Research published this week in Frontiers in Immunology details a mouse model exhibiting persistent lung and neurological symptoms following SARS-CoV-2 infection, mirroring some aspects of Long COVID observed in humans. The study, led by researchers who tracked mice up to 28 days post-infection, found that while both SARS-CoV-2 and influenza A viruses caused acute illness, the long-term consequences differed significantly.
Investigators used a mouse-adapted version of SARS-CoV-2 (MA30) and influenza A (PR8) to infect adult C57BL/6 mice. Both viruses induced substantial weight loss during the acute phase, but the mice generally recovered their weight by the end of the observation period. However, this clinical recovery masked ongoing tissue damage, a finding researchers say is crucial for understanding the complexities of post-viral syndromes.
The study revealed prolonged lung inflammation and collagen deposition in both groups, indicative of subchronic inflammatory lung injury and fibrotic remodeling. A key distinction emerged in the patterns of recovery. Mice infected with influenza A showed signs of epithelial regeneration, with persistent basal epithelial markers and activation of repair programs. In contrast, mice infected with the SARS-CoV-2 variant exhibited sustained activation of inflammatory, complement, and coagulation pathways, alongside extracellular matrix remodeling. This suggests a continued disruption of lung barrier function rather than successful repair, according to the research.
Researchers propose this divergence could explain why some patients experience prolonged breathlessness after SARS-CoV-2 infection, even after the virus is no longer detectable. The influenza model aligns with a repair-dominant recovery, while the SARS-CoV-2 model suggests persistent inflammation and vascular signaling contribute to ongoing symptoms. This finding supports a hypothesis that post-viral dyspnea may not stem from a single underlying mechanism.
Notably, the study also investigated neurological effects. Neither virus directly infected the brain, yet the SARS-CoV-2 infected mice experienced an increased frequency of microhemorrhages early in the infection and persistent neuroinflammation throughout the 28-day period. Brain profiling of the SARS-CoV-2 group revealed enrichment of pathways associated with vascular dysfunction, extracellular matrix remodeling, and IL-6 signaling. Researchers also observed disruption of hypothalamic-pituitary-axis programs, a finding not seen in the influenza-infected mice.
These neurological findings suggest that Long COVID-related symptoms, such as brain fog and cognitive difficulties, may arise from inflammatory and microvascular mechanisms rather than direct viral invasion of the brain. The research underscores the need for continued monitoring of neurocognitive and neuropsychiatric complaints in patients following SARS-CoV-2 infection, even after acute illness resolves. Recent research published in Nature indicates that blocking eicosanoid signaling may protect middle-aged mice from severe COVID-19, potentially offering a therapeutic avenue for mitigating some of these inflammatory responses [2]. Further investigation into the role of macrophage peroxisomes in alveolar regeneration and limiting SARS-CoV-2 tissue damage, as detailed in a study published by Science | AAAS [3], may also provide insights into long-term lung health following infection.
The study was published under DOI:10.3389/fimmu.2026.1755141.
