Type 1 Interferon Induction of Natural Killer Cell Gamma Interferon Production for Defense during Lymphocytic Choriomeningitis Virus Infection

Division of Biology and Medicine, Department of Molecular Microbiology and Immunology, Brown University, Providence, Rhode Island, USA.
mBio (Impact Factor: 6.79). 06/2011; 2(4). DOI: 10.1128/mBio.00169-11
Source: PubMed


Natural killer (NK) cells are equipped to innately produce the cytokine gamma interferon (IFN-γ) in part because they basally express high levels of the signal transducer and activator of transcription 4 (STAT4). Type 1 interferons (IFNs) have the potential to activate STAT4 and promote IFN-γ expression, but concurrent induction of elevated STAT1 negatively regulates access to the pathway. As a consequence, it has been difficult to detect type 1 IFN stimulation of NK cell IFN-γ during viral infections in the presence of STAT1 and to understand the evolutionary advantage for maintaining the pathway. The studies reported here evaluated NK cell responses following infections with lymphocytic choriomeningitis virus (LCMV) in the compartment handling the earliest events after infection, the peritoneal cavity. The production of type 1 IFNs, both IFN-α and IFN-β, was shown to be early and of short duration, peaking at 30 h after challenge. NK cell IFN-γ expression was detected with overlapping kinetics and required activating signals delivered through type 1 IFN receptors and STAT4. It took place under conditions of high STAT4 levels but preceded elevated STAT1 expression in NK cells. The IFN-γ response reduced viral burdens. Interestingly, increases in STAT1 were delayed in NK cells compared to other peritoneal exudate cell (PEC) populations. Taken together, the studies demonstrate a novel mechanism for stimulating IFN-γ production and elucidate a biological role for type 1 IFN access to STAT4 in NK cells.

