Interferon Regulatory Factor 1 and Type I Interferon Cooperate To Control Acute Gammaherpesvirus Infection

Abstract

Gammaherpesviruses are ubiquitous pathogens that establish lifelong infection in Ͼ95% of adults worldwide and are associated with a variety of malignancies. Coevolution of gammaherpesviruses with their hosts has resulted in an intricate relationship between the virus and the host immune system, and perturbation of the virus-host balance results in pathology. Interferon regulatory factor 1 (IRF-1) is a tumor suppressor that is also involved in the regulation of innate and adaptive immune responses. Here, we show that type I interferon (IFN) and IRF-1 cooperate to control acute gammaherpesvirus infection. Specifically, we demonstrate that a combination of IRF-1 and type I IFN signaling ensures host survival during acute gammaherpesvirus infection and supports IFN gamma-mediated suppression of viral replication. Thus, our studies reveal an intriguing cross talk between IRF-1 and type I and II IFNs in the induction of the antiviral state during acute gammaherpesvirus infection.IMPORTANCE Gammaherpesviruses establish chronic infection in a majority of adults, and this long-term infection is associated with virus-driven development of a range of malignancies. In contrast, a brief period of active gammaherpesvirus replication during acute infection of a naive host is subclinical in most individuals. Here, we discovered that a combination of type I interferon (IFN) signaling and interferon regulatory factor 1 (IRF-1) expression is required to ensure survival of a gammaherpesvirus-infected host past the first 8 days of infection. Specifically, both type I IFN receptor and IRF-1 expression potentiated antiviral effects of type II IFN to restrict gammaherpesvirus replication in vivo, in the lungs, and in vitro, in primary macrophage cultures.KEYWORDS IRF-1, acute infection, gammaherpesvirus, interferon, viral replication G ammaherpesviruses are ubiquitous pathogens that establish lifelong infection in a majority of the adult population and are associated with cancer (1-3). Similar to replication of other viruses, replication of both human (Epstein-Barr virus [EBV] and Kaposi's sarcoma-associated herpesvirus [KSHV]) and murine (mouse gammaherpesvirus 68[MHV68]) gammaherpesviruses is suppressed by type I and type II interferons (IFNs), two partially overlapping yet distinct host networks that are critical for the control of gammaherpesvirus infection (4-10). In the case of MHV68, both acute and chronic MHV68 infection is attenuated by type I and type II IFNs (4,6,11,12). While the antiviral role of IFNs in the context of gammaherpesvirus infection, including in vivo, is firmly established, the mechanism by which this restriction is imposed and the molecular players involved in this response are still being defined.Interferon regulatory factor 1 (IRF-1) is a broadly antiviral transcription factor that restricts replication of diverse RNA and DNA viruses in cell culture via a poorly understood mechanism (13, 14). While initially IRF-1 was thought to induce type I interferon (IFN) expression (15)

ATM supports gammaherpesvirus replication by attenuating type I interferon pathway

“…4A and viral titers measured at 72h post infection. IFNγ treatment attenuated MHV68 replication in IFNAR −/− macrophages, albeit not to the same extent as that observed in type I IFN competent cultures, as we previously reported (Mboko et al, 2016). Specifically, ~50-fold increase of MHV68 titers above baseline was readily observed at 72 hours post infection of IFNγ-treated IFNAR deficient cells (Fig.…”

“…Not surprisingly, IFNγ is a critical antiviral factor that also controls MHV68 infection in vivo (Lee, Cool et al, 2009; Lee, Groshong et al, 2009; Steed, Barton et al, 2006; Steed, Buch et al, 2007; Tibbetts, Van Dyk et al, 2002). We have recently shown that IFNγ-mediated restriction of MHV68 replication was attenuated in macrophages lacking type I IFN receptor (Mboko, Rekow et al, 2016). Our published observation in the MHV68 system is consistent with other publications that demonstrated decreased expression of Stat1 in type I IFN deficient cells and constitutive association between IFNAR1 and IFNGR2, indicating an intimate crosstalk between type I and type II IFN signaling networks (Gough, Messina et al, 2010; Takaoka, Mitani et al, 2000).…”

“…Analysis was performed using previously published primers (Mboko et al, 2014; Mboko et al, 2012; Mboko et al, 2016) or primers shown in Table 1. All primers used in this study were validated for sensitivity and specificity using both bioinformatic and wet lab approaches; the slope and linear range was established for each primer pair, all measurements were confined to the linear range of the particular primer pair, and minus RT controls were tested for each experimental sample.…”

Interferon regulatory factor 8 regulates caspase-1 expression to facilitate Epstein-Barr virus reactivation in response to B cell receptor stimulation and chemical induction

“…In contrast to the positive role of IRF8 in EBV lytic replication observed in our study, most of the IRFs contribute to anti-viral immunity and block the infection or lytic reactivation of herpesviruses. For example, it was reported that IRF1 restricts gammaherpesvirus replication through IFN-mediated suppression of viral replication [ 73 , 74 , 75 , 76 ]. IRF2 also suppresses gammaherpesvirus replication and reactivation by inhibiting the M2 gene promoter [ 77 ].…”

p53 Controls Murine Gammaherpesvirus Latency and Prevents Infection-AssociatedIgH/c-MycTranslocations

“…To test this hypothesis, we evaluated MHV68 infection in p53 +/+ and p53 -/mice. Although p53 is reportedly an interferon (IFN) stimulated gene that functions in limiting acute viral replication and MHV68 replication is controlled by type I IFNs (37,38), viral loads were equivalent in lungs of p53 -/and WT animals after intranasal inoculation and mortality was not observed during the acute phase of infection ( Fig. S2).…”