SARS-CoV-2 spike triggers TLR7-dependent endolysosome dysfunction and senescence in human astrocytes
SARS-CoV-2 infection is associated with long-lasting neuropsychiatric and cognitive symptoms, collectively referred to as neuro-PASC. Emerging studies indicates that accelerate brain aging and cellular senescence in COVID brain could lead to altered neuroimmune responses and neurodegenerative outcomes. However, little is known about how cellular senescence is development in neuro-PASC.
Here, we examined the role of spike protein subunit S1, a persistent viral antigen, in driving the development of cellular senescence in primary human astrocytes. We have demonstrated that S1 enters endolysosomes and induces endolysosome dysfunction and cellular senescence. Moreover, the multibasic motif is critical for such S1-induced damaging effects.
Importantly, we identified Toll-like receptor 7 (TLR7), an endolysosome-resident pattern recognition receptor, as a critical mediator of S1-induced damaging effects. Mechanistically, S1 interacts with TLR7 at the site of the endolysosome lumen and activates p38 MAPK signaling of downstream of TLR7, which drive the development of cellular senescence.
Together, these findings suggest that TLR7 mediates S1-induced endolysosome dysfunction and cellular senescence, and that TLR7 represents a therapeutic target for mitigating neuro-PASC.
Web | PDF | Journal of Neuroinflammation | Open Access
Hasler, Wendie A; McKay, Emily; Datta, Gaurav; Johnson, Samantha; Rezagholizadeh, Neda; Chen, Xuesong
SARS-CoV-2 infection is associated with long-lasting neuropsychiatric and cognitive symptoms, collectively referred to as neuro-PASC. Emerging studies indicates that accelerate brain aging and cellular senescence in COVID brain could lead to altered neuroimmune responses and neurodegenerative outcomes. However, little is known about how cellular senescence is development in neuro-PASC.
Here, we examined the role of spike protein subunit S1, a persistent viral antigen, in driving the development of cellular senescence in primary human astrocytes. We have demonstrated that S1 enters endolysosomes and induces endolysosome dysfunction and cellular senescence. Moreover, the multibasic motif is critical for such S1-induced damaging effects.
Importantly, we identified Toll-like receptor 7 (TLR7), an endolysosome-resident pattern recognition receptor, as a critical mediator of S1-induced damaging effects. Mechanistically, S1 interacts with TLR7 at the site of the endolysosome lumen and activates p38 MAPK signaling of downstream of TLR7, which drive the development of cellular senescence.
Together, these findings suggest that TLR7 mediates S1-induced endolysosome dysfunction and cellular senescence, and that TLR7 represents a therapeutic target for mitigating neuro-PASC.
Web | PDF | Journal of Neuroinflammation | Open Access