Systemic spread of EHEC virulence by host cell-derived microparticles
Final Report Abstract
Infections with enterohemorrhagic E. coli (EHEC) can be complicated by hemolytic uremic syndrome (HUS), which is defined by hemolytic anemia, thrombocytopenia, and acute kidney failure. Shiga toxin (Stx) is the crucial virulence factor produced by EHEC. In patients with HUS Stx is found within blood cell-derived microvesicles (MVs). MVs possess prothrombotic and pro-inflammatory potential and Stx might be transferred within MVs to the target organs (e.g. kidney). In this study we used well-established mouse models of EHEC infection and Stx injection mimicking certain aspects of HUS. We used the P2X1 purinergic receptor inhibitor Suramin to reduce the release of MVs from platelets and thus interfere with the transfer of Stx to its target organs. We can show that platelet-derived MVs are significantly increased in mice infected with EHEC and injected with Stx2 i. p. prior to the development of symptoms. These MVs contain Stx2. Furthermore the amount of MVs could be significantly reduced in mice treated with Suramin, a P2X1 purinergic receptor inhibitor. There was a tendency to a lower prevalence of signs of disease in mice injected with Stx2 and treated with Suramin. Mice lacking the purinergic receptor P2X1 had lower MV levels and were protected from development of signs of disease. MVs were significantly reduced in mice treated with a purinergic receptor inhibitor and in mice lacking this receptor. A microvesicle-targeted treatment could potentially reduce signs of disease in the mouse model. This might offer a treatment concept in the future in patients considering the pathomechanisms involved in the development of HUS.
Publications
- A novel mechanism of bacterial toxin transfer within host blood cell-derived microvesicles. PLoS Pathog, 2015, Feb 26; 11(2):e1004619
AL Stähl, I Arvidsson, KE Johansson, M Chromek, J Rebetz, S Loos, AC Kristoffersson, ZD Bekässy, M Mörgelin, D Karpman
(See online at https://doi.org/10.1371/journal.ppat.1004619) - Complement Interactions with Blood Cells, Endothelial Cells and Microvesicles in Thrombotic and Inflammatory Conditions. JD Lambris et al. (eds.), Immune Responses to Biosurfaces, Advances in Experimental Medicine and Biology 865, Springer, 2015
D Karpman, AL Stähl, I Arvidsson, KE Johansson, S Loos, R Tati, Z Bekässy, AC Kristoffersson, M Mossberg, R Kahn
(See online at https://doi.org/10.1007/978-3-319-18603-0_2) - Early terminal complement blockade and C6 deficiency are protective in enterohemorrhagic Escherichia coli-infected mice. The Journal of Immunology, 2016
I Arvidsson, J Rebetz, S Loos, M Herthelius, AC Kristoffersson, E Englund, M Chromek, D Karpman
(See online at https://doi.org/10.4049/jimmunol.1502377) - Hemolytic Uremic Syndrome. Journal of Internal Medicine, Vol 281 Issue 2, 2017 Feb: 123-148
D Karpman, S Loos, R Tati, I Arvidsson
(See online at https://doi.org/10.1111/joim.12546)
