Cutting Edge: Antibody-mediated TLR7-dependent recognition of viral RNA

Department of Medicine, University of Massachusetts, 364 Plantation, Worcester, MA 01605, USA.
The Journal of Immunology (Impact Factor: 4.92). 04/2007; 178(6):3363-7. DOI: 10.4049/jimmunol.178.6.3363
Source: PubMed


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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    • "Innate immune response may play crucial role in the outcome of enteroviral infections. Recent reports show that Enteroviruses (EV) can stimulate production of type 1 IFN through endosomal Toll-like receptors (TLR) like TLR7 and TLR81112. TLR3 and TLR4 play a role in pathogenesis of coxsackievirus B4 and EV711314. Cytoplasmic RNA helicases like melanoma differentiation associated protein 5 (MDA5) and retinoic acid inducible gene 1 (RIG I) which are known to activate production of type 1 IFN are degraded in poliovirus infected cells1516. "
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    ABSTRACT: Background & objectives: Polioviruses are the causative agent of paralytic poliomyelitis. Attenuated polioviruses (Sabin oral poliovirus vaccine strains) do not replicate efficiently in neurons as compared to the wild type polioviruses and therefore do not cause disease. This study was aimed to investigate the differential host immune response to wild type 1 poliovirus (wild PV) and Sabin attenuated type 1 poliovirus (Sabin PV) in cultured human neuronal cells. Methods: By using flow cytometry and real time PCR methods we examined host innate immune responses and compared the role of toll like receptors (TLRs) and cytoplasmic RNA helicases in cultured human neuronal cells (SK-N-SH) infected with Sabin PV and wild PV. Results: Human neuronal cells expressed very low levels of TLRs constitutively. Sabin PV infection induced significantly higher expression of TLR3, TLR7 and melanoma differentiation-associated protein-5 (MDA-5) m-RNA in neuronal cells at the beginning of infection (up to 4 h) as compared to wild PV. Further, Sabin PV also induced the expression of interferon α/β at early time point of infection. The induced expression of IFN α/β gene by Sabin PV in neuronal cells could be suppressed by inhibiting TLR7. Interpretation & conclusions: Neuronal cell innate immune response to Sabin and wild polioviruses differ significantly for TLR3, TLR7, MDA5 and type 1 interferons. Effects of TLR7 activation and interferon production and Sabin virus replication in neuronal cells need to be actively investigated in future studies.
    The Indian Journal of Medical Research 08/2013; 138(2):209-18. · 1.40 Impact Factor
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    • "Viruses such as influenza virus enter PDC via receptor-mediated uptake into the TLR-sensing endolysosomal compartment, which is their natural infection route (Patterson et al., 1979; Londrigan et al., 2012). In contrast, fusogenic viruses such as Coxsackie virus and foot-and-mouse-disease virus are dependent on the presence of anti-viral antibodies and complex formation for uptake into endosomes via Fcγ R expressed by PDC (Guzylack-Piriou et al., 2006; Wang et al., 2007). In addition to the recognition of genomic viral material, PDC can become activated by viral ssRNA replication intermediates, which accumulate in the cytoplasm upon infection and are then shuttled into the endolysosomal compartment for recognition by TLR7 by autophagy (Lee et al., 2007). "
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    ABSTRACT: The innate immune system has evolved endosomal and cytoplasmic receptors for the detection of viral nucleic acids as sensors for virus infection. Some of these pattern recognition receptors (PRR) detect features of viral nucleic acids that are not found in the host such as long stretches of double-stranded RNA (dsRNA) and uncapped single-stranded RNA (ssRNA) in case of Toll-like receptor (TLR) 3 and RIG-I, respectively. In contrast, TLR7/8 and TLR9 are unable to distinguish between viral and self-nucleic acids on the grounds of distinct molecular patterns. The ability of these endosomal TLR to act as PRR for viral nucleic acids seems to rely solely on the mode of access to the endolysosomal compartment in which recognition takes place. The current dogma states that self-nucleic acids do not enter the TLR-sensing compartment under normal physiological conditions. However, it is still poorly understood how dendritic cells (DC) evade activation by self-nucleic acids, in particular with regard to specific DC subsets, which are specialized in taking up material from dying cells for cross-presentation of cell-associated antigens. In this review we discuss the current understanding of how the immune system distinguishes between foreign and self-nucleic acids and point out some of the key aspects that still require further research and clarification.
    Frontiers in Cellular and Infection Microbiology 07/2013; 3:37. DOI:10.3389/fcimb.2013.00037 · 3.72 Impact Factor
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    • "Various studies have reported that HEV-B RNA can be detected in blood/PBMCs of type 1 diabetes patients [14], [48], although the source for the viral RNA remains unknown. Previous studies have shown that monocytes can be infected by HEV-B via antibody-dependent mechanisms [49], and more recently it has been described that pDCs become activated by CVB in an antibody-dependent fashion – although whether the virus also productively infects pDC was not extensively studied [50]. Our data reveal that myeloid DCs can be infected with EVs (in the absence of antiviral antibodies) and thus might be an enterovirus target in vivo and serve as a virus reservoir in blood. "
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    ABSTRACT: Coxsackie B viruses (CVBs) and echoviruses (EVs) form the Human Enterovirus-B (HEV-B) species within the family Picornaviridae. HEV-B infections are widespread and generally cause mild disease; however, severe infections occur and HEV-B are associated with various chronic diseases such as cardiomyopathy and type 1 diabetes. Dendritic cells (DCs) are the professional antigen-presenting cells of our immune system and initiate and control immune responses to invading pathogens, yet also maintain tolerance to self-antigens. We previously reported that EVs, but not CVBs, can productively infect in vitro generated monocyte-derived DCs. The interactions between HEV-B and human myeloid DCs (mDCs) freshly isolated from blood, however, remain unknown. Here, we studied the susceptibility and responses of BDCA1(+) mDC to HEV-B species and found that these mDC are susceptible to EV, but not CVB infection. Productive EV7 infection resulted in massive, rapid cell death without DC activation. Contrary, EV1 infection, which resulted in lower virus input at the same MOI, resulted in DC activation as observed by production of type I interferon-stimulated genes (ISGs), upregulation of co-stimulatory and co-inhibitory molecules (CD80, CD86, PDL1) and production of IL-6 and TNF-α, with a relative moderate decrease in cell viability. EV1-induced ISG expression depended on virus replication. CVB infection did not affect DC viability and resulted in poor induction of ISGs and CD80 induction in part of the donors. These data show for the first time the interaction between HEV-B species and BDCA1(+) mDCs isolated freshly from blood. Our data indicate that different HEV-B species can influence DC homeostasis in various ways, possibly contributing to HEV-B associated pathology.
    PLoS ONE 04/2013; 8(4):e62502. DOI:10.1371/journal.pone.0062502 · 3.23 Impact Factor
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