ORF3a and exosomes mediated lung-brain axis drives neuroinflammation and neurological complications in long COVID

The Post-Acute Sequelae of COVID-19 (PASC, commonly known as long COVID) are chronic symptoms often persist for months after viral clearance, including neurological complications and multi-organ dysfunctions. Yet, the underlying mechanism remains elusive and effective treatment is still unavailable. Here, we report SARS-CoV-2 accessory protein ORF3a hijacks host exosomes and alters the cargo towards a more proinflammatory profile. These ORF3a-containing exosomes (ORF3a-EVs) can enter circulation during infection and activate a lung-brain axis. In the brain, choroid plexus (ChP) is particularly vulnerable to ORF3a-EVs, and the breakdown of the ChP barrier allows activated border-associated macrophages (BAMs) to migrate across the ventricle and infiltrate into the ependymal layer, resulting in neuroinflammation and white matter damage. Importantly, we found that pharmacological inhibition of exosome secretion with GW4869 effectively reduced ORF3a brain penetration, mitigated ChP damage and BAM infiltration, and alleviated the chronic neuroinflammation. These findings identify ORF3a as a key SARS-CoV-2 virulence factor driving neurological complications in COVID-19, as well as the therapeutic potential of targeting exosomes and this lung-brain axis in PASC.