Quantitative Trait Locus Analysis, Pathway Analysis, and Consomic Mapping Show Genetic Variants of Tnni3k, Fpgt, or H28 Control Susceptibility to Viral Myocarditis

Wiltshire, S; Leiva‐Torres, Gabriel André; Vidal, Silvia M.

doi:10.4049/jimmunol.1100159

Cited by 55 publications

(43 citation statements)

References 46 publications

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“…However, not all studies have demonstrated that elevated IFN-β correlates with protection in acute CVB3-induced myocarditis. For example, analysis of resistant B10.A and susceptible A/J mice revealed a relationship between higher cardiac viral titer in the first 4 days after infection and increased serum IFN-β expression [50], a finding that is similar to our observations in the Unc93b1 Letr/Letr model. TLR3 deficiency significantly increased mortality and serum viral load, but did not affect cardiac IFN-β expression at day 3 after infection [11].…”

Section: Discussionsupporting

confidence: 83%

Unc93b1-Dependent Endosomal Toll-Like Receptor Signaling Regulates Inflammation and Mortality during Coxsackievirus B3 Infection

Lafferty

Wiltshire²,

Angers

et al. 2015

J Innate Immun

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Coxsackievirus strain B serotype 3 (CVB3)-inducedmyocarditis is an important human disease that causes permanent tissue damage and can lead to death from acute infection or long-term morbidity caused by chronic inflammation. The timing and magnitude of immune activation following CVB3 infection can mediate a positive host outcome or increase tissue pathology. To better elucidate the role of endosomal Toll-like receptor (TLR) signaling in acute CVB3 infection, we studied mice with a loss-of-function mutation, known as Letr for ‘loss of endosomal TLR response', in Unc93b1, which is a chaperone protein for TLR3, TLR7 and TLR9. Using Unc93b1^Letr/^Letr mice, we determined that Unc93b1-dependent TLR activation was essential for the survival of acute CVB3-induced myocarditis. We also determined that a lack of endosomal TLR signaling was associated with a higher viral load in target organs and that it increased inflammation, necrosis and fibrosis in cardiac tissue. Loss of Unc93b1 function was also associated with increased cardiac expression of Ifn-b and markers of tissue injury and fibrosis including Lcn2 and Serpina3n early after CVB3 infection. These observations establish a significant role for Unc93b1 in the regulation of the host inflammatory response to CVB3 infection and also reveal potential mediators of host tissue damage that merit further investigation in acute viral myocarditis.

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Section: Discussionsupporting

confidence: 83%

Unc93b1-Dependent Endosomal Toll-Like Receptor Signaling Regulates Inflammation and Mortality during Coxsackievirus B3 Infection

Lafferty

Wiltshire²,

Angers

et al. 2015

J Innate Immun

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“…142,143 This led to the identification of several susceptibility genes including IFN-related genes (Fpgt, H28, and Tnni3k). 144 In acute viral coxsackievirus B-induced myocarditis, IFN-α and IFN-β (type I interferons) are important mediators of a Th1 response and reduced viral replication, whereas IFN-γ (type II interferon) regulates monocyte mobilization and fibrosis. 145,146 A mouse model of limited IFN-β activity, induced by knocking out the TRIF protein, had severe chronic myocarditis and dilated cardiomyopathy.…”

Section: Infectious Viral Myocarditismentioning

confidence: 99%

Chronic Heart Failure and Inflammation

Dick

Epelman

2016

Circulation Research

544

380

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As a greater proportion of patients survive their initial cardiac insult, medical systems worldwide are being faced with an ever-growing need to understand the mechanisms behind the pathogenesis of chronic heart failure (HF). There is a wealth of information about the role of inflammatory cells and pathways during acute injury and the reparative processes that are subsequently activated. We discuss the different causes that lead to chronic HF development and how the sum of initial inflammatory and reparative responses only sets the trajectory for disease progression. Unfortunately, comparatively little is known about the contribution of the immune system once the trajectory has been set, and chronic HF has been established—which clinically represents the majority of patients. It is known that chronic HF is associated with circulating inflammatory cytokines that can predict clinical outcomes, yet the causative role inflammation plays in disease progression is not well defined, and the majority of clinical trials that target aspects of inflammation in patients with chronic HF have largely been negative. This review will present what is currently known about inflammation in chronic HF in both humans and animal models as a means to highlight the gap in our knowledge base that requires further examination.

