IFN-α expression and antiviral effects are subtype and cell type specific in the cardiac response to viral infection

Li, Lianna; Sherry, Barbara

doi:10.1016/j.virol.2009.10.013

Cited by 33 publications

(33 citation statements)

References 64 publications

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“…These proposals are consistent with our current understanding of T1IFN production by cardiomyocytes. Cardiac cells express several of the IFN-␣ subtypes, and the expression pattern varies in a cell-specific manner (89). IRF7, too, is expressed, at a low level, in resting cardiomyocytes, along with additional interferon-stimulated genes (ISGs) and even a low level of IFN-␤ (86); indeed, it has been proposed that the constitutive expression of these proteins renders the cardiomyocytes poised to respond to virus infection, perhaps to protect against the death of these hard-to-replace cells (86).…”

Section: Discussionmentioning

confidence: 99%

“…IRF7, too, is expressed, at a low level, in resting cardiomyocytes, along with additional interferon-stimulated genes (ISGs) and even a low level of IFN-␤ (86); indeed, it has been proposed that the constitutive expression of these proteins renders the cardiomyocytes poised to respond to virus infection, perhaps to protect against the death of these hard-to-replace cells (86). Furthermore, T1IFN expression is upregulated in neonatal cardiomyocytes within 8 h of in vitro reovirus infection (89). In addition, elegant work from the Vallejo group has shown that cardiomyocyte-specific in vivo overexpression of TRIF and MDA5, which are important for triggering T1IFN synthesis, confers a substantial degree of protection against the picornavirus encephalomyocarditis virus, limiting both cardiac titers and myocarditis (90,91).…”

Section: Discussionmentioning

confidence: 99%

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In VivoAblation of Type I Interferon Receptor from Cardiomyocytes Delays Coxsackieviral Clearance and Accelerates Myocardial Disease

Althof

Harkins

Kemball

et al. 2014

J Virol

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Acute coxsackievirus B3 (CVB3) infection is one of the most prevalent causes of acute myocarditis, a disease that frequently is identified only after the sudden death of apparently healthy individuals. CVB3 infects cardiomyocytes, but the infection is highly focal, even in the absence of a strong adaptive immune response, suggesting that virus spread within the heart may be tightly constrained by the innate immune system. Type I interferons (T1IFNs) are an obvious candidate, and T1IFN receptor (T1IFNR) knockout mice are highly susceptible to CVB3 infection, succumbing within a few days of challenge. Here, we investigated the role of T1IFNs in the heart using a mouse model in which the T1IFNR gene can be ablated in vivo, specifically in cardiomyocytes. We found that T1IFN signaling into cardiomyocytes contributed substantially to the suppression of viral replication and infectious virus yield in the heart; in the absence of such signaling, virus titers were markedly elevated by day 3 postinfection (p.i.) and remained high at day 12 p.i., a time point at which virus was absent from genetically intact littermates, suggesting that the T1IFN-unresponsive cardiomyocytes may act as a safe haven for the virus. Nevertheless, in these mice the myocardial infection remained highly focal, despite the cardiomyocytes' inability to respond to T1IFN, indicating that other factors, as yet unidentified, are sufficient to prevent the more widespread dissemination of the infection throughout the heart. The absence of T1IFN signaling into cardiomyocytes also was accompanied by a profound acceleration and exacerbation of myocarditis and by a significant increase in mortality. IMPORTANCEAcute coxsackievirus B3 (CVB3) infection is one of the most common causes of acute myocarditis, a serious and sometimes fatal disease. To optimize treatment, it is vital that we identify the immune factors that limit virus spread in the heart and other organs. Type I interferons play a key role in controlling many virus infections, but it has been suggested that they may not directly impact CVB3 infection within the heart. Here, using a novel line of transgenic mice, we show that these cytokines signal directly into cardiomyocytes, limiting viral replication, myocarditis, and death. Myocarditis is a potentially serious and sometimes fatal disease, with several infectious and noninfectious causes. In developed countries, it most commonly results from a virus infection, often by type B coxsackieviruses (CVB), and in particular by serotype 3 (CVB3) (1-8). It is found at routine necropsy at a prevalence that greatly exceeds its rate of clinical diagnosis (9, 10), a discrepancy that may be explained by the fact that only a subset of individuals with acute myocarditis develop marked symptoms such as chest pains, palpitations, or signs of heart failure. Consistent with this, acute myocarditis was identified as the cause of death in 39 of 2,560 serial autopsies (ϳ1.5%), but it had been clinically suspected in only one of the cases (11); thus, in this s...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

In VivoAblation of Type I Interferon Receptor from Cardiomyocytes Delays Coxsackieviral Clearance and Accelerates Myocardial Disease

