interleukin-8 and Herpes-Simplex

Herpes simplex virus (HSV) naturally infects skin and mucosal surfaces, causing lifelong recurrent disease worldwide, with no cure or vaccine. Biomimetic human tissue and organ platforms provide attractive alternatives over animal models to recapitulate human diseases. Combining prevascularization and microfluidic approaches, we present a vascularized, three-dimensional skin-on-chip that mimics human skin architecture and is competent to immune-cell and drug perfusion. The endothelialized microvasculature embedded in a fibroblast-containing dermis responds to biological stimulation, while the cornified epidermis functions as a protective barrier. HSV infection of the skin-on-chip displays tissue-level key morphological and pathophysiological features typical of genital herpes infection in humans, including the production of proinflammatory cytokine IL-8, which triggers rapid neutrophil trans-endothelial extravasation and directional migration. Importantly, perfusion with the antiviral drug acyclovir inhibits HSV infection in a dose-dependent and time-sensitive manner. Thus, our vascularized skin-on-chip represents a promising platform for human HSV disease modeling and preclinical therapeutic evaluation.

Topics: Acyclovir; Animals; Antiviral Agents; Herpes Simplex; Herpesvirus 1, Human; Humans; Interleukin-8

We demonstrated similarities and differences in the effects of IFN-α and IFN-β compared to IFN-γ on the production of factors deposited in the Weibel-Palade bodies in cultures of endothelial cells (intact and infected with herpes simplex virus 1). IFN-α and IFN-β reduced the content of von Willebrand factor, endothelin-1, and soluble P-selectin and increased IL-8 concentration in the culture medium of human umbilical vein endothelial cells. IFN-γ reduced the content of all studied factors in the endothelial cell culture medium. Possible mechanisms of these effects are discussed.

Topics: Cells, Cultured; Endothelin-1; Herpes Simplex; Herpesvirus 1, Human; Human Umbilical Vein Endothelial Cells; Humans; Interferons; Interleukin-8; P-Selectin; von Willebrand Factor; Weibel-Palade Bodies

Toll-like receptors (TLRs)--and their associated signal-transducing proteins--on the surface of cells have been demonstrated to account for most, if not all, of the events associated with bacterial sepsis. Using human cells expressing different TLRs, we demonstrated that the interaction between TLR2 and herpes simplex virus (HSV)-1-2 leads to the production of cytokines. Using peripheral-blood mononuclear cells, we tested the ability of cells from people of different age groups to make cytokines in response to HSV. An examination of the host responses of neonates to HSV indicates that, rather than producing less interleukin-6 and interleukin-8 in response to HSV than adults do, neonates produce more of these cytokines than adults do. This may explain the sepsis syndrome that is seen with HSV (and other virus infections) in neonates.

Topics: Adult; Age Factors; Cells, Cultured; Cytokines; Herpes Simplex; Herpesvirus 1, Human; Herpesvirus 2, Human; Humans; Infant, Newborn; Interleukin-6; Interleukin-8; Leukocytes, Mononuclear; Membrane Glycoproteins; Receptors, Cell Surface; Toll-Like Receptor 2; Toll-Like Receptors

Chemokines (chemoattractant cytokines) attract and activate specific leukocyte subsets. With regard to their expression by brain parenchymal cells, they may represent the key molecules that control leukocyte entry into the subarachnoid space. In order to evaluate the contribution of chemokines in vivo, we determined the levels of MCP-1, MIP-1alpha, RANTES, IL-8, as well as of the sIL-2R in three patients with proven herpes simplex encephalitis type 1 (HSE-1). CSF samples were drawn by a subarachnoid catheter system throughout the time course of hospitalisation. Results were compared to chemokine levels in serum drawn in parallel. The clinical status was documented by the Modified Barthel Index and correlated with chemokine levels in the CSF. The results were compared with the chemokine levels in the CSF of 17 control patients with normal CSF routine parameters. High chemokine levels were detectable in the CSF of all HSE-patients. MCP-1 peak levels were found at the time of admission, while maximal IL-8 levels occurred 4 to 8 h later. The levels of MIP-1alpha and RANTES were lower than those of MCP-1 with a maximum at the time of admission. In all patients the levels of the sIL-2R increased later in the time course, at 14 to 20 h after admission. When the levels of MCP-1 were compared with the clinical status by Modified Barthel Index, we found a high reciprocal correlation (r=-0.82). Routine CSF parameters, such as leukocytes, albumin and immunoglobulins did not correlate with the clinical status. Chemokine levels in serum were found to be close to the detection limits of the ELISA systems. Our data suggest that chemokines play an important role in the pathogenesis of HSE. They may be useful parameters to monitor the stage and severity of the disease. The late increase of sIL2-R levels may indicate the beginning of the reconstitution phase.

Topics: Cell Count; Cerebrospinal Fluid; Chemokine CCL2; Chemokine CCL3; Chemokine CCL4; Chemokine CCL5; Chemokines; Encephalitis, Viral; Herpes Simplex; Herpesvirus 1, Human; Humans; Immunoglobulins; Interleukin-8; Macrophage Inflammatory Proteins; Receptors, Interleukin-2; Serum Albumin; Time Factors