The Role of LEF1-AS1 in Prolonged Symptoms and Long COVID

Medical News: Long COVID, also referred to as post-COVID syndrome, is an emerging condition defined by persistent symptoms that linger three months after an initial SARS-CoV-2 infection. These symptoms endure for at least two months without any identifiable cause. It is estimated that between 10 and 20 percent of individuals recovering from COVID-19 experience these prolonged effects. Long COVID is now challenging healthcare systems worldwide as cases rise.


The Role of LEF1-AS1 in Prolonged Symptoms and Long COVID

Symptoms of long COVID vary greatly. Fatigue, cognitive impairments like brain fog, and shortness of breath are some of the most common complaints, though the condition can impact various organs and systems. The underlying mechanisms remain elusive, but they likely involve lingering viral particles, immune system dysfunction, and residual tissue damage. Research has begun exploring biomarkers to aid in diagnosing and managing long COVID, particularly noncoding RNAs (ncRNAs), which regulate gene expression and show promise as indicators of disease severity and progression.
 
The Focus on LEF1-AS1
A recent study conducted by researchers from IRCCS Policlinico San Donato, IRCCS MultiMedica, and ICS Maugeri IRCCS in Italy that is covered in this Medical News report, has identified specific ncRNAs that may help diagnose and understand long COVID. Among these, the ncRNA LEF1-AS1 has emerged as a promising candidate. This study enrolled 98 patients approximately 18 months after their initial COVID-19 hospitalization to investigate the relationship between ncRNA expression and lingering symptoms.
 
LEF1-AS1 - an antisense RNA associated with the lymphoid enhancer binding factor 1 (LEF1) gene - stood out as a potential biomarker. This RNA belongs to a class of long noncoding RNAs (lncRNAs) that, unlike protein-coding RNAs, do not produce proteins but instead regulate other genetic activities. LEF1-AS1 has been found to play key roles in regulating immune responses, inflammation, and cellular processes, which are critical in the context of long COVID.
 
What Is LEF1-AS1 and Its Role in the Human Body?
LEF1-AS1, or lymphoid enhancer-binding factor 1 antisense RNA 1, is a long noncoding RNA transcribed from the opposite strand of the LEF1 gene. LEF1 itself is a transcription factor that is primarily involved in Wnt/β-catenin signaling, a pathway essential for various cellular processes including immune response, cell proliferation, and differentiation. LEF1 is also known to play roles in the development of certain tissues, such as lymphoid organs, and in regulating inflammation.
 
LEF1-AS1 is considered a regulator of LEF1’s activity. It can influence LEF1 expression through multiple mechanisms. For example, in cancer studies, LEF1-AS1 has been shown to recruit histone-modifying enzymes to the LEF1 promoter region, thereby enhancing its transcription. In other cases, LEF1-AS1 acts as a molecular sponge, binding to microRNAs that would otherwise inhibit LEF1 expression. This dual regulatory role positions LEF1-AS1 as a key modulator of the Wnt/β-catenin pathway an d associated inflammatory responses.
 
LEF1-AS1 is also implicated in cancer, promoting tumor growth and metastasis in gliomas and non-small cell lung cancer. These findings highlight its relevance in diseases beyond long COVID.
 
LEF1-AS1’s Role in Long COVID
In the context of long COVID, LEF1-AS1’s downregulation appears to be associated with the persistent physical symptoms that many patients experience. These symptoms include fatigue, shortness of breath, and muscle pain - collectively referred to as major physical symptoms (MPS). The study found that patients with MPS exhibited significantly lower levels of LEF1-AS1 compared to those without these symptoms. This reduction was also mirrored in the expression of the LEF1 gene, suggesting a direct link between LEF1-AS1 activity and immune regulation in long COVID patients.
 
LEF1-AS1’s role likely involves modulating inflammation and immune cell behavior. For instance, the Wnt/β-catenin pathway, which LEF1-AS1 influences through LEF1, is critical for maintaining immune homeostasis. Dysregulation of this pathway can lead to prolonged inflammation, a hallmark of long COVID.
 
Additionally, the correlation between reduced LEF1-AS1 levels and elevated white blood cell counts observed in the study indicates an ongoing immune response that could contribute to the chronic symptoms experienced by these patients.

