Abstract
Murine neural stem cells (NSCs) were recently shown to release piRNA-containing exosomes/microvesicles (Ex/Mv) for exerting antiviral immunity, but it remains unknown if these Ex/Mv could target SARS-CoV-2 and whether the PIWI-piRNA system is important for these antiviral actions. Here, using in vitro infection models, we show that hypothalamic NSCs (htNSCs) Ex/Mv provided an innate immunity protection against SARS-CoV-2. Importantly, enhanced antiviral actions were achieved by using induced Ex/Mv that were derived from induced htNSCs through twice being exposed to several RNA fragments of SARS-CoV-2 genome, a process that was designed not to involve protein translation of these RNA fragments. The increased antiviral effects of these induced Ex/Mv were associated with increased expression of piRNA species some of which could predictably target SARS-CoV-2 genome. Knockout of piRNA-interacting protein PIWIL2 in htNSCs led to reductions in both innate and induced antiviral effects of Ex/Mv in targeting SARS-CoV-2. Taken together, this study demonstrates a case suggesting Ex/Mv from certain cell types have innate and adaptive immunity against SARS-CoV-2, and the PIWI-piRNA system is important for these antiviral actions.
Highlights
Murine neural stem cells (NSCs), in particular hypothalamic NSCs [1, 2, 3, 4, 5, 6], are known to abundantly release exosomes/ microvesicles (Ex/Mv) that are enriched with small RNAs such as miRNAs [3, 4]
Using in vitro models of SARS-CoV-2 infection, we studied if murine NSC Ex/Mv could have an innate immunity action against this pandemic virus, whether adaptive immunity response could be developed to enhance the antiviral action of NSC Ex/Mv, and if the PIWIL2-piRNA system could be involved in the antiviral immunity of NSC Ex/Mv
A549 cells contain human angiotensin-converting enzyme 2 which is known to facilitate the entry of SARS-CoV-2 into cells, our pilot experiment revealed that SARS-CoV-2 infection in A549 cells was relatively modest, most likely due to low expression level of hACE2 on the surface of A549 cells
Summary
Murine neural stem cells (NSCs), in particular hypothalamic NSCs (htNSCs) [1, 2, 3, 4, 5, 6], are known to abundantly release exosomes/ microvesicles (Ex/Mv) that are enriched with small RNAs such as miRNAs [3, 4]. We revealed that murine NSC Ex/Mv comprise both innate and adaptive immunity effects in breaking pseudotyped SARS-CoV-2 and HIV-based recombinant lentivirus [2]. PiRNAs induce genic and intergenic silencing such as transposon silencing and splicing [14, 15, 16], a function which manifests an immunity-like action against transposon invasion. Using in vitro models of SARS-CoV-2 infection, we studied if murine NSC Ex/Mv could have an innate immunity action against this pandemic virus, whether adaptive immunity response could be developed to enhance the antiviral action of NSC Ex/Mv, and if the PIWIL2-piRNA system could be involved in the antiviral immunity of NSC Ex/Mv
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