SARS-CoV-2 spike S1 triggered TLR7-dependent endolysosome dysfunction and senescence in human astrocytes.
Evidence
This cell study examined primary human astrocytes and found that S1 entered endolysosomes, required its multibasic motif for damaging effects, interacted with TLR7, and activated downstream p38 MAPK signaling.
Caveat
The findings identify a mechanism in cultured astrocytes exposed to spike S1, not direct evidence that TLR7 targeting mitigates in patients.
Simplified
SARS-CoV-2 infection is associated with long-lasting neuropsychiatric and cognitive symptoms, collectively referred to as . Emerging studies indicates that accelerate brain aging and 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.
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