LONG COVID continues to affect millions worldwide, causing persistent breathing problems, fatigue, and neurological symptoms long after the initial infection has resolved. New laboratory research offers fresh insight into why coronavirus infection may lead to long COVID, while influenza often does not.
In a longitudinal mouse study, researchers compared the long-term effects of coronavirus infection with those of influenza A on the lungs and brain. The findings suggest that the two viruses trigger markedly different biological responses, with coronavirus driving prolonged tissue damage that closely mirrors features of long COVID.
Long COVID and Prolonged Lung Injury
Both coronavirus and influenza caused lasting lung inflammation weeks after infection. However, the nature of that damage differed substantially. Coronavirus-infected lungs showed ongoing activation of inflammatory, clotting, and fibrotic pathways, alongside disruption of normal tissue structure and metabolism. These changes are consistent with scarring and impaired lung repair.
By contrast, influenza infection triggered a strong early immune response followed by signs of epithelial regeneration. Influenza-infected lungs showed activation of repair cells that migrated into damaged areas, suggesting a more effective healing process. This divergence in lung recovery may help explain why persistent breathlessness is more common after coronavirus infection.
Brain Changes Linked to Long COVID
Neither virus was detected directly in the brain. Despite this, coronavirus infection led to clear neurological effects. Mice infected with coronavirus developed early microvascular bleeding and sustained brain inflammation at all time points studied. Gene expression analysis revealed changes linked to blood vessel dysfunction, immune activation, and extracellular matrix remodelling.
Notably, coronavirus infection disrupted pathways related to hormonal regulation and sensory processing in the brain, patterns that resemble neurological symptoms reported in long COVID, such as brain fog and fatigue. These changes were absent in mice infected with influenza.
Implications for Understanding Long COVID
The study highlights that long COVID is unlikely to be driven by persistent viral infection alone. Instead, ongoing immune activation, vascular injury, and impaired tissue repair appear central to disease development. The findings also suggest that coronavirus uniquely alters communication between organs, including lung–brain interactions, long after acute infection.
What This Means for Patients and Clinicians
While animal studies cannot fully replicate human disease, these results provide a biological framework for understanding long COVID. Identifying virus-specific pathways may support the development of targeted therapies aimed at reducing inflammation, preventing fibrosis and protecting the brain after coronavirus infection.
The researchers emphasise that further clinical studies are needed to confirm whether these mechanisms operate in people with long COVID. Nonetheless, the work represents an important step toward explaining why coronavirus leaves a longer-lasting imprint on the body than influenza.
Reference
Currey J et al. Characterization of subchronic lung and brain consequences caused by mouse-adapted SARS-CoV-2 and influenza A infection of C57BL6 mice. Front Immunol. 2026; doi:10.3389/fimmu.2026.1755141.
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