Inflammation from mild COVID-19 results in persistent neurological and behavioral changes in rhesus macaques

Although most SARS-CoV-2 infections result in mild or moderate symptoms not requiring hospitalization, many patients experience persistent symptoms after their initial recovery, a condition termed Post-Acute Sequelae of SARS-CoV-2 infection (PASC). The underlying pathogenesis behind infection associated chronic illnesses, such as PASC, are poorly understood, thus critically limiting the development of therapeutics to prevent or alleviate symptoms. The current study examined the neurocognitive impact of SARS-CoV-2 induced inflammation in a nonhuman primate model. Ten adult rhesus macaques (5 female, 5 male) were monitored before, during, and after recovery from a mild COVID-19 illness (SARS-CoV-2 strain 2019-noCoV/USA-WA1/2020). Macaques exhibited persistent alterations in taste and smell, as well as decreased cognitive flexibility up to 3 months post-infection. Female macaques experienced sleep disturbances, greater stress and poorer autonomic function months after SARS-CoV-2 infection. Importantly, the development of these neurocognitive changes were associated with acute cytokine response to infection and increased microglia activation in brain tissue at 4 months post-infection. These findings suggest a causative link between the inflammatory response to mild COVID-19 symptoms and persistent neurocognitive changes associated with PASC and provide rationale for therapeutic strategies aimed at reducing acute inflammatory responses to the virus.