Persistent Infection of Human Microvascular Endothelial Cells by Coxsackie B Viruses Induces Increased Expression of Adhesion Molecules

Abstract

Numerous studies indicate that enteroviruses, such as the Coxsackievirus (CV) group, are linked to autoimmune diseases. Virus tropism and tissue access are modulated by vascular endothelial cells (ECs), mainly at the level of the microvasculature. Data on the permissiveness of ECs to CV are, however, scanty and derived from studies on large vessel ECs. To examine the susceptibility of microvascular ECs to infection of group B CV (CVB), human dermal microvascular ECs (HMEC-1) were infected with three CVB strains, and the immunological phenotype of the infected cells was analyzed. All CVB persistently infected the EC cultures without producing overt cytopathic effects. Infected ECs retained endothelial characteristics. Release of infectious particles in cell supernatants persisted for up to 3 mo of culture. Infection up-regulated expression of the adhesion molecules ICAM-1 and VCAM-1, with the highest values detected during the first 30 days of infection (p < 0.05 vs uninfected HMEC-1). CVB infection increased production of the proinflammatory cytokines, IL-6, IL-8, and TNF-α, which may account for the enhanced expression of adhesion molecules. Parallel infection of macrovascular HUVEC had less evident effects on induction of ICAM-1 and did not significantly increase expression of VCAM-1. Moreover, mononuclear cell adhesion to CVB-infected HMEC-1 monolayers was increased, compared with uninfected monolayers. These results provide evidence that small vessel ECs can harbor a persistent viral infection, resulting in quantitative modification of adhesion molecule expression, which may contribute to the selective recruitment of subsets of leukocytes during inflammatory immune responses. Furthermore, our data confirm that the behavior against a viral challenge of ECs in large vessels and microvessels may differ.

Expression of nephrin by human pancreatic islet endothelial cells

“…Phenotypic characterisation and detection of endothelial cell surface molecules From the earliest passages for which sufficient cells were available for study, endothelial phenotype was assessed by flow cytometric analysis of the cell surface phenotype, staining for basal expression of endothelial markers and adhesion molecules, or of permeabilised cells for intracellular von Willebrand factor (vWF) staining, as described [32]. The following antibodies were used: anti-human monoclonal antibody against CD105-R-phycoerythrin (undiluted; Serotec, Oxford, UK), CD146-fluorescein isothiocyanate (FITC) (clone P1H12, final dilution 1:100) (Chemicon, Temecula, CA, USA), E-selectin (CD62E, final dilution 1:100), intercellular adhesion molecule-1 (ICAM-1) (CD54, 1:10), CD106 (vascular cell adhesion molecule-1 [VCAM-1], 1:20) (all from Serotec), rabbit anti-human vWF antiserum (1:200) (Sigma) and R-phycoerythrin-conjugated F (ab′) 2 fragment of goat anti-mouse immunoglobulins or R-phycoerythrin-conjugated anti-rabbit immunoglobulins (Dako, Glostrup, Denmark).…”

Islet Endothelium: Role in Type 1 Diabetes and in Coxsackievirus Infections

“…Amongst these, vascular endothelial cells have an established role as mediators of tissue tropism and access for virus, influencing organ and tissue specific susceptibility to viral infection. Therefore, they can modulate the pathological expression of virus-induced diseases (Friedman et al, 1981;Huber et al, 1990;Conaldi et al, 1997;Zanone et al, 2003). For instance, in murine studies on CVB infectivity of different organs, CVB3 isolates from the heart showed greater infectivity and replication in heart endothelial cells than endothelial cells derived from liver or lung (Huber et al, 1990), thus confirming the essential role of host factors in developing specific diseases.…”

“…However, physiological and pathological events take place mainly at the level of the microvasculature. Using a dermal microvascular endothelial cell line, we have provided evidence that small vessel endothelial cells can harbour a persistent CVB viral infection (Zanone et al, 2003). All 3 CVB tested productively infected microvascular endothelial cells for up to 3 months without obvious cytolysis.…”

“…In line with this scenario, it is essential that, to gain access to secondary organs, viruses pass through the vascular endothelium by transcytosis or infection, or via infected circulating cells migrating into the target tissues. Endothelial cells derived from different organs show distinct susceptibility to CVB infections, and the behaviour against a viral challenge of endothelial cells in large vessels and microvessels may differ (Friedman et al, 1981;Huber et al, 1990;Conaldi et al, 1997;Zanone et al, 2003;Saijets et al, 2003). Endothelial cells expressing appropriate receptors would fail to act as effective barrier to infections, allowing viral particles to pass through, and replicate in, the vascular endothelium.…”

Miosite e rabdomiólise na doença mão-pé-boca na infância

“…O tropismo desses vírus pela musculatura também foi demonstrado pelo isolamento do vírus do miocárdio de pacientes com miocardite aguda (11) . Nas infecções pelo vírus Coxsackie há aumento significativo de moléculas de adesão celulares ICAM-1 e VCAM-1 no endotélio capilar e venoso e aumento na produção de citocinas proinflamatórias, como IL-6, IL-8 e TNF-α, fatores que modificam a resposta imune do hospedeiro (12) . O quadro crônico de miosite, como a miocardite crônica induzida pelo Coxsackie, é explicado por mecanismos de imunidade cruzada relacionados com homologias entre os peptídeos virais e os próprios da membrana celular, assim como a inclusão de antígenos virais no sarcolema durante a regeneração das fibras musculares (13) .…”