Coxsackievirus-induced myocarditis in mice: A model of autoimmune disease for studying immunotoxicity

Fairweather, De Lisa; Rose, Noel R.

doi:10.1016/j.ymeth.2006.07.009

Cited by 176 publications

(193 citation statements)

References 31 publications

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“…The lack of models that recapitulate the complexity of the GI tract has hindered studies into many aspects of enterovirus infection in this specialized environment. Although murine models have been developed for the study of enterovirusinduced disease (1)(2)(3)(4), many of these models require intraperitoneal (i.p.) infection, thereby bypassing the GI tract, or require ablation of the host innate immune system (5,6).…”

mentioning

confidence: 99%

Enteroviruses infect human enteroids and induce antiviral signaling in a cell lineage-specific manner

Drummond

Bolock

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

131

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Enteroviruses are among the most common viral infectious agents of humans and are primarily transmitted by the fecal-oral route. However, the events associated with enterovirus infections of the human gastrointestinal tract remain largely unknown. Here, we used stem cell-derived enteroids from human small intestines to study enterovirus infections of the intestinal epithelium. We found that enteroids were susceptible to infection by diverse enteroviruses, including echovirus 11 (E11), coxsackievirus B (CVB), and enterovirus 71 (EV71), and that contrary to an immortalized intestinal cell line, enteroids induced antiviral and inflammatory signaling pathways in response to infection in a virus-specific manner. Furthermore, using the Notch inhibitor dibenzazepine (DBZ) to drive cellular differentiation into secretory cell lineages, we show that although goblet cells resist E11 infection, enteroendocrine cells are permissive, suggesting that enteroviruses infect specific cell populations in the human intestine. Taken together, our studies provide insights into enterovirus infections of the human intestine, which could lead to the identification of novel therapeutic targets and/or strategies to prevent or treat infections by these highly clinically relevant viruses.E nteroviruses are significant sources of human infections worldwide and are primarily transmitted by the fecal-oral route. Nonpoliovirus enteroviruses include coxsackievirus, echovirus, enterovirus 71 (EV71), and enterovirus D68 (EV-D68) and are small (∼30 nm) single-stranded RNA viruses belonging to the Picornaviridae family. In many cases, enterovirus infections remain asymptomatic, whereas in others, infection is associated with mild flu-like symptoms or much more severe outcomes such as type I diabetes, encephalomyelitis, encephalitis, myocarditis, dilated cardiomyopathy, pleurodynia, acute flaccid paralysis, or even death.The human gastrointestinal (GI) tract is a complex organ, with an epithelial surface that must provide a protective and immunological barrier in a complex and diverse microbial environment. The epithelium of the small intestine contains at least seven distinct cell subtypes that are responsible for the physiological functions of the intestine, which include nutrient absorption and defense against pathogens. The lack of models that recapitulate the complexity of the GI tract has hindered studies into many aspects of enterovirus infection in this specialized environment. Although murine models have been developed for the study of enterovirusinduced disease (1-4), many of these models require intraperitoneal (i.p.) infection, thereby bypassing the GI tract, or require ablation of the host innate immune system (5, 6). Coupled with species differences between humans and mice, there remains a need to develop human-based platforms to model enterovirus infections of the GI tract.The full repertoire of mature cells in the small intestine in vivo includes those of absorptive (enterocytes) and secretory (Paneth, goblet, and enteroendocrine) lin...

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mentioning

confidence: 99%

Enteroviruses infect human enteroids and induce antiviral signaling in a cell lineage-specific manner

Drummond

Bolock

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

131

173

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“…In the present investigation, an isolate of coxsackievirus B3 (CVB3) originally obtained from a patient was passaged through the heart of BALB/c mice to produce a viral stock that contains cardiac myosin and virus (9). Acute myocarditis develops from days 7 to 14 postinfection (p.i.)…”

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confidence: 99%

“…and progresses to chronic myocarditis and dilated cardiomyopathy from day 28 p.i. (9). Previously we showed that TLR4 signaling increases myocarditis and IL-1␤/IL-18 levels in the heart following CVB3 infection in male BALB/c mice (10), whereas inflammation is controlled by T cell Ig mucin (Tim)-3 signaling and regulatory T cell populations (Treg) (11).…”

