Bacterial pore-forming toxin pneumolysin drives pathogenicity through shed toxin-loaded host extracellular vesicles

Parveen, S.; Bhat, C. V.; Aziz, S.; J, A.; Dutta, A.; Dutta, S.; Show, S.; Sharma, K.; Johnson, J. B.; Nongthomba, U.; Banerjee, A.; Subramanian, K.

doi:10.1101/2023.10.12.561978

bioRxiv · 10.1101/2023.10.12.561978

Bacterial pore-forming toxin pneumolysin drives pathogenicity through shed toxin-loaded host extracellular vesicles

Parveen, S.·Bhat, C. V.·Aziz, S.·J, A.·Dutta, A.·Dutta, S.·Show, S.·Sharma, K.·Johnson, J. B.·Nongthomba, U.·Banerjee, A.·Subramanian, K.

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Abstract

Streptococcus pneumoniae is a global priority respiratory pathogen that kills over a million people annually and produces the pore-forming cytotoxin, pneumolysin (PLY). Host cells expel membrane assembled toxin by shedding microvesicles, but the composition and pathophysiological sequelae of the toxin-induced host extracellular vesicles (EVs) are unknown. Here, we found that EVs shed from PLY-challenged monocytes (PLY-EVs) harbor membrane-bound toxin that induced cytotoxicity upon fusion with recipient cells. EVs from human monocytes challenged with recombinant PLY as well as PLY-expressing pneumococcal strains, but not the isogenic PLY mutant, primed dendritic cells and evoked higher pro-inflammatory cytokines upon infection. Proteomic analysis revealed that PLY-EVs are enriched for key antimicrobial and inflammatory host proteins such as IFI16, NLRC4, PTX3 and MMP9. In vivo, zebrafish and mice administered with PLY-EVs showed mortality, pericardial edema, tissue damage and inflammation. Our findings show that host EVs bearing the cytotoxin PLY constitute a previously unexplored mechanism of pneumococcal pathogenesis.

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Parveen, S., Bhat, C. V., Aziz, S., J, A., Dutta, A., Dutta, S., Show, S., Sharma, K., Johnson, J. B., Nongthomba, U., Banerjee, A., Subramanian, K.. 2023-10-12. Bacterial pore-forming toxin pneumolysin drives pathogenicity through shed toxin-loaded host extracellular vesicles. https://doi.org/10.1101/2023.10.12.561978

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