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“…In the mouse, TNNI3K has been identified as a potentially important gene in host response to viral cardiomyopathies caused by Coxsackie B virus. 12 In this context, the murine allele with normally, high TNNI3K expression seems to confer a protective role in viral cardiomyopathy. Apart from response to cardiac injury, recent human genetic studies have suggested an intriguing role for TNNI3K in the development of obesity.…”

Section: Abraham and Marchukmentioning

confidence: 99%

Inhibition of the Cardiomyocyte-Specific Troponin I–Interacting Kinase Limits Oxidative Stress, Injury, and Adverse Remodeling due to Ischemic Heart Disease

Abraham

Marchuk

2014

Circulation Research

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Ischemia-reperfusion injury is strongly associated with increased oxidative stress, mitochondrial dysfunction, and cell death. These processes are diminished in an animal model of ischemia-reperfusion by the genetic loss or pharmacological inhibition of troponin I-interacting kinase.During the past 3 decades, we have seen significant advances in our ability to reestablish perfusion after myocardial infarction, which has resulted in improvements in cardiac function and mortality. However, reperfusion itself can induce cell death in the area at risk called ischemia-reperfusion injury.1 This type of injury is thought to develop when cardiomyocytes, injured by ischemia, are killed by rapid normalization of pH, calcium overload, cellular swelling, or oxidative stress. Oxidative stress, in particular reactive oxygenation species production, is thought to induce calcium handling abnormalities, protein oxidation, lipid peroxidation, and cell death. The mitigation of cellular death from oxidative stress from ischemia-reperfusion injury is the focus of a recent article by Vagnozzi et al. 3 Their work investigates the novel role of the cardiac-specific protein, troponin I-interacting kinase (TNNI3K), in the development of this injury and provides an approach for treating ischemia-perfusion injury in a clinical setting. In mice, genetic overexpression of TNNI3K increased infarct size and cellular death after ischemic injury in comparison with wild-type animals or animals overexpressing kinase inactive versions of TNNI3K. The observed increase in infarct size was associated with increased reactive oxygen species production in the TNNI3K-overexpressing mice. Using an in vitro model of ischemic injury, the authors show that the overexpression of TNNI3K resulted in increased reactive oxygen species generation, altered mitochondrial membrane potentials, and diminished mitochondrial calcium flux. Mitogen-activated protein kinase (MAPK) p38 phosphorylation was enhanced in TNNI3K-overexpressing cells and was associated with increased cell death, which was blocked by pharmacological inhibitors of p38. Because TNNI3K gain of function resulted in increased infarct size and myocyte energetic abnormalities, the authors tested whether TNNI3K loss of function was protective in ischemia-reperfusion injury. To accomplish this, inducible TNNI3K knockout mice were generated and tested in an ischemia-reperfusion model. TNNI3K knockout mice developed smaller infarcts and diminished biomarker elevations 24 hours after ischemic injury in comparison with TNNI3K-competent mice. TNNI3K knockout did not improve cardiac function, dimensions, or the development of hypertrophy after permanent left coronary artery occlusion. Next, to test whether TNNI3K inhibition would be a viable therapeutic target, the authors developed chemical inhibitors of TNNI3K and tested these in an in vivo ischemia-reperfusion injury model. Mice pretreated with these compounds developed a 10% reduction in infarct size, which was associated with diminished cellular death and p...

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Quantitative Trait Locus Analysis, Pathway Analysis, and Consomic Mapping Show Genetic Variants of Tnni3k, Fpgt, or H28 Control Susceptibility to Viral Myocarditis

Cited by 55 publications

References 46 publications

<b><i>Unc93b1</i></b>-Dependent Endosomal Toll-Like Receptor Signaling Regulates Inflammation and Mortality during Coxsackievirus B3 Infection

<b><i>Unc93b1</i></b>-Dependent Endosomal Toll-Like Receptor Signaling Regulates Inflammation and Mortality during Coxsackievirus B3 Infection

Chronic Heart Failure and Inflammation

Inhibition of the Cardiomyocyte-Specific Troponin I–Interacting Kinase Limits Oxidative Stress, Injury, and Adverse Remodeling due to Ischemic Heart Disease

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