Bacterial RNA as a signal to eukaryotic cells as part of the infection process

Abstract

The discovery of regulatory RNA has identified an underappreciated area for microbial subversion of the host. There is increasing evidence that RNA can be delivered from bacteria to host cells associated with membrane vesicles or by direct release from intracellular bacteria. Once inside the host cell, RNA can act by activating sequence-independent receptors of the innate immune system, where recent findings suggest this can be more than simple pathogen detection, and may contribute to the subversion of immune responses. Sequence specific effects are also being proposed, with examples from nematode, plant and human models providing support for the proposition that bacteria-to-human RNA signaling and the subversion of host gene expression may occur.

Keywords: RNAi; Regulatory RNA; cross-kingdom communication; innate immunity; membrane vesicles; pathogenicity.

Figure 1. Interactions of bacterial RNA with an eukaryotic host cell

a)Entry of bacterial RNA (blue shaded area): Bacterial RNA in double and single stranded forms (red) of extracellular bacteria (green) can enter human cells with MVs, whilst intracellular bacteria can secrete RNA into phagosomes and the cytosol. Bacterial RNA can translocate from phagosomes into the cytosol due to the inherent leakiness of phagosome or when bacterial pore-forming toxins (green stars) disrupt integrity of phagosomes. b) Interactions with the innate immune system (red shaded area): In the endosome, bacterial RNA is sensed by TLR3, TLR7, and TLR8, whilst in the cytosol DExD/H motif helicases such as MDA5 and RIG-I and the NLRP3 inflammasome (via a yet unknown intermediate RNA helicase) can interact with bacterial RNA to trigger downstream signaling cascades. c) Modulation of host cell by bacterial RNA (grey-shaded area): Engagement of innate immune system RNA sensors leads to expression and secretion of type I and type III interferons as well as NF-κB-controlled cytokines which can skew the immune system away from antibacterial response and promote bacterial colonization and dissemination. Activation of the NLRP3 inflammasome leads to Caspase 1 mediated cleavage of pro–IL-1β into active IL-1β. It is postulated that bacterial RNA may also exert post-transcriptional control of human gene expression via sequence-specific interactions with host RNAs. Please refer to the main article for more details and definitions of the abbreviations used.