The study also found that lower LEF1-AS1 levels were associated with older age and reduced lymphocyte counts. These findings further emphasize the role of LEF1-AS1 in regulating immune function, particularly in mitigating the age-related decline in immune efficiency. By influencing immune cells and inflammatory pathways, LEF1-AS1 may help explain why some individuals develop severe and persistent symptoms after recovering from the acute phase of COVID-19.
 
Key Findings
The study revealed that all tested isoforms of LEF1-AS1, including LEF1-AS1-202 and LEF1-AS1-207, showed reduced levels in patients with MPS such as fatigue, shortness of breath, and muscle pain. Additionally, the LEF1 gene itself, which plays a critical role in inflammation and immune regulation, was also downregulated. The researchers noted correlations between lower LEF1-AS1 levels and older age, as well as certain clinical markers like elevated white blood cell counts and reduced lymphocyte counts. These findings suggest a possible link between LEF1-AS1 and the persistent inflammatory state often seen in long COVID.
 
Importantly, while other ncRNAs previously associated with acute COVID-19 - such as HCG18 and lncCEACAM21 - did not show significant changes, LEF1-AS1 consistently emerged as a unique marker for MPS. The study’s authors hypothesize that LEF1-AS1 may influence the regulation of immune responses and inflammatory pathways, contributing to the physical symptoms seen in long COVID patients.
 
Broader Implications
The significance of these findings extends beyond biomarker discovery. By highlighting the specific downregulation of LEF1-AS1 in MPS patients, the study offers insights into the molecular mechanisms underlying long COVID. LEF1-AS1 is known to interact with the LEF1 gene, which is involved in the Wnt/β-catenin signaling pathway. This pathway regulates various biological processes, including immune function and inflammation. Abnormalities in this signaling cascade could help explain the persistent symptoms experienced by long COVID patients.

The research team also explored the potential role of LEF1-AS1 in other conditions, noting its involvement in cancer and other inflammatory diseases. In gliomas and non-small cell lung cancer, for instance, LEF1-AS1 is associated with tumor growth and immune evasion. These parallels further underscore the complexity of LEF1-AS1’s role in human health and disease.
 
The Study’s Methodology
The research involved detailed RNA analyses from peripheral blood mononuclear cells (PBMCs) of long COVID patients. Using advanced techniques like quantitative polymerase chain reaction (qPCR), the team measured LEF1-AS1 and LEF1 expression levels. Clinical data, including blood cell counts and symptom profiles, were collected to identify correlations between RNA expression and patient characteristics. This comprehensive approach allowed researchers to pinpoint the specific downregulation of LEF1-AS1 in patients with MPS.
 
Challenges and Limitations
While the study offers promising avenues for understanding long COVID, it also has limitations. First, the cohort was limited to patients who had been hospitalized during the acute phase of their illness. This focus excludes individuals with milder cases of COVID-19, whose long-term symptoms might differ. Second, the study relied on patient-reported symptoms without incorporating objective measures to validate the presence and severity of long COVID. Third, the monocentric nature of the research may limit its generalizability to broader populations.
 
Despite these challenges, the study represents a significant step forward. By identifying LEF1-AS1 as a potential biomarker, it lays the groundwork for future research aimed at developing targeted diagnostics and therapies for long COVID.
 
Conclusions
In conclusion, the study findings highlight the potential of LEF1-AS1 as a biomarker for the physical symptoms of long COVID. LEF1-AS1 plays a critical role in regulating inflammation and immune responses through its interaction with the LEF1 gene. By uncovering its downregulation in patients with major physical symptoms, the study provides new insights into the molecular pathways contributing to long COVID.
 
Understanding the molecular underpinnings of long COVID is crucial for developing effective treatments. This study not only advances our knowledge of ncRNAs like LEF1-AS1 but also underscores the importance of personalized approaches in addressing this complex and multifaceted condition. By building on these findings, future research can explore targeted interventions to alleviate the burden of long COVID and improve the quality of life for affected individuals.
 
The study findings were published on a preprint server and are currently being peer reviewed.
https://www.biorxiv.org/content/10.1101/2024.12.20.629131v1
 
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