Murine γ-Herpesvirus-68-Induced IL-12 Contributes to the Control of Latent Viral Burden, but Also Contributes to Viral-Mediated Leukocytosis

Abstract

Early IFN-α/β production, followed by the development of a viral-specific CTL response, are critical factors in limiting the level of murine γ-herpesvirus-68 (γHV-68) infection. Development of a long-lived CTL response requires T cell help, and these CTLs most likely function to limit the extent of infection following reactivation. The importance of IL-12 in the development and/or activity of Th1 cells and CTLs is well documented, and we investigated the kinetics and magnitude of γHV-68-induced IL-12 production. Following intranasal infection, IL-12 and IL-23 mRNA expression was up-regulated in lung and spleen and lung, respectively, followed by increased levels of IL-12p40 in lung homogenates and sera. Exposure of cultured macrophages or dendritic cells to γHV-68 induced secretion of IL-12, suggesting that these cells might be responsible for IL-12 production in vivo. γHV-68 infection of mice made genetically deficient in IL-12p40 expression (IL-12p40−/−) resulted in a leukocytosis and splenomegaly that was significantly less than that observed in syngeneic C57BL/6 mice. IL-12p40−/− mice showed increased levels of infectious virus in the lung, but only at day 9 postinfection. Increased levels of latent virus in the spleen at day 15 postinfection were also observed in IL-12p40−/− mice when compared with syngeneic C57BL/6 mice. An overall reduction in γHV-68-induced IFN-γ production was observed in IL-12p40−/− mice, suggesting that most of the viral-induced IFN-γ in C57BL/6 mice was IL-12 dependent. Taken together, these results suggest that γHV-68-induced IL-12 contributes to the pathophysiology of viral infection while also functioning to limit viral burden.

TLR9 Contributes to Antiviral Immunity during Gammaherpesvirus Infection

“…For MCMV, both TLR9/MyD88-dependent and -independent processes for IFN-␣ release have been described (35). MHV-68 infection induces a number of cytokines, for example, IFN-␣/IFN-␤, IFN-␥, IL-6, IL-10, and IL-12 (25,33,36). The type I IFNs have been shown to play a key role in the control of early (37) as well as latent MHV-68 infection (38).…”

“…The type I IFNs have been shown to play a key role in the control of early (37) as well as latent MHV-68 infection (38). MHV-68-induced IL-12 functions to limit the viral burden but also contributes to virus-mediated splenomegaly (25). Although the cellular sources of the MHV-68-induced IFN-␣/IFN-␤ have not yet been analyzed in detail, DCs have been shown to be a source for MHV-68-induced IL-12 (25).…”

“…This activation was dependent on cell-to-cell contact and was partially linked to TLR9 signaling (24). MHV-68 can induce IL-12 production in macrophages and DCs (25). HSV-1-induced IL-12 production during infection is mediated by TLR9 (26).…”

IL-18, but not IL-12, Regulates NK Cell Activity following Intranasal Herpes Simplex Virus Type 1 Infection

“…HSV-1 infection has been reported to induce up-regulation of IL-23 mRNA in TG (42) and prominent IL-12 responses in the eye (43) following corneal infection. A number of reports confirm IL-12 production in the respiratory tract following infection with viruses such as murine gammaherpesvirus 68 and influenza virus (44,45). In this study we report that despite early induction of IL-12 in respiratory fluids recovered from HSV-1-infected mice (Fig.…”

Ecstasy (3,4-methylenedioxymethamphetamine) limits murine gammaherpesvirus-68 induced monokine expression

“…Isolation of bone marrow cells-Bone marrow-derived macrophages were matured in LADMAC-supplemented medium (Sklar et al, 1985) as previously described (Bowman and Bost, 2004;Elsawa and Bost, 2004). Typically, a mouse was anesthetized with isofluorane and sacrificed by cervical dislocation.…”