In vivo characterization of cytokine profiles and viral load during murine cytomegalovirus-induced acute myocarditis

Ritter, J Trees; Tang-Feldman, Yajarayma; Lochhead, G. Raymond; Эстрада, Марко; Lochhead, Stephanie R.; Yu, Cindy; Ashton-Sager, Amanda; Tuteja, Dipika; Leutenegger, Christian M.; Pomeroy, Claire

doi:10.1016/j.carpath.2008.12.001

Cited by 28 publications

(40 citation statements)

References 23 publications

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“…This finding is very interesting since chronic proinflammatory cytokine production, such as IFN-γ and TNF-α, plays a pathogenic role in T. cruzi-induced cardiomyopathy [9]. A deleterious effect of these factors has already been also in other experimental and human heart diseases [25][26][27]. On the other hand, it has been suggested that chronic production of TNF-α prior to heart failure may play a role in chronic Chagas' disease cardiomyopathy progression [28], probably altering myocytes contractility [29].…”

Section: Discussionmentioning

confidence: 90%

Immunomodulatory and anti-fibrotic effects of ganglioside therapy on the cardiac chronic form of experimental Trypanosoma cruzi infection

Cutrullis¹,

Poklépovich²,

Postan³

et al. 2011

International Immunopharmacology

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Section: Discussionmentioning

confidence: 90%

Immunomodulatory and anti-fibrotic effects of ganglioside therapy on the cardiac chronic form of experimental Trypanosoma cruzi infection

Cutrullis¹,

Poklépovich²,

Postan³

et al. 2011

International Immunopharmacology

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“…One striking finding of this study is that there are significant correlations between the levels of antigenstimulated cIL-10 production in PBMC and RhCMV genome copy numbers detected in saliva. This is not unique to RhCMV, as cIL-10 levels have been positively associated, either alone or with other biomarkers, with increased burdens of other pathogens, including human papillomavirus, HIV, hepatitis B virus, EpsteinBarr virus (EBV), Mycobacterium tuberculosis, Leishmania spp., dengue virus, and murine and human CMV (45,(55)(56)(57)(58)(59)(60)(61)(62)(63)(64)(65)(66)(67)(68)(69)(70)(71)(72). While the specific cell type(s) responsible for elevated cIL-10 expression in response to RhCMV antigen exposure was not explored, multiple cell types have been implicated for other pathogens, including regulatory B and T cells.…”

Section: Discussionmentioning

confidence: 99%

Exploitation of Interleukin-10 (IL-10) Signaling Pathways: Alternate Roles of Viral and Cellular IL-10 in Rhesus Cytomegalovirus Infection

Eberhardt

Deshpande

Fike

et al. 2016

J Virol

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There is accumulating evidence that the viral interleukin-10 (vIL-10) ortholog of both human and rhesus cytomegalovirus (HCMV and RhCMV, respectively) suppresses the functionality of cell types that are critical to contain virus dissemination and help shape long-term immunity during the earliest virus-host interactions. In particular, exposure of macrophages, peripheral blood mononuclear cells, monocyte-derived dendritic cells, and plasmacytoid dendritic cells to vIL-10 suppresses multiple effector functions including, notably, those that link innate and adaptive immune responses. Further, vaccination of RhCMV-uninfected rhesus macaques with nonfunctional forms of RhCMV vIL-10 greatly restricted parameters of RhCMV infection following RhCMV challenge of the vaccinees. Vaccinees exhibited significantly reduced shedding of RhCMV in saliva and urine following RhCMV challenge compared to shedding in unvaccinated controls. Based on the evidence that vIL-10 is critical during acute infection, the role of vIL-10 during persistent infection was analyzed in rhesus macaques infected long term with RhCMV to determine whether postinfection vaccination against vIL-10 could change the virus-host balance. RhCMV-seropositive macaques, which shed RhCMV in saliva, were vaccinated with nonfunctional RhCMV vIL-10, and shedding levels of RhCMV in saliva were evaluated. Following robust increases in vIL-10-binding and vIL-10-neutralizing antibodies, shedding levels of RhCMV modestly declined, consistent with the interpretation that vIL-10 may play a functional role during persistent infection. However, a more significant association was observed between the levels of cellular IL-10 secreted in peripheral blood mononuclear cells exposed to RhCMV antigens and shedding of RhCMV in saliva. This result implies that RhCMV persistence is associated with the induction of cellular IL-10 receptor-mediated signaling pathways. IMPORTANCEHuman health is adversely impacted by viruses that establish lifelong infections that are often accompanied with increased morbidity and mortality (e.g., infections with HIV, hepatitis C virus, or human cytomegalovirus). A longstanding but unfulfilled goal has been to develop postinfection vaccine strategies that could "reboot" the immune system of an infected individual in ways that would enable the infected host to develop immune responses that clear reservoirs of persistent virus infection, effectively curing the host of infection. This concept was evaluated in rhesus macaques infected long term with rhesus cytomegalovirus by repeatedly immunizing infected animals with nonfunctional versions of the rhesus cytomegalovirus-encoded viral interleukin-10 immune-modulating protein. Following vaccine-mediated boosting of antibody titers to viral interleukin-10, there was modest evidence for increased immunological control of the virus following vaccination. More significantly, data were also obtained that indicated that rhesus cytomegalovirus is able to persist due to upregulation of the cellular interleukin-...

