<i>Streptococcus mutans</i> -derived extracellular vesicles promote herpes simplex virus infection in oral epithelia

The oral cavity contains the second most diverse bacterial community after the intestines, with bacteria and viruses coexist. <i>Streptococcus mutans</i> is a major pathogenic bacterium in the oral cavity, commonly associated with dental caries. We investigated the effects of <i>S. mutans-</i>derived extracellular vesicles (Sm EVs) on herpes simplex virus 1 (HSV-1) infection, which is prevalent in the oral cavity. We performed our experiments in human oral keratinocyte (HOK) cells and mucosal tissue-derived organoids, and analyzed human whole saliva (<i>n</i> = 50) for associations between <i>S. mutans</i> and HSV-1 envelope glycoprotein D (gD) mRNA levels by qPCR. Sm EVs significantly enhanced HSV-1 production in mucosal organoids. Indeed, mRNA and/or protein levels of type I (IFN-α and IFN-β), type II (IFN-γ), and type III (IFN-λ₁, IFN-λ₂, and IFN-λ₃) interferons were significantly lower in Sm EV-treated mucosal organoids compared with the vehicle control under mock-infection. When HSV-1 was introduced after Sm EV pretreatment, these IFN levels showed a general trend of statistically significant reduction compared with those in the vehicle control. Moreover, Sm EVs suppressed IFN mRNA and protein levels by upregulating the EGFR - ERK pathway in mucosal cells, creating an environment that enhances HSV-1 production. Interestingly, a positive correlation was noted between <i>S. mutans</i> and HSV-1 detected in human whole saliva samples. These results suggest that <i>S. mutans</i> can negatively modulate the host innate antiviral responses by secreting EVs, thereby enhancing viral production. This study might provide a new perspective for controlling viral infections in humans.