Alterations in the Expression of Toll-Like Receptors (TLRs) 3, 4,and 7 in Patients with COVID-19: The Role of Disease Severity andGender

<P> Introduction: The expression dynamics of Toll-like receptors (TLRs) in response to SARS-CoV-2, particularly regarding disease severity, remain poorly understood. This study aimed to investigate the gene expression of TLR3, TLR4, and TLR7 in COVID-19 patients and correlate them with disease severity and gender. </P> <P> Methods: This case-control study enrolled 470 COVID-19 patients (categorized as moderate, severe, and critical) and 100 healthy controls. The mRNA expression levels of these genes in peripheral blood leukocytes were quantified using RT-qPCR. </P> <P> Results: Expression of all three TLRs was significantly higher in patients than in the control group. Overall, male patients exhibited higher expression than females. Notably, a significant decrease in TLR3, TLR4, and TLR7 expression was observed in the critical group compared with the moderate and severe groups. </P> <P> Discussion: This paradoxical downregulation of TLRs in critical patients, reported for the first time in such a large cohort (N=470), aligns with reports of 'immunoparalysis' or 'immune exhaustion' observed in other severe inflammatory conditions. This phenomenon might represent a negative feedback mechanism to prevent overwhelming systemic inflammation, although it may concurrently compromise pathogen clearance. </P> <P> Conclusion: The findings suggest that while TLR expression is upregulated in COVID-19, its downregulation in critical stages may be associated with an unfavorable disease outcome. Therefore, TLR expression levels could be considered potential biomarkers for identifying patients at risk of progressing to the critical phase of the disease.