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confidence: 99%

Cutting Edge: Cross-Regulation by TLR4 and T cell Ig Mucin-3 Determines Sex Differences in Inflammatory Heart Disease

Frisancho-Kiss

Davis

Nyland

et al. 2007

The Journal of Immunology

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Recent clinical studies have reinforced the importance of sex-related differences in the pathogenesis of cardiovascular diseases, with an increased incidence and mortality in men. Similar to humans, male BALB/c mice infected with coxsackievirus B3 (CVB3) develop more severe inflammation in the heart even though viral replication is no greater than in females. We show that TLR4 and IFN-γ levels are significantly elevated and regulatory T cell (Treg) populations significantly reduced in the heart of males following CVB3 infection, whereas females have significantly increased T cell Ig mucin (Tim)-3, IL-4 and Treg. Blocking Tim-3 in males significantly increases inflammation and TLR4 expression while reducing Treg. In contrast, defective TLR4 signaling significantly reduces inflammation while increasing Tim-3 expression. Cross-regulation of TLR4 and Tim-3 occurs during the innate and adaptive immune response. This novel mechanism may help explain why inflammatory heart disease is more severe in males.

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“…6 -8 Both cellmediated and antibody-mediated immunity contribute to the final pathological picture of chronic inflammation and DCM in EAM and CVB3-induced myocarditis. 9,10 We previously demonstrated that EAM in A/J mice carry hallmarks of Th2-like pathology. Blockade of interleukin (IL)-4 partially suppresses the development of EAM, indicating that IL-4 is cardiopathogenic in this strain.…”

mentioning

confidence: 99%

Interleukin-13 Protects Against Experimental Autoimmune Myocarditis by Regulating Macrophage Differentiation

Čiháková

Barin

Afanasyeva

et al. 2008

The American Journal of Pathology

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138

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We report here that interleukin (IL)-13 protects BALB/c mice from myocarditis, whether induced by peptide immunization or by viral infection. In contrast to mild disease in IL-4 knockout (KO) BALB/c mice, IL-13 KO BALB/c mice developed severe coxsackievirus B3 (CVB3)-induced autoimmune myocarditis and myocarditogenic peptide-induced experimental autoimmune myocarditis. Such severe disease was characterized by increased cardiac inflammation, increased total intracardiac CD45 ؉ leukocytes, elevated anti-cardiac myosin autoantibodies, and increased cardiac fibrosis. Echocardiography revealed that IL-13 KO mice developed severe dilated cardiomyopathy with impaired cardiac function and heart failure. Hearts of IL-13 KO mice had increased levels of the proinflammatory and profibrotic cytokines IL-1␤, IL-18, interferon-␥, transforming growth factor-␤1, and IL-4 as well as histamine. The hallmark of the disease in IL-13 KO mice was the up-regulation of T-cell responses. CD4 ؉ T cells were increased in IL-13 KO hearts both proportionally and in absolute number. Splenic T cells from IL-13 KO mice were highly activated, and myosin stimulation additionally increased T-cell proliferation. CD4؉ CD25 ؉ Foxp3 ؉ regulatory T-cell numbers were decreased in the spleens of IL-13 KO mice. IL-13 deficiency led to decreased levels of alternatively activated CD206؉ and CD204؉ macrophages and increased levels of classically activated macrophages. IL-13 KO mice had increased caspase-1 activation, leading to increased production of both IL-1␤ and IL-18. Therefore, IL-13 protects against myocarditis by modulating monocyte/macrophage populations and by regulating their function. (Am J

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Coxsackievirus-induced myocarditis in mice: A model of autoimmune disease for studying immunotoxicity

Cited by 176 publications

References 31 publications

Enteroviruses infect human enteroids and induce antiviral signaling in a cell lineage-specific manner

Enteroviruses infect human enteroids and induce antiviral signaling in a cell lineage-specific manner

Cutting Edge: Cross-Regulation by TLR4 and T cell Ig Mucin-3 Determines Sex Differences in Inflammatory Heart Disease

Interleukin-13 Protects Against Experimental Autoimmune Myocarditis by Regulating Macrophage Differentiation

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