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    • "NK cells are the major source of IFN and activation of NK cells by IFN is essential for their lytic activity (Wang et al., 2012). Studies have shown that the increase in frequency , activity of NK cells and IFN production by NK cells is essential for reduction of viral load in mice infected with lymphocytic choriomeningitis virus or influenza virus (Biron et al., 1983; Mack et al., 2011; Stein-Streilein et al., 1988). Further, production of IFN and IFN in intestine of mice was essential and sufficient to induce innate immune cells to eliminate certain bacterial pathogens in mice (Sotolongo et al., 2011). "
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    ABSTRACT: Porcine epidemic diarrhea (PED) is an enteric coronaviral infection that causes severe morbidity and mortality in suckling pigs, but less severe disease in older pigs. Consequently, it causes significant economic losses to the pork industry. There are limited studies on the innate immune responses to PED virus (PEDV) in pigs. The aims of our study were to investigate differences in innate immune responses to PEDV infection in suckling and weaned pigs and to examine if disease severity coincides with reduced innate immune responses. Weaned 26-day-old pigs (n = 20) and 9-day-old nursing pigs (n = 20) were assigned to PEDV inoculated or uninoculated control groups. The pigs were observed daily for clinical signs, virus shedding and were euthanized at post-inoculation days (PIDs) 1 and 5 to assay immune responses. Blood samples were collected at PIDs 1, 3 and 5. The natural killer (NK) cell frequencies, NK cell activities (lysis of target K562 tumor cells in vitro), CD3+CD4+ T cell and CD3+CD8+ T cell frequencies were measured in blood and ileum at PIDs 1 and 5. The PEDV infected suckling pigs showed severe diarrhea and vomiting at PID 1, whereas the PEDV infected weaned pigs showed milder clinical signs starting at PID 3. PEDV infected suckling pigs had significantly higher diarrhea scores, earlier fecal PEDV RNA shedding and significantly higher viremia (viral RNA in serum) compared to weaned pigs. There was no mortality in either infected suckling or infected weaned pigs. The control pigs not inoculated with PEDV did not show any clinical signs and no detectable fecal or serum PEDV RNA. Strikingly, PEDV infected suckling pigs had significantly lower NK cell frequencies, undetectable NK cell activity and lower IFN producing NK cells in blood and ileum compared to PEDV infected weaned pigs. Pro-inflammatory cytokine profiles of PEDV infected suckling pigs differed from those of PEDV infected weaned pigs and coincided with onset of fecal PEDV RNA shedding and serum PEDV RNA titers. The infected suckling pigs have higher and earlier increases in serum IFN, but lower serum IL-8 and TNF levels compared to infected weaned pigs. CD3+CD4+ T cell frequencies were significantly higher in ileum of suckling pigs than in weaned pigs, whereas there was no difference in CD3+CD8+ T cell frequencies. In conclusion, the observations of impaired lytic activity and IFN-production by NK cells in suckling pigs coincided with the increased severity of PEDV infection in the suckling pigs compared with the weaned pigs.
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    • "For IFN-α/β, this is expected because type I IFN production relies on a positive-feedback loop through the type I IFN receptor (26). In addition, previous studies have shown that type I IFNs play a critical role in induction of IFN-γ gene expression through the activation of STAT4 (32, 33) or increased signaling through other cytokine receptors such as IFN-γ receptor by increased levels of STAT1 (19, 34). Furthermore, since the IFN responses were reduced in IFNAR1−/− mice, this resulted in a diminished induction of ISGs as has previously been shown for TLR stimulation (35, 36) and for bone marrow-derived DCs (BMDCs) stimulated with RSV (37). "
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    ABSTRACT: Unlabelled: Type I interferons (IFNs) are produced early upon virus infection and signal through the alpha/beta interferon (IFN-α/β) receptor (IFNAR) to induce genes that encode proteins important for limiting viral replication and directing immune responses. To investigate the extent to which type I IFNs play a role in the local regulation of inflammation in the airways, we examined their importance in early lung responses to infection with respiratory syncytial virus (RSV). IFNAR1-deficient (IFNAR1(-/-)) mice displayed increased lung viral load and weight loss during RSV infection. As expected, expression of IFN-inducible genes was markedly reduced in the lungs of IFNAR1(-/-) mice. Surprisingly, we found that the levels of proinflammatory cytokines and chemokines in the lungs of RSV-infected mice were also greatly reduced in the absence of IFNAR signaling. Furthermore, low levels of proinflammatory cytokines were also detected in the lungs of IFNAR1(-/-) mice challenged with noninfectious innate immune stimuli such as selected Toll-like receptor (TLR) agonists. Finally, recombinant IFN-α was sufficient to potentiate the production of inflammatory mediators in the lungs of wild-type mice challenged with innate immune stimuli. Thus, in addition to its well-known role in antiviral resistance, type I IFN receptor signaling acts as a central driver of early proinflammatory responses in the lung. Inhibiting the effects of type I IFNs may therefore be useful in dampening inflammation in lung diseases characterized by enhanced inflammatory cytokine production. Importance: The initial response to viral infection is characterized by the production of interferons (IFNs). One group of IFNs, the type I IFNs, are produced early upon virus infection and signal through the IFN-α/β receptor (IFNAR) to induce proteins important for limiting viral replication and directing immune responses. Here we examined the importance of type I IFNs in early responses to respiratory syncytial virus (RSV). Our data suggest that type I IFN production and IFNAR receptor signaling not only induce an antiviral state but also serve to amplify proinflammatory responses in the respiratory tract. We also confirm this conclusion in another model of acute inflammation induced by noninfectious stimuli. Our findings are of relevance to human disease, as RSV is a major cause of infant bronchiolitis and polymorphisms in the IFN system are known to impact disease severity.
    Full-text · Article · Mar 2014 · Journal of Virology
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    • "The relatively noncytopathic LCMV infection does not cause appreciable stress to cells nor does it down-regulate class I MHC antigens (Bukowski and Welsh, 1985). Although IFNg production by NK cells may slightly restrict LCMV replication at the peripheral inoculation site (Mack et al., 2011), we can generally categorize LCMV as a relatively NK-resistant virus and contrast it to MCMV, the prototypic NK-sensitive virus. Nevertheless, depletion of NK cells under certain conditions can greatly alter the patterns of LCMV pathogenesis and persistence (Fig. 2). "
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    ABSTRACT: Viral infections characteristically induce a cytokine-driven activated natural killer (NK) cell response that precedes an antigen-driven T cell response. These NK cells can restrain some but not all viral infections by attacking virus-infected cells and can thereby provide time for an effective T cell response to mobilize. Recent studies have revealed an additional immunoregulatory role for the NK cells, where they inhibit the size and functionality of the T cell response, regardless of whether the viruses are themselves sensitive to NK cells. This subsequent change in T cell dynamics can alter patterns of immunopathology and persistence and implicates NK cells as rheostat-like regulators of persistent infections.
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