Reversible Inhibition of Murine Cytomegalovirus Replication by Gamma Interferon (IFN-γ) in Primary Macrophages Involves a Primed Type I IFN-Signaling Subnetwork for Full Establishment of an Immediate-Early Antiviral State

Abstract

Activated macrophages play a central role in controlling inflammatory responses to infection and are tightly regulated to rapidly mount responses to infectious challenge. Type I interferon (alpha/beta interferon [IFN-␣/␤]) and type II interferon (IFN-␥Murine cytomegalovirus (MCMV) infection in mice is a well-established model system for the study of acute, persistent, and latent infections of betaherpesviruses and their control by the host immune system (32,35,58,60). Both human CMV (HCMV) and MCMV infect a broad range of tissues in their respective hosts, including fibroblasts, endothelial and epithelial cells, and, significantly, immune cells of the myeloid lineage (13,57,69,70). Differentiated macrophages of this lineage residing in infected tissues play a key role in eliciting the host immune response but are also permissive for CMV infection and serve as disseminators of the virus throughout the host (reviewed in reference 29).In immunocompetent hosts, primary CMV infections are generally asymptomatic, with immune cells either killing virusinfected cells or restricting viral cell-to-cell spread and replication. The latter effect occurs via induction of an antiviral state in noninfected cells or the activation of immune cells by soluble mediators such as type I interferon (alpha/beta interferon [IFN-␣/␤]) and type II interferon (IFN-␥) (8,10,41,50,60,73). Several hundred genes stimulated in response to both type I and type II IFNs have been identified by microarrays in various cell types over the years (18,19,37,38,66). In contrast, the recently discovered type III IFNs are not well characterized but may have comparable functions to the type I IFNs, mediated by shared downstream signaling and IFN-stimulated genes (ISGs) (3, 33, 42, 63, 72, 78, 84). Type III IFNs are

The Transcription Factor STAT-1 Couples Macrophage Synthesis of 25-Hydroxycholesterol to the Interferon Antiviral Response

“…Interestingly, in this study noticeable amounts of 25HC were found in unstimulated Mϕ but not media—a result that perhaps reflects a pre-existing subprimed activation of Mϕ (Kropp et al., 2011). Strikingly, amounts of only 25HC were markedly increased by infection or treatment with MCMV or Ifn (β or γ), respectively (Figures 1C and 1D).…”

Infergen Stimulated Macrophages Restrict Mycobacterium tuberculosis Growth by Autophagy and Release of Nitric Oxide

“…This cytokine plays an important role in T cell activation and inhibition of the growth of Mtb 25262728293031. IFG stimulated H37Ra infected Mφ produced considerably (p < 0.001) higher level of IL-6, as compared to unstimulated (no Infergen) macrophages infected with H37Ra [Fig.…”

“…It has been reported that signaling through IFN-α/β can activate macrophages and other cells of the immune system during viral infection3132333435. Further, MHC and costimulatory molecules expressed on the surface of the macrophages are crucial for the optimum activation of T cells.…”

“…As a result, it enhances the activation and cytolytic activity of CD8 + cytotoxic T lymphocytes (CTLs)495051. Further, like IFN-α/β, IFG exhibits an optimized affinity for IFNAR and augments the survival and activation of neutrophils, macrophages, DCs, NK cells, B cells and CD8 T cells313233343552. Furthermore, it is reported that IFG activates various cell types to endorse viral clearance by promoting apoptosis of infected cells3452.…”

Interplay Between CMVs and Interferon Signaling: Implications for Pathogenesis and Therapeutic Intervention

“…Shortening of the preincubation period significantly decreases their biological effect [41][42][43]. In this context, it is noteworthy to recall that in common virus growth kinetics, the initial infectious dose in terms of virus per cell is mostly far below 1 (usually between 0.1 and 0.5% of cells are initially infected) and that, even when IFN and virus are administered simultaneously, the majority of cells are necessarily preincubated for the duration of at least one virus replication cycle until the replicating virus reaches the un infected, but at this time IFN-experienced, cells.…”