Even after the fever and cough are gone, some people continue to feel unwell following a case of COVID-19 or seasonal flu. Tulane National Biomedical Research Center (NBRC) scientist Dr. Xuebin Qin and colleagues set out to understand which long-term effects are shared between COVID-19 and the flu, and which may be unique to COVID-19.
The Study
Their new study, published in Frontiers in Immunology, compared how SARS-CoV-2 (the virus that causes COVID-19) and influenza affect the body after the acute infection has resolved. Using a carefully controlled mouse model, the team examined lung and brain tissue weeks after infection to identify what kind of biological “footprint” each virus leaves behind. While animal models cannot capture every aspect of human disease, they allow researchers to closely examine biological changes that are difficult to study in patients. The findings may help explain why both COVID-19 and the flu can leave behind lasting lung problems, while long COVID is more often linked to neurological symptoms such as brain fog, fatigue and mood changes.
When researchers studied the lungs, they saw a similar pattern after both infections. Immune cells remained more active than normal instead of fully standing down, and there was an increased buildup of collagen, a protein associated with scarring. These changes can stiffen lung tissue and make breathing feel harder, offering a potential biological explanation for why some people have persistent shortness of breath after respiratory infections.
What Was Discovered
A key difference emerged when the team examined how the lungs were trying to heal. After influenza, the lungs showed signs of switching into repair mode: specialized cells moved into damaged areas to rebuild the lining of the airways. After COVID-19, that repair response appeared to be limited. This suggests that SARS-CoV-2 may interfere with the lung’s natural healing process, potentially setting the stage for longer recovery and lasting respiratory symptoms.
The most striking findings came from the brain. Even though neither virus was detectable in brain tissue at the time of analysis, mice that had recovered from COVID-19 still showed signs of ongoing brain inflammation. The researchers also observed small areas of bleeding earlier in the infection, pointing to potential damage to tiny blood vessels.
Gene expression analysis revealed that inflammatory signaling remained elevated, and that key pathways related to serotonin and dopamine regulation were disrupted. These chemical systems are closely tied to mood, cognition and energy levels, which are frequently affected in people with long COVID. In contrast, brains from influenza-infected animals showed far fewer of these persistent changes.
“In both infections, we observed lasting lung injury,” Qin noted. “But long-term effects in the brain were unique to SARS-CoV-2. That distinction is critical to understanding long COVID.”
Connecting Infection, Blood Vessels and The Brain
The findings suggest that inflammation and damage to small blood vessels in the brain may play a role in long-lasting neurological symptoms. Even without the virus present, these changes can affect how brain cells communicate.
By clearly defining these biological changes, researchers at Tulane NBRC are helping to create a roadmap for future clinical studies. The patterns they identified could guide how clinicians monitor patients after infection, which biomarkers to track, and which pathways might be most promising for new therapies aimed at preventing or reducing lasting damage.
Why This Matters for Patients and Future Therapies
By directly comparing COVID-19 with flu in the same experimental framework, Tulane NBRC investigators provide a clearer picture of which long-term issues are shared across severe respiratory infections, and which are specific to SARS-CoV-2. That knowledge can help clinicians and scientists focus their efforts on where they are most likely to make a difference for patients still waiting to feel fully recovered.
