Antibody‐Dependent Enhancement of Coxsackievirus B4 Infectivity of Human Peripheral Blood Mononuclear Cells Results in Increased Interferon‐α Synthesis

Centre Hospitalier Régional Universitaire de Lille, Lille, Nord-Pas-de-Calais, France
The Journal of Infectious Diseases (Impact Factor: 6). 11/2001; 184(9):1098-1108. DOI: 10.1086/323801


IgG devoid of neutralizing activity and isolated from donor plasma by chromatography formed immune complexes with coxsackievirus
B4 (CVB4) and significantly increased the infection of peripheral blood mononuclear cells with CVB4. The major host cells
for CVB4 infection enhanced with IgG are monocytic CD14+ cells. The roles of CVB and adenovirus receptor and Fcγ receptor II and ΙΙΙ have been shown. Increased viral replication
and the release of infectious particles were demonstrated when interferon (IFN)–α produced by infected cells was first neutralized
by use of antibodies. The CVB4 IgG-induced synthesis of IFN-α by monocytes reflected entry and uncoating of CVB4 but not of
viral replication and required the presence of CVB4 RNA inside the cells. Thus, CVB4 can infect monocytes by an antibody-dependent
mechanism through interactions between the virus, antiviral antibodies, and specific receptors that result in IFN-α production

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    • "Monocytes are not spontaneously permissive to the virus; however, the infection can be enhanced by antibodies, as described in previous papers[11,13]. The infection of monocytes with CVB4 can be obtained by pre-incubation of the virus with non-neutralizing dilution of an immune serum before inoculation to cells[11,13]. Enhanced CVB infection of monocytes was shown to rely on both the specific receptor CAR and FCγ receptors, and the target of enhancing antibodies was reported to be the viral protein VP4[14,29]. However, monocytes are not long-life cells and usually leave the bloodstream after 2–3 days to reach tissues and differentiate into mature cells, such as macrophages[16]. "
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    ABSTRACT: Beyond acute infections, group B coxsackieviruses (CVB) are also reported to play a role in the development of chronic diseases, like type 1 diabetes. The viral pathogenesis mainly relies on the interplay between the viruses and innate immune response in genetically-susceptible individuals. We investigated the interaction between CVB4 and macrophages considered as major players in immune response. Monocyte-derived macrophages (MDM) generated with either M-CSF or GM-CSF were inoculated with CVB4, and infection, inflammation, viral replication and persistence were assessed. M-CSF-induced MDM, but not GM-CSF-induced MDM, can be infected by CVB4. In addition, enhancing serum was not needed to infect MDM in contrast with parental monocytes. The expression of viral receptor (CAR) mRNA was similar in both M-CSF and GM-CSF MDM. CVB4 induced high levels of pro-inflammatory cytokines (IL-6 and TNFα) in both MDM populations. CVB4 effectively replicated and persisted in M-CSF MDM, but IFNα was produced in the early phase of infection only. Our results demonstrate that CVB4 can replicate and persist in MDM. Further investigations are required to determine whether the interaction between the virus and MDM plays a role in the pathogenesis of CVB-induced chronic diseases.
    Full-text · Article · Nov 2015 · Viruses
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    • "The results showed that preexisting antibodies against EV71 in local mucosal surfaces correlated with following viral infection , which suggesting an antibody dependent enhancement (ADE) of viral infection. The phenomenon of ADE has been documented for many viruses, including dengue virus, respiratory syncytial virus, human immunodeficiency virus, and Ebola virus (Girn et al., 2002; Halstead and O'Rourke, 1977; Hober et al., 2001). ADE was also observed in many members of the Picornaviridae family including poliovirus and enterovirus such as EV71, coxsackievirus B, which were identified for targeting macrophage and monocyte in vitro (Tirado and Yoon, 2003; Wang et al., 2010). "
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    ABSTRACT: Enterovirus 71 (EV71) infection causes severe central nervous system damage, particularly for children under the age of 5 years old, which remains a major public health burden worldwide. Clinical data released that children may be repeatedly infected by different members in enterovirus and get even worsen. Mucosa, especially epithelium of alimentary canal, was considered the primary site of EV71 infection. It has been elusive whether the preexsiting viral antibody in mucosa plays a role in EV71 infection. To answer this question, we respectively measured viral antibody response and EV71 RNA copy number of one hundred throat swab specimens from clinically confirmed EV71-infected children. The results released that low-level of mucosal IgG antibody against EV71 broadly existed in young population. More importantly, it further elucidated that the children with mucosal preexsiting EV71 IgG were prone to be infected, which suggested a former viral IgG mediated enhancement of viral infection in vivo.
    Full-text · Article · Mar 2015 · Virologica Sinica
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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.
    Full-text · Article · Apr 2013 · PLoS ONE
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