al, 2011), cytomegalovirus (Daley-Bauer et al,retroviruses: SIV (Sui et al, 2014), HIV (Bowers et al, 2014;Garg & Spector, 2014;Qin et al, 2013;Vollbrecht et al, 2012) and LP-BM5 murine retrovirus (Green et al, 2013). In murine models, MDSCs are identified as CD11b + CD15 2 M-MDSCs, although a phenotypic consensus on these subsets has not been achieved (reviewed, for example, by Talmadge & Gabrilovich, 2013).…”

“…In the few available studies, retrovirus-induced MDSCs frequently display a monocytic phenotype (Garg & Spector, 2014;Green et al, 2013;Qin et al, 2013), in contrast to the granulocytic phenotype more prominently observed in cancer models, and are hypothesized to contribute to in vivo immunosuppression displayed in these retroviral models. Regardless of the disparate MDSC markers used in these studies, retrovirus-induced MDSCs consistently suppress in vitro T-cell responses, utilizing suppressive mechanisms including, but not limited to, nitric oxide (NO) and reactive oxygen species production (Garg & Spector, 2014;Green et al, 2013;Qin et al, 2013;Sui et al, 2014;Vollbrecht et al, 2012). MDSCs contribute to in vitro and ex vivo immunosuppression, but how MDSCs influence retroviral infection in vivo remains unclear.…”

Use of IRF-3 and/or IRF-7 Knockout Mice To Study Viral Pathogenesis: Lessons from a Murine Retrovirus-Induced AIDS Model

“…1). The extent of pathogenesis was calculated from established disease parameters, and a disease index was assigned, with disease severity ranging from 0 (no disease) to 5 (most-severe disease) (37)(38)(39). Infected IRF-3 Ϫ/Ϫ mice were almost as resistant as MAIDS-resistant 129 mice, whereas IRF-7 Ϫ/Ϫ mice developed disease equivalent to that seen with the susceptible B6 controls.…”