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Pelargonium sidoides radix extract EPs 7630 reduces rhinovirus infection through modulation of viral binding proteins on human bronchial epithelial cells.

ABSTRACT: Bronchial epithelial cells are the first target cell for rhinovirus infection. The course of viral infections in patients with acute bronchitis, asthma and COPD can be improved by oral application of Pelargonium sidoides radix extract; however, the mechanism is not well understood. This study investigated the in vitro effect of Pelargonium sidoides radix extract (EPs 7630) on the expression of virus binding cell membrane and host defence supporting proteins on primary human bronchial epithelial cells (hBEC). Cells were isolated from patients with severe asthma (n = 6), moderate COPD (n = 6) and non-diseased controls (n = 6). Protein expression was determined by Western-blot and immunofluorescence. Rhinovirus infection was determined by immunofluorescence as well as by polymerase chain reaction. Cell survival was determined by manual cell count after live/death immunofluorescence staining. All parameters were determined over a period of 3 days. The results show that EPs 7630 concentration-dependently and significantly increased hBEC survival after rhinovirus infection. This effect was paralleled by decreased expression of the inducible co-stimulator (ICOS), its ligand ICOSL and cell surface calreticulin (C1qR). In contrast, EPs 7630 up-regulated the expression of the host defence supporting proteins ?-defensin-1 and SOCS-1, both in rhinovirus infected and un-infected hBEC. The expression of other virus interacting cell membrane proteins such as MyD88, TRL2/4 or ICAM-1 was not altered by EPs 7630. The results indicate that EPs 7630 may reduce rhinovirus infection of human primary BEC by down-regulating cell membrane docking proteins and up-regulating host defence proteins.

SUBMITTER: Roth M

PROVIDER: S-EPMC6358071 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Pelargonium sidoides radix extract EPs 7630 reduces rhinovirus infection through modulation of viral binding proteins on human bronchial epithelial cells.

Roth Michael M Fang Lei L Stolz Daiana D Tamm Michael M

PloS one 20190201 2

Bronchial epithelial cells are the first target cell for rhinovirus infection. The course of viral infections in patients with acute bronchitis, asthma and COPD can be improved by oral application of Pelargonium sidoides radix extract; however, the mechanism is not well understood. This study investigated the in vitro effect of Pelargonium sidoides radix extract (EPs 7630) on the expression of virus binding cell membrane and host defence supporting proteins on primary human bronchial epithelial ...[more]

PMID: 30707726

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Project description:Treatment options for COVID-19 are currently limited. Drugs reducing both viral loads and SARS-CoV-2-induced inflammatory responses would be ideal candidates for COVID-19 therapeutics. Previous in vitro and clinical studies suggest that the proprietary Pelargonium sidoides DC. root extract EPs 7630 has antiviral and immunomodulatory properties, limiting symptom severity and disease duration of infections with several upper respiratory viruses. Here we assessed if EPs 7630 affects SARS-CoV-2 propagation and the innate immune response in the human lung cell line Calu-3. In direct comparison to other highly pathogenic CoV (SARS-CoV, MERS-CoV), SARS-CoV-2 growth was most efficiently inhibited at a non-toxic concentration with an IC50 of 1.61 μg/ml. Particularly, the cellular entry step of SARS-CoV-2 was significantly reduced by EPs 7630 pretreatment (10-100 μg/ml) as shown by spike protein-carrying pseudovirus particles and infectious SARS-CoV-2. Using sequential ultrafiltration, EPs 7630 was separated into fractions containing either prodelphinidins of different oligomerization degrees or small molecule constituents like benzopyranones and purine derivatives. Prodelphinidins with a low oligomerization degree and small molecule constituents were most efficient in inhibiting SARS-CoV-2 entry already at 10 μg/ml and had comparable effects on immune gene regulation as EPs 7630. Downregulation of multiple pro-inflammatory genes (CCL5, IL6, IL1B) was accompanied by upregulation of anti-inflammatory TNFAIP3 at 48 h post-infection. At high concentrations (100 μg/ml) moderately oligomerized prodelphinidins reduced SARS-CoV-2 propagation most efficiently and exhibited pronounced immune gene modulation. Assessment of cytokine secretion in EPs 7630-treated and SARS-CoV-2-coinfected Calu-3 cells showed that pro-inflammatory cytokines IL-1β and IL-6 were elevated whereas multiple other COVID-19-associated cytokines (IL-8, IL-13, TNF-α), chemokines (CXCL9, CXCL10), and growth factors (PDGF, VEGF-A, CD40L) were significantly reduced by EPs 7630. SARS-CoV-2 entry inhibition and the differential immunomodulatory functions of EPs 7630 against SARS-CoV-2 encourage further in vivo studies.

Project description:The phytotherapeutic compound EPs® 7630, an extract manufactured from Pelargonium sidoides roots, is frequently used for the treatment of airway infections. Nevertheless, the knowledge of the mode of action of EPs® 7630 is still sparse. Our study aimed at further elucidating the underlying pharmacological mechanisms by focusing on antimicrobial defense mechanisms of EPs® 7630. While investigating the influence of EPs® 7630 on lymphokine production by PBMCs, we found that EPs® 7630 is a novel inducer of IL-22 and IL-17. This cytokine-inducing effect was most pronounced for IL-22 and clearly dose-dependent starting from 1 ?g/ml of the extract. Furthermore, EPs® 7630 pretreatment selectively enhanced the IL-22 and IL-17 production capacity of CD3/28-activated PBMCs while strongly limiting the IFN-? production capacity of innate lymphoid cells. The relevance of EPs® 7630-induced IL-22 production was proven in vitro and in vivo, where IL-22 provoked a strong increase of the antimicrobial protein S100A9 in lung epithelial cells and pulmonary tissue, respectively. A detailed analysis of IL-22 induction modi revealed no direct influence of EPs® 7630 on the basal or anti-CD3/CD28 antibody-induced IL-22 production by CD4+ memory T cells. In fact, EPs® 7630-induced IL-22 production by CD4+ memory T cells was found to be essentially dependent on soluble mediators (IL-1/IL-23) as well as on direct cellular contact with monocytes. In summary, our study reveals a new immune-modulating function of EPs® 7630 that might confer IL-22 and IL-17-induced protection from bacterial airway infection. KEY MESSAGES: EPs® 7630 selectively strengthens IL-22 and IL-17 production of memory T cells. EPs® 7630 limits the IFN-y production capacity of innate lymphoid cells. EPs® 7630-caused IL-22 production by T cells is essentially dependent on monocytes. IL-22 increase antimicrobial proteins (AMPs) in airway epithelium. EPs® 7630 might protect against airway infection by induction of AMP-inducers.

Dataset Information

Pelargonium sidoides radix extract EPs 7630 reduces rhinovirus infection through modulation of viral binding proteins on human bronchial epithelial cells.

Publications

Pelargonium sidoides radix extract EPs 7630 reduces rhinovirus infection through modulation of viral binding proteins on human bronchial epithelial cells.

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