SARS-CoV-2 Spike Targets USP33-IRF9 Axis via Exosomal miR-148a to Activate Human Microglia

Abstract

SARS-CoV-2, the novel coronavirus infection has consistently shown an association with neurological anomalies in patients, in addition to its usual respiratory distress syndrome. Multi-organ dysfunctions including neurological sequelae during COVID-19 persist even after declining viral load. We propose that SARS-CoV-2 gene product, Spike, is able to modify the host exosomal cargo, which gets transported to distant uninfected tissues and organs and can initiate a catastrophic immune cascade within Central Nervous System (CNS). SARS-CoV-2 Spike transfected cells release a significant amount of exosomes loaded with microRNAs such as miR-148a and miR-590. microRNAs gets internalized by human microglia and suppress target gene expression of USP33 (Ubiquitin Specific peptidase 33) and downstream IRF9 levels. Cellular levels of USP33 regulate the turnover time of IRF9 via deubiquitylation. Our results also demonstrate that absorption of modified exosomes effectively regulate the major pro-inflammatory gene expression profile of TNFα, NF-κB and IFN-β. These results uncover a bystander pathway of SARS-CoV-2 mediated CNS damage through hyperactivation of human microglia. Our results also attempt to explain the extra-pulmonary dysfunctions observed in COVID-19 cases when active replication of virus is not supported. Since Spike gene and mRNAs have been extensively picked up for vaccine development; the knowledge of host immune response against spike gene and protein holds a great significance. Our study therefore provides novel and relevant insights regarding the impact of Spike gene on shuttling of host microRNAs via exosomes to trigger the neuroinflammation.

Altered increase in STAT1 expression and phosphorylation in severe COVID‐19

“…IRF9 also prevents exhaustion of CD8+ T cells in lymphocytic choriomeningitis infection [ 33 ]. Interestingly, SARS‐CoV‐2 spike transfected cells secrete miR‐148a and ‐590 via exosomes which induce degradation of IRF9 in human microglia [ 34 ].…”

Urinary Extracellular Vesicles Are a Novel Tool to Monitor Allograft Function in Kidney Transplantation: A Systematic Review

“…SARS-CoV-2 is hardly detected in the urine [ 74 ], but SARS-CoV-2 infected kidney cells might release more uEV with specific markers. In vitro, the spike protein of SARS-CoV-2 could promote embryonic kidney cells (HEK 293) to release EVs with higher expression of miR-590-3p and miR-148a [ 75 ].…”

NOX2 Activation in COVID-19: Possible Implications for Neurodegenerative Diseases

“…Indeed, IRF9 downregulation causes harmful effects in microglia, promoting microglial activation and neuroinflammation. Hence, the disruption of the SP33-IRF9 axis promoted by SARS CoV-2 infection would activate the inflammatory phenotype of microglia which over time can induce neurodegeneration [41]. This evidence was found in a patient with COVID-19 in whom a strong microglial activation was found within the white matter [42].…”