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BACKGROUND: Although multiple studies have demonstrated a role for exosomes during virus infections, our understanding of the mechanisms by which exosome exchange regulates immune response during viral infections and affects viral pathogenesis is still in its infancy. In particular, very little is known for cytoplasmic single-stranded RNA viruses such as SARS-CoV-2 and Rift Valley fever virus (RVFV). We have used RVFV infection as a model for cytoplasmic single-stranded RNA viruses to address this gap in knowledge. RVFV is a highly pathogenic agent that causes RVF, a zoonotic disease for which no effective therapeutic or approved human vaccine exist. RESULTS: We show here that exosomes released from cells infected with RVFV (designated as EXi-RVFV) serve a protective role for the host and provide a mechanistic model for these effects. Our results show that treatment of both naïve immune cells (U937 monocytes) and naïve non-immune cells (HSAECs) with EXi-RVFV induces a strong RIG-I dependent activation of IFN-B. We also demonstrate that this strong anti-viral response leads to activation of autophagy in treated cells and correlates with resistance to subsequent viral infection. Since we have shown that viral RNA genome is associated with EXi-RVFV, RIG-I activation might be mediated by the presence of packaged viral RNA sequences. CONCLUSIONS: Using RVFV infection as a model for cytoplasmic single-stranded RNA viruses, our results show a novel mechanism of host protection by exosomes released from infected cells (EXi) whereby the EXi activate RIG-I to induce IFN-dependent activation of autophagy in naïve recipient cells including monocytes. Because monocytes serve as reservoirs for RVFV replication, this EXi-RVFV-induced activation of autophagy in monocytes may work to slow down or halt viral dissemination in the infected organism. These findings offer novel mechanistic insights that may aid in future development of effective vaccines or therapeutics, and that may be applicable for a better molecular understanding of how exosome release regulates innate immune response to other cytoplasmic single-stranded RNA viruses.
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BACKGROUND: The ongoing global pandemic of coronavirus disease 2019 (COVID-19) has resulted in the infection of over 128 million people and has caused over 2.8 million deaths as of April 2021 in more than 220 countries and territories. Currently, there is no effective treatment for COVID-19 to reduce mortality. We investigated the potential anti-coronavirus activities from an oral liquid of traditional medicine, Respiratory Detox Shot (RDS), which contains mostly herbal ingredients traditionally used to manage lung diseases. RESULTS: Here we report that RDS inhibited the infection of target cells by lenti-SARS-CoV, lenti-SARS-CoV-2, and hybrid alphavirus-SARS-CoV-2 (Ha-CoV-2) pseudoviruses, and by infectious SARS-CoV-2 and derived Ha-CoV-2 variants including B.1.1.7, B.1.351, P.1, B.1.429, B.1.2, B.1.494, B.1.1.207, B.1.258, and B.1.1.298. We further demonstrated that RDS directly inactivates the infectivity of SARS-CoV-2 virus particles. In addition, we found that RDS can also block the infection of target cells by Influenza A virus. CONCLUSIONS: These results suggest that RDS may broadly inhibit the infection of respiratory viruses.
RESUMEN
The intense effort of investigators, in particular during the past decade, has highlighted the importance of extracellular vesicles (EVs) such as exosomes in regulating both innate and adaptive immunity in the course of a variety of infections, with clear implications for development of novel vaccines, therapeutics, and diagnostics. Current and future efforts now need to focus strongly on teasing apart the intricate and complex molecular mechanisms that operate during EV regulation of immunity. In this review, we discuss recent advances that bear on our current understanding of how EVs, including exosomes, can contribute to the innate immune functions of microglia within the central nervous system (CNS), and we also highlight future important mechanistic questions that need to be addressed. In particular, recent findings that highlight the crosstalk between autophagy and exosome pathways and their implications for innate immune functions of microglia will be presented. Microglial activation has been shown to play a key role in neuroAIDS, a neuro-infectious disease for which the importance of exosome functions, including exosome-autophagy interplay, has been reported. The importance of exosomes and exosome-autophagy crosstalk involving microglia has also been shown for the Parkinson's disease (PD), a neurodegenerative disease that is thought to be linked with immune dysfunction and involve infectious agents as trigger. Considering the accumulation of recent findings and the vibrancy of the EV field, we anticipate that future studies will continue to have a deep impact on our understanding of the CNS pathologies that are influenced by the functions of microglia and of the infectious disease mechanisms in general. Graphical Abstract.
