Effect of human complement proteins on the activity of binary bacterial toxins of Clostridium botulinum and Bacillus anthracis
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Date
2024-02-28
Authors
Wohlfart, Jonas
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Dissertation
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Abstract
C2 toxin from Clostridium botulinum and lethal toxin from Bacillus anthracis are both composed of an enzymatically active A component and a pore-forming B component. These binary bacterial toxins enter the cell via a comparable intoxication mechanism, where finally C2I of Clostridium botulinum catalyzes the adenosine diphosphate-ribosylation of globular actin with subsequent depolymerization of filamentous actin, while lethal factor of Bacillus anthracis leads to degradation of the mitogen-activated protein kinase signaling. Since bacterial infections in general are mainly treated with antibiotics, a specific targeting of their toxins could be a desirable additional or alternative therapeutic option. Regarding the fact, that other human peptides like alpha-defensins were shown to possess anti-toxin properties, in this study, the complement proteins C3a and C5a, as well as far less active degradation products C3a_desArg and C5a_desArg were investigated for effects on the course of intoxication with C2 toxin or lethal toxin. Interestingly, all four complement proteins were able to slow down C2 intoxication of HeLa, HCT and CaCo2 cells in cell culture experiments and transepithelial electrical resistance measurements. However, this effect was not observed in all individual experiments. The inconsistent results for C3a and C3a_desArg might be explained by binding to plastic surfaces, however, this effect is not described yet for C5a and C5a_desArg. From all possible inhibiting mechanism of the intoxication process, direct binding of complement proteins to C2 toxin components appears to be most likely since cationic charged regions of C3a and C5a might bind to anionic cis-side vestibules of the C2IIa prepore. Notably, no inhibition at all was detected against lethal toxin. One possible explanation might be potential phagocytosis of the complement proteins by J774A.1 macrophages, before binding to the toxin would be possible. Moreover, the prepores are known to effectively bind polyanionic molecules, which makes binding of complement proteins less likely. Taken together, complement proteins might represent a possible new basis for the development of new toxin-targeting drugs. In future, the effect of complement proteins on further, structurally related toxins with clinically relevant diseases must be analyzed.
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Faculties
Medizinische Fakultät
Institutions
UKU. Institut für Pharmakologie und Toxikologie
UKU. Institut für Klinische und Experimentelle Trauma-Immunologie
UKU. Institut für Klinische und Experimentelle Trauma-Immunologie
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DFG Project uulm
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CC BY 4.0 International
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DFG Project THU
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Keywords
Binary toxins, Clostridium botulinum, Botulinus-C2-Toxin, Bakteriengift, Bacillus anthracis, Milzbrand, Komplement C3a, Komplement C5a, Bacterial toxins, Anthrax, Complement system proteins, Complement C3a, DDC 610 / Medicine & health