SARS-CoV-2 Causes Persistent Brain Inflammation Weeks After Infection Clears; Flu Does Not

Both COVID-19 and influenza are respiratory infections that can make people feel terrible for weeks and sometimes months beyond the acute phase. But the nature of that prolonged suffering differs between the two diseases in ways that patients and clinicians have observed and that a Tulane University study now traces to distinct patterns of biological damage.

Tulane researchers infected mice with either SARS-CoV-2 or influenza and then examined lung and brain tissue after the infections had cleared. Both viruses left similar damage signatures in the lungs. In the brain, the picture diverged sharply: only COVID-19 produced lasting inflammation, and only COVID-19 disrupted the neural signaling pathways tied to mood, energy, and cognition. The findings, published in Frontiers in Immunology, provide a cellular and molecular foundation for understanding why long COVID so frequently includes neurological symptoms while post-influenza illness typically does not.

Lung damage: similar but not identical

In the lungs, both viruses produced findings consistent with incomplete immune resolution after infection cleared. Immune cells that would normally stand down after clearing an infection remained elevated. Collagen buildup - a marker of tissue scarring - increased in both groups, consistent with the lung stiffening that can make breathing feel more labored even after acute illness passes.

A key difference emerged when examining the repair response. After influenza, the lungs showed activity consistent with regenerative repair - specialized cells moving into damaged airway areas to help rebuild the lining. After COVID-19, this repair response was largely absent. The virus appears to impair the lung tissue restoration process even after it has been cleared, potentially explaining why some post-COVID patients report persistent shortness of breath without active infection.

Brain effects: unique to COVID-19

Neither virus was detected in brain tissue in the study. Despite the absence of direct viral invasion, mice that had recovered from COVID-19 showed persistent brain inflammation weeks after infection had cleared. Tiny areas of bleeding - microhemorrhages in small blood vessels - were also present.

Gene expression analysis added specificity to these observations. Inflammatory signaling pathways remained active in the brains of COVID-19-recovered mice. Crucially, the analysis revealed ongoing disruption in the pathways regulating serotonin and dopamine, two neurotransmitters central to mood regulation, cognitive function, attention, and energy levels. These disruptions were largely absent in mice that had recovered from influenza.

"In both infections, we observed lasting lung injury," said Dr. Xuebin Qin, lead author and professor of microbiology and immunology at the Tulane National Biomedical Research Center. "But long-term effects in the brain were unique to SARS-CoV-2. That distinction is critical to understanding long COVID."

Why this matters for long COVID neurological symptoms

Long COVID affects an estimated 10 to 30 percent of people who have had COVID-19, with symptoms that frequently include brain fog - difficulty with concentration, memory, and word retrieval - alongside fatigue and mood disturbances. These are precisely the domains governed by serotonin and dopamine signaling. Disruption of these pathways, even without active infection in the brain, could produce the cognitive and affective symptoms that patients describe.

The microhemorrhage finding is also clinically relevant. Small blood vessel damage in the brain can affect neural circuit function without producing the dramatic symptoms of a stroke, contributing to subtle but meaningful changes in cognition, mood regulation, and fatigue over time.

Limitations of the mouse model

This work used a mouse model - an important distinction when interpreting how directly the findings apply to human long COVID. Mouse immune responses and brain physiology differ from humans in meaningful ways, and the severity and duration of infection in controlled mouse experiments may not replicate the full range of COVID-19 illness seen in humans. The study was supported by the American Heart Association Long COVID Impact Project and the National Institutes of Health.

The research does not establish which aspect of SARS-CoV-2 infection causes the observed brain effects - whether it is the initial immune response, a sustained immune activation, vascular damage, or some combination. Identifying the specific mechanism would be necessary to design targeted interventions. What the study does establish is a clear biological difference between the two most consequential respiratory infections of recent decades, at the level of brain tissue months after recovery.