IFN-γ production dominates the early human natural killer cell response to Coxsackievirus infection

Hühn, Michael; Hultcrantz, Monica; Lind, Katharina; Ljunggren, Hans‐Gustaf; Malmberg, Karl‐Johan; Flodström‐Tullberg, Malin

doi:10.1111/j.1462-5822.2007.01056.x

Cited by 20 publications

(28 citation statements)

References 70 publications

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“…This is consistent with a recent report indicating that IL-33 could drive protective antiviral CD8 + T cell responses during LCMV infection in mice (35). NK cells were also thought to be important in controlling CVB5 infection (36). We observed a decrease in the total number of NK cells in T1/ST2 2/2 mice, which may also account for the higher viral load in these animals.…”

Section: Discussionsupporting

confidence: 93%

The IL-33/ST2 Pathway Controls Coxsackievirus B5–Induced Experimental Pancreatitis

Sesti-Costa

Silva

Proença-Modena

et al. 2013

The Journal of Immunology

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Coxsackievirus B (CVB) is a common cause of acute and chronic infectious myocarditis and pancreatitis. Th1 cells producing IFN-γ and TNF-α are important for CVB clearance, but they are also associated with the pathogenesis of inflammatory lesions, suggesting that the modulation of Th1 and Th2 balance is likely important in controlling CVB-induced pancreatitis. We investigated the role of IL-33, which is an important recently discovered cytokine for induction of Th2-associated responses, in experimental CVB5 infection. We found that mice deficient in IL-33R, T1/ST2, significantly developed more severe pancreatitis, had greater weight loss, and contained higher viral load compared with wild-type (WT) mice when infected with CVB5. Conversely, WT mice treated with rIL-33 developed significantly lower viral titers, and pancreatitis was attenuated. Mechanistic studies demonstrated that IL-33 enhances the degranulation and production of IFN-γ and TNF-α by CD8+ T and NK cells, which is associated with viral clearance. Furthermore, IL-33 triggers the production of IL-4 from mast cells, which results in enhanced differentiation of M2 macrophages and regulatory T cells, leading to the attenuation of inflammatory pancreatitis. Adoptively transferred mast cells or M2 macrophages reversed the heightened pancreatitis in the T1/ST2−/− mice. In contrast, inhibition of regulatory T cells exacerbated the disease in WT mice. Together, our findings reveal an unrecognized IL-33/ST2 functional pathway and a key mechanism for CVB5-induced pancreatitis. These data further suggest a novel approach in treating virus-induced pancreatitis, which is a major medical condition with unmet clinical needs.

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Section: Discussionsupporting

confidence: 93%

The IL-33/ST2 Pathway Controls Coxsackievirus B5–Induced Experimental Pancreatitis

Sesti-Costa

Silva

Proença-Modena

et al. 2013

The Journal of Immunology

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“…Cells were fixed and directly analysed by flow cytometry to detect GFP-positive cells. Alternatively, the cells were fixed and permeabilized using Cytofix/Cytoperm (BD) followed by intracellular staining with a mAB to VP-1 (clone 5-D8/1, DAKO), followed by a goat anti-mouse Alexa 647-conjugated secondary antibody (Invitrogen), as previously described (Hühn et al, 2008). VP-1-or GFP-positive cells were detected using a FACS Calibur (BD) and analysed with FlowJo version 9.5.1 (Treestar).…”

Section: Methodsmentioning

confidence: 99%

Coxsackievirus counters the host innate immune response by blocking type III interferon expression

Lind

Svedin

Domsgen

et al. 2016

Journal of General Virology

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Type I IFNs play an important role in the immune response to enterovirus infections. Their importance is underscored by observations showing that many enteroviruses including coxsackie B viruses (CVBs) have developed strategies to block type I IFN production. Recent studies have highlighted a role for the type III IFNs (also called IFNls) in reducing permissiveness to infections with enteric viruses including coxsackievirus. However, whether or not CVBs have measures to evade the effects of type III IFNs remains unknown. By combining virus infection studies and different modes of administrating the dsRNA mimic poly I : C, we discovered that CVBs target both Toll-like receptor 3-and MDA5/RIG-I-mediated type III IFN expression. Consistent with this, the cellular protein expression levels of the signal transduction proteins TRIF and IPS1 were reduced and no hyperphosphorylation of interferon regulatory factor 3 was observed following infection with the virus. Notably, decreased expression of full-length TRIF and IPS1 and the appearance of cleavage products was observed upon both CVB3 infection and in cellular protein extracts incubated with recombinant 2A pro , indicating an important role for the viral protease in subverting the cellular immune system. Collectively, our study reveals that CVBs block the expression of type III IFNs, and that this is achieved by a similar mechanism as the virus uses to block type I IFN production. We also demonstrate that the virus blocks several intracellular viral recognition pathways of importance for both type I and III IFN production. The simultaneous targeting of numerous arms of the host immune response may be required for successful viral replication and dissemination.

