Mild COVID-19 can have long-term effects on the brain via neuroinflammatory mechanisms, according to new research published in Cell. The findings provide therapeutic targets for future work.

After COVID-19, some people have long-term neurological symptoms that are similar to those of cancer therapy-related cognitive impairment (CRCI). Neuroinflammatory processes are key to CRCI pathophysiology, so the aim of the new study was to assess these processes in COVID-19.

“Moderate-to-severe and systemic SARS-CoV-2 infection can affect the brain in several ways — including vasculopathy and direct infection — but we set out to test the effects of mild respiratory infection alone on the brain,” explains Michelle Monje, who led the study with Akiko Iwasaki.

SARS-CoV-2 enters cells via the human ACE receptor (hACE), so the researchers limited the location of the infection in mice by selectively inducing expression of hACE in the respiratory tract. Mice received either intranasal SARS-CoV-2 or mock infection, and cerebrospinal fluid (CSF) samples were taken either 7 days or 7 weeks after infection to assess inflammatory markers.

Compared with uninfected mice, infected mice had higher CSF levels of multiple cytokines and chemokines, as well as increased microglial activation in subcortical and hippocampal white matter. Neuron generation in the hippocampus and the amount of myelin in the subcortical white matter were also both lower in infected mice than in uninfected mice.

“These findings point to the possibility that the infection does not need to happen directly within the brain to cause long-term damage,” says Iwasaki. The researchers now plan to test therapies being developed for CRCI in preclinical models of COVID-19-related cognitive impairment as a step towards clinical trials.