Althof

Harkins

Kemball

et al. 2014

J Virol

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“…This idea has been supported by the fact that stimulating human leukocytes with agonists for TLR3, -7, -8, and -9 resulted in different IFN-␣ subtype patterns (11,12). Furthermore, different type I IFN subtype profiles can also be induced in a cell-type-specific manner (26), as different cell types express varying levels of both PRRs and transcription factors that can affect subtype promoter regulation. Our present study, however, presents the novel finding that the same virus can induce different type I IFN profiles in the same cell type, depending on the MOI used to infect the cells.…”

Section: Discussionmentioning

confidence: 97%

Virus Multiplicity of Infection Affects Type I Interferon Subtype Induction Profiles and Interferon-Stimulated Genes

Zaritsky

Bedsaul

Zoon

2015

J Virol

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Type I IFNs are induced in response to viral infection in two phases of innate immune signaling. The first occurs when pathogen-associated molecular patterns (PAMPs) activate either cytosolic or membrane-bound pattern recognition receptors (PRRs). These interactions stimulate signaling pathways that eventually converge on the activation of the transcription factors IRF3, IRF7, and/or NF-B, which lead to the transcription of early type I IFN subtypes. In mice, these early subtypes consist of IFN-␤ and IFN-␣4 (2). However, in humans, it is not known exactly which type I IFN subtypes are induced early. These early subtypes are secreted from the cells and bind to the IFN receptor (IFNAR), which stimulates the phosphorylation of the receptor-associated kinases JAK1 and Tyk2 and subsequently the transcription factors STAT1 and STAT2. Serine phosphorylation of STAT proteins also occurs and is required for optimal transcriptional activity (3). These phosphorylated STATs complex with IRF9 to form the interferon-stimulated gene factor 3 (ISGF3) complex, which translocates into the nucleus to activate the transcription of hundreds of ISGs, IRF7, and additional type I IFNs to amplify the response (4-6). This positive-feedback amplification loop continues until negative regulators of IFN signaling, such as SOCS proteins and IRF2, become activated.Sendai virus (SeV) has long been used to study type I IFN regulation due to its robust ability to induce large quantities of the type I IFN subtypes (7-9). Reports studying the transcriptional regulation of the IFN-␣ subtypes in response to SeV infection have indicated that IRF3 and IRF7 play central roles (1). In these stud- Citation Zaritsky LA, Bedsaul JR, Zoon KC. 2015. Virus multiplicity of infection affects type I interferon subtype induction profiles and interferon-stimulated genes.

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“…Baig and Fish (4) demonstrated that murine IFN expression profiles differed according to whether the IFN was expressed by lung fibroblast cell lines or tissue stimulated in vivo. Similarly, murine cardiac myocytes and fibroblasts were reported to express different IFNa subtypes in response to reovirus (22). On the other hand, a study of Easlick and coworkers (9) demonstrated that relative IFN-a expression patterns are identical irrespective of the cellular background.…”

Section: Discussionmentioning

confidence: 99%

Induction of IFN-αSubtypes and Their Antiviral Activity in Mumps Virus Infection

Markušić

Šantak²,

Košutić-Gulija³

et al. 2014

Viral Immunology

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Human type I interferons (IFNs) comprise one IFN-b, -x, -j, and -e and 12 different IFN-a subtypes, which play an important role in early host antiviral response. Despite their high structural homology and signaling through the same receptor, IFN-a subtypes exhibit different antiviral, antiproliferative, and immunomodulatory activities. Differences in the production of IFN-a subtypes therefore determine the quality of an antiviral response. In this study, we investigated the pattern of IFN-a subtypes induced in infection with different mumps virus (MuV) strains and examined the MuV sensitivity to the action of IFN-a subtypes. We found that all IFN-a subtypes are being expressed in response to MuV infection with a highly similar IFN-a subtype pattern between the virus strains. We assessed an antiviral activity of several IFN-a subtypes: IFN-a1, IFN-a2, IFN-a4, IFN-a6, IFN-a8, IFN-a14, IFN-a17, and IFN-a21. Although they were all effective in suppressing MuV replication, the intensity and pattern of their action varied between MuV strains. Our results indicate that the overall IFN antiviral activity as well as the activity of specific IFN-a subtypes against MuV depend on a virus strain.

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IFN-α expression and antiviral effects are subtype and cell type specific in the cardiac response to viral infection

Cited by 33 publications

References 64 publications

In VivoAblation of Type I Interferon Receptor from Cardiomyocytes Delays Coxsackieviral Clearance and Accelerates Myocardial Disease

In VivoAblation of Type I Interferon Receptor from Cardiomyocytes Delays Coxsackieviral Clearance and Accelerates Myocardial Disease

Virus Multiplicity of Infection Affects Type I Interferon Subtype Induction Profiles and Interferon-Stimulated Genes

Induction of IFN-αSubtypes and Their Antiviral Activity in Mumps Virus Infection

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