Staphylococcus aureus secretes immunomodulatory RNA and DNA via membrane vesicles

Blanca V Rodriguez,Meta J Kuehn

doi:10.1038/s41598-020-75108-3

Abstract

Bacterial-derived RNA and DNA can function as ligands for intracellular receptor activation and induce downstream signaling to modulate the host response to bacterial infection. The mechanisms underlying the secretion of immunomodulatory RNA and DNA by pathogens such as Staphylococcus aureus and their delivery to intracellular host cell receptors are not well understood. Recently, extracellular membrane vesicle (MV) production has been proposed as a general secretion mechanism that could facilitate the delivery of functional bacterial nucleic acids into host cells. S. aureus produce membrane-bound, spherical, nano-sized, MVs packaged with a select array of bioactive macromolecules and they have been shown to play important roles in bacterial virulence and in immune modulation through the transmission of biologic signals to host cells. Here we show that S. aureus secretes RNA and DNA molecules that are mostly protected from degradation by their association with MVs. Importantly, we demonstrate that MVs can be delivered into cultured macrophage cells and subsequently stimulate a potent IFN-β response in recipient cells via activation of endosomal Toll-like receptors. These findings advance our understanding of the mechanisms by which bacterial nucleic acids traffic extracellularly to trigger the modulation of host immune responses.

Highlights

Bacterial nucleic acids are well recognized as important pathogen associated molecular patterns (PAMPs) sensed by host innate immune cells during infection[1,2,3]
Nucleic acids and how they modulate the immune response during infection[18,19,20], these studies have not reported on the specific mechanisms by which outer membrane vesicles (OMVs)-associated RNA and DNA are taken up by host cells or provided evidence to show that OMV-associated nucleic acids interact directly with host cells to modulate the immune response
Those immunomodulatory nucleic acids are secreted by bacteria in general–and by the extracellular human pathogen S. aureus in particular—and how they are transferred to host cells to eventually reach IFN signaling receptors[2,3,18,19,20]

Summary

Introduction

Bacterial nucleic acids are well recognized as important pathogen associated molecular patterns (PAMPs) sensed by host innate immune cells during infection[1,2,3]. MVs were shown to stabilize and protect their protein cargo from extracellular proteolytic digestion and likely protect their nucleic acid cargo from degradation by nucleases present in the extracellular space This feature enables MVs to deliver a selection of protected, biologically active macromolecules to host cells both proximal and distal from the site of bacterial infection[27]. MVs are internalized by host cells via endocytosis, macropinocytosis, or phagocytosis—which facilitates the delivery of bacterial-derived immunomodulatory cargo to mammalian host cells in a coordinated fashion[27,34,35] Such reports position MVs as a likely, non-canonical secretion mechanism for bacterial nucleic acids to gain access to the interior of host cells and to play a functional role in the host–pathogen interface. No specialized nucleic acid secretion systems have been reported for S. aureus

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Conclusion