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“…7,9,26 Reports already documented that cardiomyocytes apoptosis occurs and contributes to development and severity of CVB3-induced AVMC. 37,38 About the link between ER stress/CHOP signaling and apoptosis, it suggests that ER stress and its downstream activator CHOP may also be emerged in AVMC development induced by CVB3. Our observation truly confirmed this hypothesis by identifying CHOP activation accompanied with increased cardiomyocytes apoptosis in AVMC hearts.…”

Section: Discussionmentioning

confidence: 99%

Involvement of Endoplasmic Reticulum Stress–Mediated C/EBP Homologous Protein Activation in Coxsackievirus B3–Induced Acute Viral Myocarditis

Cai

Shen

et al. 2015

Circ: Heart Failure

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Background— This study tested the hypothesis whether endoplasmic reticulum (ER) stress/C/EBP homologous protein (CHOP) signaling is linked with coxsackievirus B3 (CVB3)–induced acute viral myocarditis (AVMC) in vivo. Methods and Results— AVMC was induced by intraperitoneal injection of 1000 tissue culture infectious dose (TCID 50 ) of CVB3 virus in mice. In AVMC mouse hearts (n=11), ER stress and CHOP were significantly activated, and were linked to the induction of proapoptotic signaling including reduction of Bcl-2, activation of Bax and caspase 3, compared with the controls (n=10), whereas these could be markedly blocked by ER stress inhibitor tauroursodeoxycholic acid administration (n=11). Moreover, chemical inhibition of ER stress significantly attenuated cardiomyocytes apoptosis, and prevented cardiac troponin I elevation, ameliorated cardiac dysfunction assessed by both hemodynamic and echocardiographic analysis, reduced viral replication, and increased survival rate after CVB3 inoculation. We further discovered that genetic ablation of CHOP (n=10) suppressed cardiac Bcl-2/Bax ratio reduction and caspase 3 activation, and prevented cardiomyotes apoptosis in vivo, compared with wild-type receiving CVB3 inoculation (n=10). Strikingly, CHOP deficiency exhibited dramatic protective effects on cardiac damage, cardiac dysfunction, viral replication, and promoted survival in CVB3-caused AVMC. Conclusions— Our data imply the involvement of ER stress/CHOP signaling in CVB3-induced AVMC via proapoptotic pathways, and provide a novel strategy for AVMC treatment.

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In vivo characterization of cytokine profiles and viral load during murine cytomegalovirus-induced acute myocarditis

Cited by 28 publications

References 23 publications

Immunomodulatory and anti-fibrotic effects of ganglioside therapy on the cardiac chronic form of experimental Trypanosoma cruzi infection

Immunomodulatory and anti-fibrotic effects of ganglioside therapy on the cardiac chronic form of experimental Trypanosoma cruzi infection

Exploitation of Interleukin-10 (IL-10) Signaling Pathways: Alternate Roles of Viral and Cellular IL-10 in Rhesus Cytomegalovirus Infection

Involvement of Endoplasmic Reticulum Stress–Mediated C/EBP Homologous Protein Activation in Coxsackievirus B3–Induced Acute Viral Myocarditis

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