IL-17 contributes to neutrophil recruitment but not to control of viral replication during acute mouse adenovirus type 1 respiratory infection

McCarthy, Mary K.; Zhu, Lingqiao; Procario, Megan C.; Weinberg, Jason B.

doi:10.1016/j.virol.2014.04.008

Cited by 34 publications

(41 citation statements)

References 29 publications

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“…In the current study, we identified robust induction of IFN-␥ in the heart after MAV-1 infection, consistent with previous studies showing induction of IFN-␥ in MAV-1-infected lungs (25,26). During acute MAV-1 respiratory infection of adult mice, CD4 ϩ and CD8 ϩ T cells are the primary producers of IFN-␥ in the lung (24). IFN-␥ induced during MAV-1 myocarditis is likely produced by infiltrating CD4 ϩ and/or CD8 ϩ T cells, because the robust IFN-␥ induction that we observe correlates closely with recruitment of these cells to the myocardium.…”

Section: Discussionsupporting

confidence: 92%

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Proinflammatory Effects of Interferon Gamma in Mouse Adenovirus 1 Myocarditis

McCarthy

Procario

Twisselmann

et al. 2015

J Virol

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Adenoviruses are frequent causes of pediatric myocarditis. Little is known about the pathogenesis of adenovirus myocarditis, and the species specificity of human adenoviruses has limited the development of animal models, which is a significant barrier to strategies for prevention or treatment. We have developed a mouse model of myocarditis following mouse adenovirus 1 (MAV-1) infection to study the pathogenic mechanisms of this important cause of pediatric myocarditis. Following intranasal infection of neonatal C57BL/6 mice, we detected viral replication and induction of interferon gamma (IFN-␥) in the hearts of infected mice. MAV-1 caused myocyte necrosis and induced substantial cellular inflammation that was composed predominantly of CD3 ؉ T lymphocytes. Depletion of IFN-␥ during acute infection reduced cardiac inflammation in MAV-1-infected mice without affecting viral replication. We observed decreased contractility during acute infection of neonatal mice, and persistent viral infection in the heart was associated with cardiac remodeling and hypertrophy in adulthood. IFN-␥ is a proinflammatory mediator during adenovirus-induced myocarditis, and persistent adenovirus infection may contribute to ongoing cardiac dysfunction. IMPORTANCEStudying the pathogenesis of myocarditis caused by different viruses is essential in order to characterize both virus-specific and generalized factors that contribute to disease. Very little is known about the pathogenesis of adenovirus myocarditis, which is a significant impediment to the development of treatment or prevention strategies. We used MAV-1 to establish a mouse model of human adenovirus myocarditis, providing the means to study host and pathogen factors contributing to adenovirus-induced cardiac disease during acute and persistent infection. The MAV-1 model will enable fundamental studies of viral myocarditis, including IFN-␥ modulation as a therapeutic strategy.

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Section: Discussionsupporting

confidence: 92%

“…MAV-1 viral loads were measured in organs and in cardiac myocytes infected ex vivo using quantitative realtime PCR (qPCR) as previously described (24). The primers and probe used to detect a 59-bp region of the MAV-1 E1A gene are listed in Table 1.…”

Section: Methodsmentioning

confidence: 99%

Proinflammatory Effects of Interferon Gamma in Mouse Adenovirus 1 Myocarditis

McCarthy

Procario

Twisselmann

et al. 2015

J Virol

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“…The presence of pThy-derived gd T cells in the dermis was required to increase cellularity near the site of infection and to amplify the overall potency of the immune response, as demonstrated by increased tissue damage in WT and BMpThy mice. Although the complete absence of gd T cells did not translate into increased viral load in this or related systems (52,53), other models showed that mice lacking gd T cells are more susceptible to bacterial infection (54) and have a decreased capacity for wound healing (13). Together, the data indicate that gd T cells are a dynamic population with a range of functions but that they might not respond equally to all inflammatory cues.…”

Section: Cd27mentioning

confidence: 81%

Dermal-Resident versus Recruited γδ T Cell Response to Cutaneous Vaccinia Virus Infection