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“…26 One mechanism by which NK cells defense against viral infection is through the secretion of antiviral cytokines such as IFN-␥. 27 Indeed, NK cells and IFN-␥ have previously been shown to play important roles in limiting CVB3 replication in the heart. 28,29 However, the factor mediating this function is unknown.…”

Section: Yuan Et Al Cxcl10 In Viral Myocarditis 635mentioning

confidence: 99%

CXCL10 Inhibits Viral Replication Through Recruitment of Natural Killer Cells in Coxsackievirus B3-Induced Myocarditis

Liu

Lim

et al. 2009

Circulation Research

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Abstract-Coxsackievirus (CV)B3 is the primary cause of viral myocarditis. We previously observed CXC chemokine ligand 10 (CXCL10) upregulation in the myocardium early in infection. However, the impact of CXCL10 in CVB3-induced myocarditis is unknown. Using isolated primary mouse cardiomyocytes we demonstrated for the first time that cardiomyocytes can express CXCL10 on interferon-␥ stimulation. To explore the role of CXCL10 in CVB3-induced myocarditis, both CXCL10 transgenic and knockout mice were used. Following CVB3 challenges, the viral titer in the hearts inversely correlated with the levels of CXCL10 at early phase of infection before visible immune infiltration. Furthermore, as compared with the control mice, the decreased virus titers in the CXCL10 transgenic mouse hearts led to less cardiac damage and better cardiac function and vice verse in the knockout mice. This antiviral ability of CXCL10 might be through recruitment of natural killer (NK) cells to the heart and increased interferon-␥ expression early in infection. At day 7 postinfection, with massive influx of mononuclear cells the expression of CXCL10 enhanced the infiltration of CXCR3 ϩ cells, CD4ϩ , and CD8 ϩ T cells, as well as the expression of associated inflammatory cytokines. However, the augmented accumulation of these immune cells and associated cytokines failed to alter the viral clearance and mice survival. These results suggest the protective role of CXCL10 during the early course of CVB3 infection, which is attributed to the recruitment of NK cells. Nonetheless, CXCL10-directed chemoattractant effect is not sufficient for host to clear the virus in the heart. (Circ Res. 2009;104:628-638.) Key Words: cardiomyocytes Ⅲ chemokine CXCL 10 Ⅲ coxsackievirus Ⅲ myocarditis Ⅲ natural killer cells C oxsackievirus (CV)B3 has been recognized as the predominant cause of viral myocarditis in humans. 1 This disease is composed of three distinct stages including viremic injury, immune infiltration, and reclamation. 2 Earlier studies have suggested that mechanisms of viral myocarditis include direct myocyte injury by CVB3 and subsequent immune-mediated damage of the heart. 3,4 The essential role of the immune response in combating viral myocarditis has been demonstrated by recent studies using a series of knockout (KO) mice. Conversely, others have argued that the robust protective response can also be deleterious to host tissue to some extent. For instance, mice lacking T cells or T cell subsets developed less severe disease following CVB3 inoculation. 5 However, general immunosuppressive therapy did not benefit patients with myocarditis, 6 raising the need for better understanding the role of major immune mediators in disease cascade of CVB-induced myocarditis.During the process of leukocyte trafficking, it is well known that chemokines are the principle chemotactic factors to mediate leukocyte migration to the site of infection. 7 CXC chemokines, including interferon (IFN)-inducible protein 10 (IP10/CXCL10), monokine induced by IFN-␥ (Mig/CXCL9), an...

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IFN-γ production dominates the early human natural killer cell response to Coxsackievirus infection

Cited by 20 publications

References 70 publications

The IL-33/ST2 Pathway Controls Coxsackievirus B5–Induced Experimental Pancreatitis

The IL-33/ST2 Pathway Controls Coxsackievirus B5–Induced Experimental Pancreatitis

Coxsackievirus counters the host innate immune response by blocking type III interferon expression

CXCL10 Inhibits Viral Replication Through Recruitment of Natural Killer Cells in Coxsackievirus B3-Induced Myocarditis

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