Decoding COVID-19: kynurenine pathway alterations and proteomic signatures in acute and long COVID manifestations

<p dir="ltr">COVID-19, caused by the novel coronavirus SARS-CoV-2, emerged as a highly transmissible infection in 2019. The disease rapidly introduced as a global pandemic and affect millions of people worldwide with high rate of mortality. The symptoms of the disease can vary from mild respiratory illness to acute respiratory distress syndrome. It has been estimated 10-30% of patients who recovered from acute infection develop persistent symptoms such as fatigue, brain fog, and shortness of breath for several weeks or months post-COVID. This condition is known as long COVID or post-acute sequelae of COVID-19 (PASC). The symptoms can continue from an existing symptom in acute COVID-19 or emerge as new ones. Despite extensive research on COVID-19, the exact mechanisms underlying long COVID remain poorly understood. In this project, we aimed to evaluate the metabolic and molecular mechanisms involved in pathophysiology of COVID-19 and long COVID. Accordingly, we designed longitudinal analyses of the kynurenine pathway (KP) and cytokines in plasma samples from COVID-19 patients from the acute phase up to 6 months post-infection. Moreover, to identify the underlying molecular mechanisms in development of long COVID, mass spectrometrybased proteomics was performed on samples from 6-month post-infection to explore the proteome profile of long COVID. The results showed activation of the KP in COVID-19 patients compared to the healthy group. Accordingly, significant elevations in levels of kynurenine, quinolinic acid, and kynurenine/tryptophan ratio were observed in COVID-19 patients. A sustained decrease in levels of tryptophan and an increase in the kynurenine/tryptophan ratio were reported over 6 months, suggesting ongoing KP activation. Elevated cytokine levels (IL-6 and IL-8) suggested a persistent inflammatory response up to 3 months post-COVID. Increased levels of quinolinic acid 3-month post-infection highlighted its potential role in persistent symptoms in long COVID. Analysis of proteome of patients revealed significant changes in proteins associated with the complement system, coagulation pathways, and thromboinflammation, which may present as biomarkers for long COVID. Upregulation of proteins related to the complement cascade and platelet activation was also observed, along with the CCR2/CCL2 axis, which is essential for immune cell migration and chronic inflammation. This study showed potential association between the KP and cytokine responses in the pathophysiology of COVID-19 and long COVID. The identified proteomic signatures provided insights into the molecular mechanisms of long COVID development and offered potential biomarkers for its diagnosis and management for the future studies.</p>