Davis

Bergsbaken

Delaney

et al. 2015

The Journal of Immunology

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The study of T cell immunity at barrier surfaces has largely focused on T cells bearing the αβ TCR. However, T cells that express the γδ TCR are disproportionately represented in peripheral tissues of mice and humans, suggesting they too may play an important role responding to external stimuli. In this article, we report that, in a murine model of cutaneous infection with vaccinia virus, dermal γδ T cell numbers increased 10-fold in the infected ear and resulted in a novel γδ T cell population not found in naive skin. Circulating γδ T cells were specifically recruited to the site of inflammation and differentially contributed to dermal populations based on their CD27 expression. Recruited γδ T cells, the majority of which were CD27+, were granzyme B+ and made up about half of the dermal population at the peak of the response. In contrast, recruited and resident γδ T cell populations that made IL-17 were CD27−. Using a double-chimera model that can discriminate between the resident dermal and recruited γδ T cell populations, we demonstrated their divergent functions and contributions to early stages of tissue inflammation. Specifically, the loss of the perinatal thymus-derived resident dermal population resulted in decreased cellularity and collateral damage in the tissue during viral infection. These findings have important implications for our understanding of immune coordination at barrier surfaces and the contribution of innate-like lymphocytes on the front lines of immune defense.

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“…CD8 T cells are recruited to the lungs, hearts, and brains of mice infected with MAV-1 (McCarthy et al, 2015a; McCarthy et al, 2015b; McCarthy et al, 2014; Procario et al, 2012; Weinberg et al, 2007). Compared to MAV-1 viral loads in wild type mice, viral loads are higher in brains of MHC class I-deficient mice following i.p.…”

Section: Discussionmentioning

confidence: 99%

“…The strict species specificity of the adenoviruses precludes detailed studies of HAdV pathogenesis in mouse models. We have used mouse adenovirus type 1 (MAV-1) to study the pathogenesis of adenovirus respiratory infection in its natural host (McCarthy et al, 2013; McCarthy et al, 2015b; McCarthy et al, 2014; Procario et al, 2012; Procario et al, 2016; Weinberg et al, 2005). Recently, we used MAV-1 to establish a mouse model of adenovirus myocarditis (McCarthy et al, 2015a) in which intranasal (i.n.)…”

Section: Introductionmentioning

confidence: 99%

Interferon-dependent immunoproteasome activity during mouse adenovirus type 1 infection

et al. 2016

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The immunoproteasome is an inducible host mechanism that aids in the clearance of damaged proteins. The immunoproteasome also influences immune function by enhancing peptide presentation by MHC class I and promotes inflammation via IκB degradation and activation of NF-κB. We used mouse adenovirus type 1 (MAV-1) to characterize the role of the immunoproteasome in adenovirus pathogenesis. Following intranasal infection of mice, immunoproteasome activity in the heart and lung was significantly increased in an IFN-γ-dependent manner. Absence of the β5i immunoproteasome subunit and pharmacological inhibition of β5i activity had minimal effects on viral replication, virus-induced cellular inflammation, or induction of cytokine expression. Likewise, the establishment of protective immunity following primary infection was not significantly altered by β5i deficiency. Thus, although immunoproteasome activity is robustly induced during acute infection with MAV-1, our data suggest that other mechanisms are capable of compensating for immunoproteasome activity to maintain antiviral immunity and appropriate inflammatory responses.

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IL-17 contributes to neutrophil recruitment but not to control of viral replication during acute mouse adenovirus type 1 respiratory infection

Cited by 34 publications

References 29 publications

Proinflammatory Effects of Interferon Gamma in Mouse Adenovirus 1 Myocarditis

Proinflammatory Effects of Interferon Gamma in Mouse Adenovirus 1 Myocarditis

Dermal-Resident versus Recruited γδ T Cell Response to Cutaneous Vaccinia Virus Infection

Interferon-dependent immunoproteasome activity during mouse adenovirus type 1 infection

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