iScience (Cell) | July 25, 2024 | DOI: https://doi.org/10.1016/j.isci.2024.110589
Saba Parveen, Chinmayi V. Bhat, Aswathy C S, Shaheena Aziz, Arya J, Asmita Dutta, Somit Dutta, Sautan Show, Kuldeep Sharma, Sumit Rakshit, John Bernet Johnson, Upendra Nongthomba, Anirban Banerjee, Karthik Subramanian
Streptococcus pneumoniae is a global priority respiratory pathogen that kills over a million people annually. The pore-forming cytotoxin, pneumolysin (PLY) is a major virulence factor. Here, we found that recombinant PLY as well as wild-type pneumococcal strains, but not the isogenic PLY mutant, upregulated the shedding of extracellular vesicles (EVs) harboring membrane-bound toxin from human THP-1 monocytes. PLY-EVs induced cytotoxicity and hemolysis dose-dependently upon internalization by recipient monocyte-derived dendritic cells. Proteomics analysis revealed that PLY-EVs are selectively enriched in key inflammatory host proteins such as IFI16, NLRC4, PTX3 and MMP9. EVs shed from PLY-challenged or infected cells induced dendritic cell maturation and primed them to infection. In vivo, zebrafish administered with PLY-EVs, showed pericardial edema and mortality. Adoptive transfer of bronchoalveolar lavage-derived EVs from infected mice to healthy recipients induced lung damage and inflammation in a PLY-dependent manner. Our findings identify that host EVs released during infection mediate pneumococcal pathogenesis.
