Cutting Edge: Antibody-mediated TLR7-dependent recognition of viral RNA.
ABSTRACT TLR7 recognizes the genome of ssRNA viruses such as Coxsackievirus B. Because TLR7 is expressed in intracellular compartments, viral RNA must be internalized before its recognition by TLR7. In this study, we define plasmacytoid dendritic cells (pDC) as peripheral blood mononuclear immune cells that respond to Coxsackievirus. pDC activation by Coxsackievirus B requires the presence of specific antiviral Abs. We show that Fc receptors mediate the recognition of virus-Ab complexes and that TLR7 is required for human and murine pDC production of cytokines. These data define a pathway by which intracellular TLR7 senses viral RNA and indicate a role for TLRs in association with Abs in sustaining virus-specific responses.
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ABSTRACT: Picornaviruses, small positive-stranded RNA viruses, cause a wide range of diseases which is based on their differential tissue and cell type tropisms. This diversity is reflected by the immune responses, both innate and adaptive, induced after infection, and the subsequent interactions of the viruses with the immune system. The defense mechanisms of the host and the countermeasures of the virus significantly contribute to the pathogenesis of the infections. Important human pathogens are poliovirus, coxsackievirus, human rhinovirus and hepatitis A virus. These viruses are the best-studied members of the family, and in this review we want to present the major aspects of the reciprocal effects between the immune system and these viruses.06/2012; 1(3):91-107. DOI:10.5501/wjv.v1.i3.91
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ABSTRACT: Acute coxsackievirus B3 (CVB3) infection is one of the most prevalent causes of acute myocarditis, a disease that frequently is identified only after the sudden death of apparently-healthy individuals. CVB3 infects cardiomyocytes, but the infection is highly focal, even in the absence of a strong adaptive immune response, suggesting that virus spread within the heart may be tightly constrained by the innate immune system. Type I interferons (T1IFN) are an obvious candidate, and T1IFN receptor knockout mice are highly susceptible to CVB3 infection, succumbing within a few days of challenge. Here, we investigated the role of T1IFNs in the heart using a mouse model in which the T1IFN receptor (T1IFNR) gene can be ablated in vivo, specifically in cardiomyocytes. We found that T1IFN signaling into cardiomyocytes contributed substantially to the suppression of viral replication and infectious virus yield in the heart; in the absence of such signaling, virus titers were markedly elevated by d3 p.i., and remained high at d12 p.i., a time point at which virus was absent from genetically-intact littermates, suggesting that the T1IFN-unresponsive cardiomyocytes may act as a safe haven for the virus. Nevertheless, in these mice the myocardial infection remained highly focal, despite the cardiomyocytes' inability to respond to T1IFN, indicating that other factors, as yet unidentified, are sufficient to prevent the more widespread dissemination of the infection throughout the heart. The absence of T1IFN signaling into cardiomyocytes also was accompanied by a profound acceleration and exacerbation of myocarditis, and by a significant increase in mortality. Acute coxsackievirus B3 (CVB3) infection is one of the most common causes of acute myocarditis, a serious, and sometimes fatal, disease. To optimize treatment, it is vital that we identify the immune factors that limit virus spread in the heart and other organs. Type 1 interferons play a key role in controlling many virus infections, but it has been suggested that they may not directly impact CVB3 infection within the heart. Here, using a novel line of transgenic mice, we show that these cytokines signal directly into cardiomyocytes, limiting viral replication, myocarditis, and death.Journal of Virology 02/2014; DOI:10.1128/JVI.00184-14 · 4.65 Impact Factor
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ABSTRACT: Increasing evidence suggests that type 1 IFN (IFN-αβ) is associated with pathogenesis of Th1-mediated type 1 diabetes (T1D). A major source of IFN-αβ is plasmacytoid dendritic cells (pDCs). In this study, we analyzed peripheral blood pDC numbers and functions in at-risk, new-onset, and established T1D patients and controls. We found that subjects at risk for T1D and new-onset and established T1D subjects possessed significantly increased pDCs but similar number of myeloid DCs when compared with controls. pDC numbers were not affected by age in T1D subjects but declined with increasing age in control subjects. It was demonstrated that IFN-α production by PBMCs stimulated with influenza viruses was significantly higher in T1D subjects than in controls, and IFN-α production was correlated with pDC numbers in PBMCs. Of interest, only T1D-associated Coxsackievirus serotype B4 but not B3 induced majority of T1D PBMCs to produce IFN-α, which was confirmed to be secreted by pDCs. Finally, in vitro studies demonstrated IFN-α produced by pDCs augmented Th1 responses, with significantly greater IFN-γ-producing CD4(+) T cells from T1D subjects. These findings indicate that increased pDCs and their IFN-αβ production may be associated with this Th1-mediated autoimmune disease, especially under certain viral infections linked to T1D pathogenesis.The Journal of Immunology 06/2014; 193(4). DOI:10.4049/jimmunol.1303230 · 5.36 Impact Factor