Genetic Determinants of Coxsackievirus B3 Pathogenesis

Abstract

The development of high throughput genomic and bioinformatic analysis tools, coupled with established molecular techniques, has allowed new insights into the pathogenesis of infectious diseases. In humans, coxasackievirus B3 (CVB3) is the primary etiological agent of viral myocarditis, an inflammatory disease process involving the heart muscle. Early host cellular survival and apoptotic mechanisms during viral infections, as well as immune events, affect myocarditis progression and outcome. Therefore, our laboratory has been keenly interested in infectomics, defined here as the transcriptional events of both virus and host. We first elucidated up- or downregulated transcriptional activities in CVB3-infected hearts by mRNA differential display. Further characterization of these regulated genes including Nip21, IP10, and IGTPase, and study of their role in CVB3-infection are underway. In further dissection of the stages of myocarditis-peak viremia, inflammatory infiltration and tissue repair-we used cDNA microarrays to probe differential gene expression in the myocardium following virus infection. Following virus infection, there are global decreases in metabolic and mitochondrial genes, increases in signaling genes and distinctive patterns in other functional groups. To establish early gene expression profiles in infected cells by themselves, we also used oligonucleotide arrays in an in vitro model of CVB3 infection. Notably, we have found increased expression of transcription factors c-fos and c-jun down-stream of extracellular signal-related kinase, a pathway which is crucial for virus replication and pathogenesis. Our investigations based on gene profiling following CVB3 infection have thus far been fruitful in providing new experimental leads. High throughput genetic analysis has allowed us to simultaneously try on greater than 12,000 potential genetic "glass slippers." Our in vitro experimental plan has enabled us to chart prominent patterns of gene expression, analyzed by novel bioinformatic approaches, and to separate varied and potentially significant gene expression events.

CXCL10 Inhibits Viral Replication Through Recruitment of Natural Killer Cells in Coxsackievirus B3-Induced Myocarditis

“…Secondly, mice infected by CVB3 were possibly died of multiple organ dysfunctions. 2 Here, as we focused on viral myocarditis we did not investigate the role of CXCL10 in other organ diseases following virus infection. It is unknown whether CXCL10 affects the viral replication and inflammation in other susceptible organs, such as liver and pancreas.…”

“…1 This disease is composed of three distinct stages including viremic injury, immune infiltration, and reclamation. 2 Earlier studies have suggested that mechanisms of viral myocarditis include direct myocyte injury by CVB3 and subsequent immune-mediated damage of the heart. 3,4 The essential role of the immune response in combating viral myocarditis has been demonstrated by recent studies using a series of knockout (KO) mice.…”

Pyrrolidine Dithiocarbamate Reduces Coxsackievirus B3 Replication through Inhibition of the Ubiquitin-Proteasome Pathway

“…Picornaviridae, is one of the most common causative pathogens for human viral myocarditis and its sequela, dilated cardiomyopathy (DCM) (3,41,42). CVB3-induced viral myocarditis is initially considered an immune-mediated disease (40), but results from our laboratory and others have shown that CVB3 can also directly injure cardiomyocytes in infected hearts (12).…”

Coxsackievirus B3 Replication and Pathogenesis

“…After the early observations noted above, almost simultaneously, multiple reports from different laboratories showed the role of another part of the network, ERK1/2, whose phosphorylation is required for CVB3 infection [95][96][97]. ERK1/2 is a member of the mitogen-activated protein kinases (MAPKs), which are evolutionarily conserved enzymes relaying extracellular signals from cell surface receptors to critical targets within cells, and thus regulate biological events such as cell proliferation, differentiation and stress responses [98].…”

“…ERK1/2 is a member of the mitogen-activated protein kinases (MAPKs), which are evolutionarily conserved enzymes relaying extracellular signals from cell surface receptors to critical targets within cells, and thus regulate biological events such as cell proliferation, differentiation and stress responses [98]. A number of studies have revealed that the early activation of ERK1/2 may stem from the engagement of CVB3 with its main receptor CAR, co-receptor DAF or both [96][97]99]. There is also a mechanism that partly depicts how ERK1/2 phosphorylation is associated with replication of CVB3 at later times postinfection.…”