Pneumococcal Extracellular Vesicles Modulate Host Immunity

Abstract

Extracellular vesicles (EVs) have recently garnered attention for their participation in host-microbe interactions in pneumococcal infections. However, the effect of EVs on the host immune system remain poorly understood. Our studies focus on EVs produced by <i>Streptococcus pneumoniae</i> (pEVs), and reveal that pEVs are internalized by macrophages, T cells, and epithelial cells. <i>In vitro</i>, pEVs induce NF-κB activation in a dosage-dependent manner and polarize human macrophages to an alternative (M2) phenotype. In addition, pEV pretreatment conditions macrophages to increase bacteria uptake and such macrophages may act as a reservoir for pneumococcal cells by increasing survival of the phagocytosed bacteria. When administered systemically in mice, pEVs induce cytokine release; when immobilized locally, they recruit lymphocytes and macrophages. Taken together, pEVs emerge as critical contributors to inflammatory responses and tissue damage in mammalian hosts. <b>IMPORTANCE</b> Over the last decade, pathogen-derived extracellular vesicles (EVs) have emerged as important players in several human diseases. Therefore, a thorough understanding of EV-mediated mechanisms could provide novel insights into vaccine/therapeutic development. A critical question in the field is: do pathogen-derived EVs help the pathogen evade the harsh environment in the host or do they help the host to mount a robust immune response against the pathogen? This study is a step towards answering this critical question for the Gram-positive pathogen, <i>Streptococcus pneumoniae</i>. Our study shows that while <i>S. pneumoniae</i> EVs (pEVs) induce inflammatory response both <i>in vitro</i> and <i>in vivo</i>, they may also condition the host macrophages to serve as a reservoir for the bacteria.