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.
Highlights
SARS-CoV-2 is the latest and seventh strain of the Coronaviruses (CoVs) family, responsible for causing pneumonia like respiratory distress syndrome termed as COVID-19 in humans [1, 2]
Since S protein is supposed to play a crucial role in inducing neutralizing antibody, T-cell response and protective immunity [57,58,59]; we were interested to evaluate the impact of spike protein in perturbing the immune response in context of Central Nervous System (CNS)
The particle size distribution analysis showed that harvested exosomes from control and S gene transfected cells were in size range of a typical exosomal population (mode: 85.9 nm for control exosomes, mode: 107.2 nm for S exosomes (Figures 1B, C)
Summary
SARS-CoV-2 is the latest and seventh strain of the Coronaviruses (CoVs) family, responsible for causing pneumonia like respiratory distress syndrome termed as COVID-19 in humans [1, 2]. SARS-CoV-2 has caused a worldwide pandemic; total number of infections have crossed 116 millions while death numbers have crossed 2.5 millions and still going on (https://covid19.who.int/). SARS-CoV-2 infects both upper and lower respiratory tract epithelial cells and causes from mild flu like symptoms to severe acute respiratory syndrome or septic shocks in severe cases [4]. In attempt to clear the viral particles from host system, an uncontrolled or inefficient immune response can lead to an array of immunopathology and causes serious systemic inflammatory reaction [8, 9]
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